Sommaire du brevet 3065560 - Base de données sur les brevets canadiens (2024)

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Liquid Dosage Forms to Treat Cancer
Cross-Reference to Related Applications
[0001] This application claims priority to U.S. Application Serial Number
62/517,736,
filed June 9, 2017, and U.S. Application Serial Number 62/520,768, filed June
16, 2017. The
entire contents of the aforementioned applications are incorporated herein by
reference.
Field of Invention
[0002] This invention relates to a liquid pharmaceutical formulation
comprising an L-
malate salt of N-(4-1[6,7-bis(methyloxy)quinolin-4-yll oxylpheny1)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide.
Background of the Invention
[0003] Multi-targeted tyrosine kinase inhibitors (TKIs) chemotherapeutics
have been
instrumental in the recent advancements of anticancer treatment over the past
several years.
Tyrosine kinase inhibitor therapies have demonstrated broad clinical effects
leading to new
approved treatment options across multiple tumor types including renal cell
carcinoma
(RCC), urothelial carcinoma (UC), melanoma, non-small-cell lung cancer
(NSCLC), and
others. The success of this therapy type as a single agent has naturally led
to interest in
evaluating novel formulations that provide enhanced pharmaco*kinetics (PK) and
pharmacodynamics (PD) of TKIs when used in combination with checkpoint
inhibitors in
search of further, possibly synergistic, anticancer clinical effects.
[0004] Medicaments, such as chemotherapeutic drugs that are administered
orally, are
dispensed to the patient in several dosage forms, including liquid forms such
as solutions,
syrups, emulsions, and suspensions, and more commonly, in solid forms such as
capsules,
caplets, and tablets. Children, older persons, and many other persons
(including disabled or
incapacitated patients) often have trouble swallowing tablets or capsules. In
these situations,
it is desirable to provide the drug either in a chewable solid form or a
liquid form.
Pharmaceutically active agents administered in solid dosage form are usually
intended to be
swallowed whole. In some cases, the unpleasant taste of the medicament in
solid form is
generally not of concern when formulating oral solid dosage forms, because the
pharmaceutical's taste can be easily masked with an exterior coating.
[0005] However, despite the convenience of formulating medicaments in oral
solid
forms, for pediatric and geriatric patients, a liquid oral dosage form is
preferred over a
1

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chewable dosage form. A liquid dosage form is especially preferred for
pediatric and geriatric
patients because of the ease with which it may be swallowed. Additionally,
patients may be
more inclined to comply with their medication instruction if the dosages are
easier to ingest,
particularly for products administered in large doses, requiring several
tablets at a time.
[0006] Some liquid pharmaceutical compositions formulated for use by
pediatric or
geriatric patients are prepared by grinding a tablet dosage form into a powder
and mixing the
powder with a diluent. Such a formulation may cause some of the drug to remain
undissolved, thereby affecting the therapeutic dose of drug in the
composition. In addition,
the powder exposes the unpleasant tasting pharmaceutically active agent, which
may result in
a lack of compliance due to the unacceptable taste. It is readily understood
that such
compositions are impractical and may result in underdosing or poor compliance.
Summary of the Invention
[0007] The problem underlying the present invention is to provide a liquid
dosage form
containing a compound of Formula I, or a pharmaceutically acceptable salt
thereof, which
does not show the above-described disadvantages of the known dosage forms. In
particular,
the pharmaceutical formulation should be stable over a long time period, as
well as
physiologically acceptable and pleasing for pediatric and geriatric patients.
In some
embodiments, the liquid formulations of the present invention find utility in
the treatment of
cancer, for example, for the treatment of a solid tumor in a patient in need
thereof
[0008] In some embodiments, the solid tumor is a locally advanced or a
metastatic solid
tumor.
[0009] In some embodiments, the present invention is directed to a liquid
pharmaceutical
composition comprising a compound of Formula I or a pharmaceutically
acceptable salt
thereof:
NIX( H
N N
CH3
¨(R2)0-5
0 0
0
\(R)0-4
0 Q
I
H3C ¨0
Formula I
or a liquid pharmaceutical composition comprising the compound of formula I or
a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable
carrier, wherein:
2

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RI- is halo;
R2 is halo; and
Q is CH or N.
[0010] In various embodiments, a single dose of the liquid pharmaceutical
composition
comprising a compound of formula I, or a pharmaceutically acceptable salt
thereof, for
example, compound 1, or a pharmaceutically acceptable salt thereof, provides
an interpatient
or intrapatient exposure variability of less than 30%, or less than 25%, or
less than 20%, or
less than 19%, or less than 18%, or less than 17%, or less than 16%, or less
than 15%, or less
than 14%, or less than 13%, or less than 12%, or less than 11%, or less than
10%. In various
embodiments, the exposure is represented by a noncompartmental PK parameter
selected
from the group consisting of: AUCo-t, AUC
_ 0_24, AUC0-72, AUCO-inf, Cmax, tmax, kel, and t112. In
some embodiments, the liquid formulation of the present invention when dosed
as a single
dose provides an AUCo_t, AUC0_24, AUC0_72, AUCo_mf, or a Cmax interpatient or
intrapatient
variability of less than 30%, or less than 25%, or less than 20%, or less than
19%, or less than
18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%,
or less than
13%, or less than 12%, or less than 11%, or less than 10%. In some
embodiments, the liquid
formulation of the present invention when dosed as a single dose provides an
AUCo-t, AUG-
24, AUC0-72, AUCO-inf, or Cmax interpatient or intrapatient variability of
less than 30%, or less
than 25%, or less than 20%, or less than 19%, or less than 18%, or less than
17%, or less than
16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%,
or less than
11%, or less than 10% relative to a tablet formulation containing a compound
of formula I, or
a pharmaceutically acceptable salt thereof, for example, compound 1, or a
pharmaceutically
acceptable salt thereof In the above related embodiments, the single dose can
include a single
dose of about: 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg,
120 mg,
110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10
mg of a
compound of formula I, or compound 1 which can be the (L)-malate salt (also
referred to
herein as the S-malate salt; S-malate salt and (L)-malate salt are used
interchangeably herein)
or the (D)-malate salt (also referred to as the R-malate salt; R-malate salt
and (D)-malate salt
are used interchangeably herein). In various embodiments, the above referenced
single doses
comprises cabozantinib. Cabozantinib is also referred to as XL184, and XL184
and
cabozantinib are used interchangeably herein.
[0011] Another aspect is directed to a method of treating a locally
advanced or metastatic
solid tumor, comprising administering to a patient in need of such treatment a
liquid
pharmaceutical composition comprising compound 1:
3

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H IX( H
NO ON
CH3 0
0
H3C-0
Compound 1
or a pharmaceutically acceptable salt thereof or a liquid pharmaceutical
composition
comprising compound 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically
acceptable carrier.
[0012] In some aspects, the locally advanced or a metastatic solid tumor
may be
advanced UC (urothelial carcinoma) or RCC (renal cell carcinoma).
[0013] In another aspect, the invention comprises a liquid pharmaceutical
dosage form
comprising a compound of formula I or compound 1, or a pharmaceutically
acceptable salt
thereof, such that each dose of the liquid pharmaceutical composition
comprising compound
1, or a pharmaceutically acceptable salt thereof provides the patient an
interpatient or
intrapatient exposure (for example, AUCo-t, AUC0-24, AUCo-tm, Cmax, or tmax)
variability of
less than 30%, or less than 25%, or less than 20%, or less than 19%, or less
than 18%, or less
than 17%, or less than 16%, or less than 15%, or less than 14%, or less than
13%, or less than
12%, or less than 11%, or less than 10% relative to a tablet formulation
containing the same
amount of compound of formula I or compound 1, or a pharmaceutically
acceptable salt
thereof
Brief Description Of The Figures
[0014] FIG. 1 depicts a line graph of the mean ( SD) cumulative excretion
of urine and
feces total radioactivity following a single 175 mg oral administration of
XL184 (L-malate
salt) containing 100 nCi [14C] XL184 to healthy male subjects (N=8).
[0015] FIG. 2 depicts a line graph of the mean ( SD) plasma total
radioactivity in plasma
and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-648
hours
following a single 175 mg oral administration of XL184 (L-malate salt)
containing 100 nCi
[14C1 XL184 to healthy male subjects - linear axes (N=8)
[0016] FIG. 3 depicts a line graph of the mean ( SD) plasma total
radioactivity in plasma
and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-120
hours
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following a single 175 mg oral administration of XL184 (L-malate salt)
containing 100 n.Ci
C,i4
r
[ ] XL184 to healthy male subjects - linear axes (N=8)
[0017] FIG. 4 depicts a line graph of the mean ( SD) plasma total
radioactivity in plasma
and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-648
hours
following a single 175 mg oral administration of XL184 (L-malate salt)
containing 100 n.Ci
['4C1 XL184 to healthy male subjects - semilogarithmic axes (N=8).
[0018] FIG. 5 depicts a line graph of the mean ( SD) plasma total
radioactivity in plasma
and whole blood and XL184 concentration (by LC/MS/MS method) vs. time 0-120
hours
following a single 175 mg oral administration of XL184 (L-malate salt)
containing 100 n.Ci
['4C1 XL184 to healthy male subjects - semilogarithmic axes (N=8).
[0019] FIG. 6 depicts a line graph of the mean ( SD) percentage of 14C
radioactivity
associated with erythrocytes in whole blood over time graph following a single
175 mg oral
administration of XL184 (L-malate salt) containing 100 n.Ci ['4C1 XL184 to
healthy male
subjects (N=8).
[0020] FIG. 7 depicts a line graph of the mean ( SD) plasma concentrations
of XL184
and metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by
LC/MS/MS method vs. time 0-648 hours following a single 175 mg oral
administration of
XL184 (L-malate salt) containing 100 n.Ci ['4C1 XL184 to healthy male subjects
- linear axes
(N=8).
[0021] FIG. 8 depicts a line graph of the mean ( SD) plasma concentrations
of XL184
and metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured by
LC/MS/MS method vs. time 0-120 hours following a single 175 mg oral
administration of
XL184 (L-malate salt) containing 100 n.Ci ['4C1 XL184 to healthy male subjects
- linear axes
(N=8).
[0022] FIG. 9 depicts a line graph of the mean ( SD) plasma concentrations
of XL184
and metabolites, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured
by
LC/MS/MS method vs. time 0-648 hours following a single 175 mg oral
administration of
XL184 (L-malate salt) containing 100 n.Ci ['4C1 XL184 to healthy male subjects
-
semilogarithmic axes (N=8).
[0023] FIG. 10 depicts a line graph of the mean ( SD) plasma concentrations
of XL184
and metabolites, XL184-half-dimer, XL184-N-oxide, and XL184-sulfate measured
by
LC/MS/MS method vs. time 0-120 hours following a single 175 mg oral
administration of
XL184 (L-malate salt) containing 100 n.Ci [14C] XL184 to healthy male subjects
-
semilogarithmic axes (N=8).

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[0024] FIG. 11 depicts a line graph of the mean ( SD) plasma concentrations
of demethyl
half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-
sulfate
measured by radio-quantitation method vs. time 0-336 hours following a single
175 mg oral
administration of XL184 (L-malate salt) containing 100 u.Ci [14C1-XL184 to
healthy male
subjects - linear axes.
[0025] FIG. 12 depicts a line graph of the mean ( SD) plasma concentrations
of demethyl
half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-
sulfate
measured by radio-quantitation method vs. time 0-80 hours following a single
175 mg oral
administration of XL184 (L-malate salt) containing 100 u.Ci [14C1-XL184 to
healthy male
subjects - linear axes.
[0026] FIG. 13 depicts a line graph of the mean ( SD) plasma concentrations
of demethyl
half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-
sulfate
measured by radio-quantitation method vs. time 0-336 hours following a single
175 mg oral
administration of XL184 (L-malate salt) containing 100 u.Ci [14C1-XL184 to
healthy male
subjects - semilogarithmic axes.
[0027] FIG. 14 depicts a line graph of the mean ( SD) plasma concentrations
of demethyl
half-dimer sulfate, P5, P7, XL-184, XL184-half-dimer, XL184-N-oxide, and XL184-
sulfate
measured by radio-quantitation method vs. time 0-80 hours following a single
175 mg oral
administration of XL184 (L-malate salt) containing 100 u.Ci [14C1-XL184 to
healthy male
subjects - semilogarithmic axes.
[0028] FIG. 15 depicts proposed major biotransformation products of XL184
(cabozantinib).
Definitions
ADME Absorption, distribution, metabolism, and excretion
AE Adverse event
ALT (SGPT) Alanine aminotransferase (serum glutamic-pyruvate transaminase)
Anti-HAV Hepatitis A total antibody
Anti-HBc Hepatitis B core antigen antibody
Anti-HBs Hepatitis B surface antigen antibody
AST (SGOT) Aspartate aminotransferase (serum glutamic-oxaloacetic
transaminase)
AUG0_01( Area under the concentration-time curve from time zero to infinity
AUG0_24 Area under the concentration-time curve from time zero to time 24
hours
AUG0_72 Area under the concentration-time curve from time zero to time 72
hours
AUCo-t Area under the concentration-time curve from time zero to time of
the last measurable
concentration
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BMI Body mass index
BUN Blood urea nitrogen
C Degrees Celsius
Chem Chemistry
Cmax Maximum observed concentration
CTCAE Common Terminology Criteria for Adverse Events
%CV Percentage coefficient of variation
CYP Cytochrome P450
% Dose (feces) Percentage of dose recovered in feces over the collection
interval
% Dose(urine) Percentage of dose recovered in urine over the collection
interval
ECG Electrocardiogram
eCRF Electronic case report form
ETR Percentage of '4C radioactivity associated with erythrocytes in
whole blood
F Degrees Fahrenheit
Gram
GI Gastrointestinal
GLP Good laboratory practice
HBsAg Hepatitis B surface antigen
HCV Hepatitis C antibodies
Hem Hematology
HIV Human immunodeficiency virus
ICF Informed consent form
ICH International Conference on Harmonization
IGm Immunoglobulin M
INN International Nonproprietary Name
LLOQ Lower limit of quantification
1RB Institutional Review Board
kei Apparent terminal elimination rate constant
kg Kilogram
LC-MS/MS Liquid chromatography-mass spectrometry/mass spectrometry
Meter
MBq Megabecquerel
MedDRA Medical Dictionary for Regulatory Activities
MET Hepatocyte growth factor receptor protein
mg Milligram
Microcurie
mL Milliliter
mmHg Micrometers of mercury
msec millisecond
MID Maximum tolerated dose
NA Not applicable
NCI National Cancer Institute
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NE Not estimated
ng Nanogram
ng,Eq An equivalent amount of XL184 freebase required to produce a
measured or calculated
amount of total radioactivity
NR Not reportable
p-FA Para-fluoroaniline
PK Pharmacolcinetic
PO Oral
QTc Corrected QT interval
RBC Red blood cell
RET Rearranged during transfection
SAE Serious adverse event
SAP Statistical analysis plan
SD Standard deviation
SOP Standard operating procedure
1hAE Treatment-emergent adverse event
tmax Time of maximum concentration
ty, Apparent terminal elimination half-life calculated as ln(2)/kei
UPCr Urine Protein/Creatinine ratio
US United States of America
USAN United States Adopted Name
VEGFR2 Vascular endothelial growth factor receptor 2
WBC White blood cell
WHO World Health Organization
XL184 The product number used by Exelixis for development of the
compound with the
USAN/INN designation of cabozantinib
Detailed Description
[0029] As indicated above, the invention is directed to a method of
treating a locally
advanced or a metastatic solid tumor, comprising administering a liquid
formulation of a
compound of formula I or compound 1, or a pharmaceutically acceptable salt
thereof
[0030] Compound 1 is known by its chemical name N-(4-1[6,7-
bis(methyloxy)quinolin-
4-ylloxylpheny1)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and by the
name
cabozantinib (also referred to as XL184). COMETRIQTm (Cabozantanib S-Malate
oral
capsules) has been approved by the Food and Drug Administration (FDA) in the
United
States on November 29, 2012, for the treatment of patients with progressive,
metastatic
medullary thyroid cancer (MTC). CABOMETYXTm (Cabozantanib S-Malate oral
tablets) has
been approved by the Food and Drug Administration (FDA) in the United States
on April 25,
2016, for the treatment of advanced renal cell carcinoma (RCC) in patients who
have
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received prior antiangiogenic therapy. Cabozantinib is formulated as the L-
malate salt of N-
(4-1[6, 7-bis (methyloxy)quinolin-4-yl] oxylpheny1)-N'-(4-
fluorophenyl)cyclopropane-1,1-
dicarboxamide. WO 2005/030140, the entire contents of which is incorporated
herein by
reference, discloses compound, describes how it is made (Example 48), and
discloses the
therapeutic activity of this compound to inhibit, regulate, and/or modulate
the signal
transduction of kinases (Assays, Table 4, entry 289). Example 48 begins at
paragraph [0353]
in WO 2005/030140. Information for compound 1 is available from the FDA at
http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process
&ApplNo
=208692 (last visited December 19, 2016) and is incorporated herein by
reference in its
entirety.
[0031] In various embodiments, the present invention provides a
pharmaceutical
composition formulated for oral administration in liquid form. When compared
to solid
forms, for example, a formulation in tablet, capsule, sachet, or powdered
form, the liquid
pharmaceutical compositions of the present invention comprising a compound of
formula I or
compound 1, which can be the (L)-malate salt or the (D)-malate salt, provides
a significantly
smaller interpatient or intrapatient variability in exposure. For example, as
published in
Nguyen, L. et al., "Pharmaco*kinetics of cabozantinib tablet and capsule
formulations in
healthy adults," (2016), Anti-Cancer Drugs 2016, 27:669-678, (the disclosure
of which is
incorporated herein by reference in its entirety), the values of Cmax, AUCo_t,
and AUCo_inf
plasma pharmaco*kinetic parameters were highly variable among study
participants, ranging
from (i.e. %CV about 48-72%, 42-56%, and 38-41% for the 20, 40, and 60 mg
(free base
equivalent, FBE) cabozantinib tablet strength treatments, respectively). Table
1 (reproduced
from the Nguyen, L. et al., reference cited herein) summarizes the plasma PK
parameters
found when healthy patients were dosed with a single dose of 140 mg (free base
equivalent,
FBE) of cabozantinib or the malate salt of compound 1. The values of Cmax,
AUCo-t, and
AUCo_im plasma pharmaco*kinetic parameters were highly variable among study
participants
(i.e. %CV about 54%, 44%, 46% and 43%, 37%, and 39% for the 140 mg (free base
equivalent, FBE) cabozantinib tablet and capsule dose treatments,
respectively).
[0032] Table 1. Summary of cabozantinib plasma pharmaco*kinetic parameters
from
healthy individuals administered a single oral dose of tablet or capsule
formulations
containing 140 mg of cabozantinib (free base equivalent, FBE).
Pharmaco*kinetic Tablet treatment .. Capsule treatment
parameter (mean CV%)a (mean
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C.,, (ng/ml) 702 54 554 43
tmax (h)e 3.49 (1.99, 24.00) 4.00 (2.00, 5.04)
AUCo-t (118 x him') 61 900 44 54 900 37
AUCo_mf (ng x h/ml) 65 800 46 58 300 39
t1/2 (h) 115 31 112 26
CL/F (1/h) 2.61 49 2.69 32
VZ/F (1) 424 58 426 37
AUC, area under the plasma concentration-time curve; CL/F, oral clearance; CV,
coefficient of variation.
aTreatment A (test): 140 mg dose (2 x 20 + 1 x 100 mg) of XL184 (cabozantinib)
tablet formulation; (n= 72).
bTreatment B (reference): 140 mg dose (3 x 20 + 1 x 80 mg) of XL184
(cabozantinib) capsule formulation; (n =
72).
'Median (minimum, maximum) are presented.
[0033] In these and other embodiments, the compound of formula I or
compound 1, or a
pharmaceutically acceptable salt thereof, is administered as a liquid
pharmaceutical
composition, wherein the liquid pharmaceutical composition additionally
comprises a
pharmaceutically acceptable carrier, excipient, or diluent. In a specific
embodiment, the
compound of formula I is compound 1, or a pharmaceutically acceptable salt
thereof
[0034] The compound of formula I or compound 1, or a pharmaceutically
acceptable salt
thereof as described herein, includes both the recited compounds as well as
individual
isomers and mixtures of isomers. In each instance, the compound of formula I
includes the
pharmaceutically acceptable salts, hydrates, and/or solvates of the recited
compounds and any
individual isomers or mixture of isomers thereof
[0035] In other embodiments, the compound of formula I or compound 1 can be
the (L)-
malate salt (also referred to herein as the S-malate salt), or the (D)-malate
salt (also referred
to as the R-malate salt). The malate salt of the compound of formula I and of
compound 1 is
disclosed in PCT/US2010/021194 and U.S. Patent Application Serial No.
61/325095, the
entire contents of each of which are incorporated herein by reference.
[0036] In other embodiments, the compound of formula I can be malate salt.
[0037] In other embodiments, the compound of formula I can be the (D)-
malate salt.
[0038] In other embodiments, the compound of formula I can be the (L)-
malate salt.
[0039] In other embodiments, compound 1 can be the malate salt.
[0040] In other embodiments, compound 1 can be (D)-malate salt.
[0041] In other embodiments, compound 1 can be the (L)-malate salt.

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[0042] In another embodiment, the malate salt is in the crystalline N-1
form of the (L)
malate salt and/or the (D) malate salt of the compound 1 as disclosed in U.S.
Patent
Application Serial No. 61/325095. In another embodiment, the malate salt is
the crystalline
N-2 form of the (L) malate salt and/or the (D) malate salt of the compound 1
as disclosed in
U.S. Patent Application Serial No. 61/325095. In yet another embodiment, the
malate salt is a
mixture of the N-1 and N-2 forms of the (L) malate salt and/or the (D) malate
salt of the
compound 1 as disclosed in U.S. Patent Application Serial No. 61/325095. See
also WO
2008/083319 for the properties of crystalline enantiomers, including the N-2
crystalline forms
of the (L)-malate salt (also referred to as the 5-malate salt) or the (D)-
malate salt (also
referred to as the R-malate salt), and/or the N-1 crystalline forms of the (L)-
malate salt (also
referred to as the 5-malate salt) or the (D)-malate salt (also referred to as
the R-malate salt) of
compound 1. Methods of making and characterizing such forms are fully
described in
PCT/US10/21194, which is incorporated herein by reference in its entirety.
[0043] In one embodiment, the compound of formula I or compound 1, or a
pharmaceutically acceptable salt thereof, is administered once daily. In a
further embodiment,
a compound of formula I or compound 1, or a pharmaceutically acceptable salt
thereof, is
administered with fasting (i.e., without eating) for approximately two hours
before and 1 hour
after administration.
[0044] In another embodiment, the compound of formula I or compound 1, or a
pharmaceutically acceptable salt thereof, is administered orally once daily as
a liquid
formulation.
[0045] In another embodiment, the compound of formula I or compound 1, or a
pharmaceutically acceptable salt thereof, is administered orally as its free
base or malate salt
as a liquid formulation.
[0046] In various embodiments, a single dose of the liquid pharmaceutical
composition
comprising a compound of formula I, or a pharmaceutically acceptable salt
thereof, for
example, compound 1, or a pharmaceutically acceptable salt thereof, provides
an interpatient
or intrapatient exposure variability of less than 30%, or less than 25%, or
less than 20%, or
less than 19%, or less than 18%, or less than 17%, or less than 16%, or less
than 15%, or less
than 14%, or less than 13%, or less than 12%, or less than 11%, or less than
10%. In various
embodiments, the exposure is represented by a noncompartmental PK parameter
selected
from the group consisting of: AUCo_t, AUC0_24, AUC0_72, AUCo-mf, Cmax, tmax,
ket, and till. In
some embodiments, the liquid formulation of the present invention when dosed
as a single
dose provides an AUCo_t, AUC0_24, AUC0_72, AUCo_mf, or a Cmax interpatient or
intrapatient
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variability of less than 30%, or less than 25%, or less than 20%, or less than
19%, or less than
18%, or less than 17%, or less than 16%, or less than 15%, or less than 14%,
or less than
13%, or less than 12%, or less than 11%, or less than 10%. In some
embodiments, the liquid
formulation of the present invention when dosed as a single dose provides an
AUCo_t, AUCo_
24, AUC0-72, AUCO-inf, or Cmax interpatient or intrapatient variability of
less than 30%, or less
than 25%, or less than 20%, or less than 19%, or less than 18%, or less than
17%, or less than
16%, or less than 15%, or less than 14%, or less than 13%, or less than 12%,
or less than
11%, or less than 10% relative to a tablet formulation containing a compound
of formula I, or
a pharmaceutically acceptable salt thereof, for example, compound 1, or a
pharmaceutically
acceptable salt thereof
[0047] In the above related embodiments, the single dose can include a
single dose of
about: 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg,
110
mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10 mg
of a
compound of formula I or compound 1, which can be the (L)-malate salt (also
referred to
herein as the S-malate salt) or the (D)-malate salt (also referred to as the R-
malate salt). In
various embodiments, the above referenced single doses comprises cabozantinib.
[0048] The amounts of the compound of formula I or compound 1, or a
pharmaceutically
acceptable salt thereof, that are administered will vary. In one embodiment,
the compound of
formula I or compound 1, or a pharmaceutically acceptable salt thereof, is
administered in an
amount of from about 1 mg to about 200 mg, or from about 5 mg to about 175 mg,
or from
about 10 mg to about 100 mg, for example, 190 mg, 180 mg, 170 mg, 160 mg, 150
mg, 140,
mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg,
60 mg,
55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, or 15 mg, within a
fixed liquid
dosage volume, for example, in a volume of about 1.0 mL to about 100 mL, or
for example
from about 10 mL to about 100 mL per unit dose. In another embodiment, the
amount of the
compound of formula I or compound 1, or a pharmaceutically acceptable salt
thereof, is
administered in an amount of 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140, mg,
130 mg,
120 mg, 110 mg, 100 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55
mg, 50 mg,
45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, or 15 mg per unit volume (equivalent
to a daily
dose or a unit dose, or some fraction or part thereof) ranging from about 1 mL
to about 100
mL, or from about 10 mL to about 100 mL per dose. In another embodiment, the
amount of
the compound of formula I or compound 1, or a pharmaceutically acceptable salt
thereof, is
administered in an amount of about 140 mg, about 80 mg, about 60 mg, about 40
mg, or
about 20 mg per unit volume (equivalent to a daily dose or a unit dose, or
some fraction or
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part thereof) ranging from about 1 mL to about 100 mL, or from about 10 mL to
about 100
mL per unit dose. In another embodiment, the amount of the compound of formula
I or
compound 1, or a pharmaceutically acceptable salt thereof, is administered in
a volume
ranging from about 1 mL to about 100 mL, or from about 10 mL to about 100 mL
per dose
(equivalent to a daily dose, or a unit dose, or some fraction or part
thereof), wherein each
dose contains about 60 mg, or about 40 mg, or about 20 mg of the compound of
formula I or
compound 1, or a pharmaceutically acceptable salt thereof, for example, an (L)-
malate salt
(also referred to as the S-malate salt) or the (D)-malate salt (also referred
to as the R-malate
salt), and/or the N-1 crystalline forms of the (L)-malate salt (also referred
to as the S-malate
salt) or the (D)-malate salt (also referred to as the R-malate salt) of
compound 1.
[0049] In these and other embodiments, the compound of formula I or
compound 1, or a
pharmaceutically acceptable salt thereof, is administered orally once daily as
its free base or
as the malate salt as a liquid dosage form, preferably in a daily dose, or a
unit dose, or some
fraction or part thereof In a further embodiment, compound 1 is administered
as the (L)-
malate salt (also referred to as the S-malate salt) or the (D)-malate salt
(also referred to as the
R-malate salt). In a further embodiment:
= up to and including 150 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 140 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 130 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 120 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 110 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 100 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 95 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 90 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
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= up to and including 85 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 80 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 75 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 70 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 65 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 60 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 55 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 50 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 45 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 40 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 35 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 30 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 25 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 20 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 15 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 10 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered; or
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= up to and including 5 mg of compound 1 or a pharmaceutically acceptable
salt thereof
is administered.
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, from about 50% to about
95%
PEG-400 (w/w), and/or from about 1% to about 30% TPGS (w/w), and/or from about
0.5% to about 20% ethanol (w/w),In each of the aforementioned examples, the
amount of compound 1 or a pharmaceutically acceptable salt thereof is admixed
with
one or more carriers to prepare an oral formulation containing, for example,
from
about 70% to about 90% PEG-400 (w/w), and/or from about 5% to about 20% TPGS
(w/w), and/or from about 1% to about 15% ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, from about 80% to about
90%
PEG-400 (w/w), and/or from about 5% to about 15% TPGS (w/w), and/or from about
1% to about 10% ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, about 85% PEG-400 (w/w),
and/or about 10% TPGS (w/w), and/or about 5% ethanol (w/w).
[0050] In these and other embodiments, a liquid formulation comprising
compound 1
which is administered orally once daily with fasting as its free base or as a
malate salt (for
example, the (L)-malate salt, which is also referred to as the S-malate salt,
or the (D)-malate
salt, which is also referred to as the R-malate salt) to a patient in need
thereof In a further
embodiment:
= up to and including 150 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 140 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 130 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 120 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;

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= up to and including 110 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 100 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 95 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 90 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 85 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 80 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 75 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 70 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 65 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 60 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 55 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 50 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 45 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 40 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 35 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 30 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
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= up to and including 25 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 20 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 15 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered;
= up to and including 10 mg of compound 1 or a pharmaceutically acceptable
salt
thereof is administered; or
= up to and including 5 mg of compound 1 or a pharmaceutically acceptable
salt thereof
is administered,
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, from about 50% to about
95%
PEG-400 (w/w), and/or from about 1% to about 30% TPGS (w/w), and/or from about
0.5% to about 20% ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, from about 70% to about
90%
PEG-400 (w/w), and/or from about 5% to about 20% TPGS (w/w), and/or from about
1% to about 15% ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, from about 80% to about
90%
PEG-400 (w/w), and/or from about 5% to about 15% TPGS (w/w), and/or from about
1% to about 10% ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to
prepare an oral formulation containing, for example, about 85% PEG-400 (w/w),
and/or about 10% TPGS (w/w), and/or about 5% ethanol (w/w).
[0051] In various embodiments, a patient with a solid tumor, for example, a
locally
advanced or metastatic solid tumor, may be treated with compound 1, or a
pharmaceutically
acceptable salt thereof, as a liquid formulation containing 140 mg, 80 mg, 60
mg, 40 mg, or
20 mg of compound 1, which is administered orally once daily with fasting as
its free base or
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as a malate salt (for example, the (L)-malate salt, which is also referred to
as the S-malate
salt, or the (D)-malate salt, which is also referred to as the R-malate salt).
[0052] In various embodiments, a patient with a solid tumor, for example, a
locally
advanced or metastatic solid tumor, may be treated with cabozantinib (S)-
malate, which is
administered orally once daily with fasting as a liquid dosage form comprising
cabozantinib
(S)-malate.
[0053] In a further embodiment, the cabozantinib (S)-malate is administered
in a liquid
pharmaceutical composition formulation containing 140 mg, 80 mg, 60 mg, 40 mg,
or 20 mg
of cabozantinib orally once daily with fasting. In a further embodiment, as
shown in Table 1,
the cabozantinib (S)-malate is administered in a liquid pharmaceutical
composition which
comprises one or more excipients, carriers, or diluents. Depending on the type
of
pharmaceutical composition, the pharmaceutically acceptable carrier may be
chosen from any
one or a combination of carriers known in the art. The choice of the
pharmaceutically
acceptable carrier depends partly upon the desired method of administration to
be used. For a
pharmaceutical composition of this disclosure, that is, one of the active
compound(s) or a
crystalline form of one of the active compound(s) of formula I or compune 1, a
carrier should
be chosen so as to substantially maintain the particular form of the active
compound(s),
whether it is crystalline or not. In other words, the carrier should not
substantially alter the
form of the active compound(s), nor should the carrier be otherwise
incompatible with the
form of the active compound(s), such as by producing any undesirable
biological effect or
otherwise interacting in a deleterious manner with any other component(s) of
the
pharmaceutical composition. Various carriers used in formulating
pharmaceutically
acceptable compositions and known techniques for their bulk preparation and
subsequent
production into unit dosage forms are employed to make the pharmaceutical
compositions
disclosed herein and are described in Remington: The Science and Practice of
Pharmacy, 21st
edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia,
and
Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,
1988-1999,
Marcel Dekker, New York. The amount of carriers and excipients used in a
composition can
be varied proportionally according to the amount of active ingredient used
(that is, a
compound of formula I or compound I, or a pharmaceutically acceptable salt
thereof). For
example, in each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to prepare an
oral formulation containing, for example, from about 50% to about 95% PEG-400
(w/w),
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and/or from about 1% to about 30% TPGS (w/w), and/or from about 0.5% to about
20%
ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to prepare an
oral formulation containing, for example, from about 70% to about 90% PEG-400
(w/w),
and/or from about 5% to about 20% TPGS (w/w), and/or from about 1% to about
15%
ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to prepare an
oral formulation containing, for example, from about 80% to about 90% PEG-400
(w/w),
and/or from about 5% to about 15% TPGS (w/w), and/or from about 1% to about
10%
ethanol (w/w).
= In each of the aforementioned examples, the amount of compound 1 or a
pharmaceutically acceptable salt thereof is admixed with one or more carriers
to prepare an
oral formulation containing, for example, about 85% PEG-400 (w/w), and/or
about 10%
TPGS (w/w), and/or about 5% ethanol (w/w).
[0054] Suitable carriers include, but are not limited to, water, saline,
aqueous dextrose,
glycerol, ethanol, and the like; solubilizing agents and emulsifiers, such as
ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate,
propyleneglycol, 1,3-butyleneglycol, and dimethylformamide; oils, such as
cottonseed oil,
groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol,
tetrahydrofurfuryl
alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures
of these
substances, and the like, to thereby form a solution or suspension.
[0055] The liquid pharmaceutical compositions of this disclosure may be
prepared by
methods know in the pharmaceutical formulation art, for example, see
Remington's
Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa.,
1990).
[0056] Pharmaceutically acceptable adjuvants known in the pharmaceutical
formulation
art may also be used in the pharmaceutical compositions of this disclosure.
These include, but
are not limited to, preserving, wetting, suspending, sweetening, flavoring,
perfuming,
emulsifying, and dispensing agents. Prevention of the action of microorganisms
can be
ensured by various antibacterial and antifungal agents, for example, parabens,
chlorobutanol,
phenol, sorbic acid, and the like. It may also be desirable to include
isotonic agents, for
example sugars, sodium chloride, and the like. If desired, a pharmaceutical
composition of
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this disclosure may also contain minor amounts of auxiliary substances, such
as wetting or
emulsifying agents, pH buffering agents, and antioxidants, such as, for
example, citric acid,
sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene.
The
pharmaceutical compositions generally contain about 0.5% to about 99.5% by
weight of the
active compound(s), or a crystalline form of the active compound(s), and 99.5%
to 0.5% by
weight of a suitable pharmaceutical excipient. In one example, the composition
will be
between about 1% and about 75% by weight of active compound, with the rest
being suitable
pharmaceutical excipients or other adjuvants, as discussed herein.
[0057] Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are
prepared, for
example, by dissolving, dispersing, etc., one or more compound(s) of this
disclosure, or a
pharmaceutically acceptable salt thereof, and optional pharmaceutical
adjuvants in a carrier,
such as, for example, water, saline, aqueous dextrose, glycerol, polyethylene
glycol (PEG),
ethanol, and the like; and further comprising solubilizing agents and
emulsifiers, as for
example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol,
benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils,
in particular,
cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and
sesame oil, glycerol,
tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of
sorbitan; or mixtures
of these substances, and the like, to thereby form a solution or suspension.
[0058] Suspensions, in addition to the active compounds, can contain
suspending agents,
as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or
mixtures of these substances, and the like.
[0059] Table 2. An example of a liquid formulation containing cabozantinib
(S)-
malate.
Ingredient Theoretical Quantity (mg/unit dose)
20-mg Dose 40-mg Dose 60-mg Dose
Cabozantinib (S)-malate 25.34 50.68 76.02
Polyethylene glycol 400 (PEG 400) 2,934.88 5,869.77 8,804.65
d-a-tocopheryl polyethylene glycol
succinate (TPGS) 345.28 690.56 1,035.84
Ethanol 172.64 345.28 517.92
Flavorings 3.45 6.91 10.36
Total 3,481.60 6,963.19 10,444.79
[0060] In a further embodiment, the cabozantinib (S)-malate is administered
orally once
daily.

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[0061] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 140 mg.
[0062] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 120 mg.
[0063] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 80 mg.
[0064] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 60 mg.
[0065] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 40 mg.
[0066] In a further embodiment, the amount of cabozantinib (S)-malate that
is
administered orally once daily is 20 mg.
[0067] In a further embodiment, the cabozantinib (R)-malate is administered
orally once
daily.
[0068] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 140 mg.
[0069] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 120 mg.
[0070] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 80 mg.
[0071] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 60 mg.
[0072] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 40 mg.
[0073] In a further embodiment, the amount of cabozantinib (R)-malate that
is
administered orally once daily is 20 mg.
[0074] In another embodiment, compound 1 is administered orally as its free
base or a
malate salt (for example, the (L)-malate salt, which is also referred to as
the S-malate salt, or
the (D)-malate salt, which is also referred to as the R-malate salt) once
daily in a liquid
pharmaceutical composition as provided in the following Table 3.
[0075] Table 3. An example of a liquid formulation containing cabozantinib
(S)-
malate.
Ingredient (% w/w)
Compound 1 0.73
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Ingredient (% w/w)
Polyethylene glycol 400 (PEG 400) 84.30
d-a-tocopheryl polyethylene glycol 9.92
succinate (TPGS)
Ethanol 4.96
Flavorings 0.10
Total 100
[0076] In another
embodiment, compound 1 is administered orally as its free base or a
malate salt ((L)-malate salt (also referred to as the S-malate salt), or the
(D)-malate salt (also
referred to as the R-malate salt)) once daily in a liquid pharmaceutical
composition as
provided in the following table 4.
[0077] Table 4. An
example of a liquid formulation containing cabozantinib (S)-
malate.
Ingredient Theoretical Quantity (mg/unit dose)
Compound 1 175.00
Polyethylene glycol 400 (PEG 20,268.53
400)
d-a-tocopheryl polyethylene glycol 2,384.53
succinate (TPGS)
Ethanol 1,192.27
Flavorings 23.85
Total 24,044.18
[0078] In another
embodiment, compound 1 is administered orally as its free base or a
malate salt ((L)-malate salt (also referred to as the S-malate salt), or the
(D)-malate salt (also
referred to as the R-malate salt)) once daily as a liquid dose as provided in
the following table
5.
[0079] Table 5. An
example of a liquid formulation containing cabozantinib (S)-
malate.
Ingredient Function % w/w
Cabozantinib (S)-malate Active Ingredient
0.73
Polyethylene glycol 400 (PEG 400) Solubility Enhancer 84.30
d-a-tocopheryl polyethylene glycol succinate Solubility Enchancer
and
9.92
(TPGS) Stabilizer
Ethanol Solvent 4.96
Cinnamon Flavoring Taste masking agent 0.10
Total 100
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[0080] Any of the liquid dosage formulations provided above can be adjusted
according
to the dose of compound 1 or a pharmaceutically acceptable salt thereof
desired. Thus, the
amount of each of the formulation ingredients can be proportionally adjusted
to provide a
liquid formulation containing various amounts of compound 1 or a
pharmaceutically
acceptable salt thereof as provided in the previous paragraphs. In another
embodiment, the
formulations can contain 20, 40, 60, or 80 mg of compound 1 or a
pharmaceutically
acceptable salt thereof
[0081] Exemplary Administration Of The Liquid Pharmaceutical Composition
And
Treatment of Solid Tumors
[0082] Through potent inhibition of RTKs including MET, VEGFR, and AXL,
cabozantinib has demonstrated clinical activity as a single agent in both
advanced UC and
RCC.
[0083] Objectives: The primary objectives of the study were: (1) to
determine the time
course for excretion of 14C radioactivity in urine and feces following a
single 175 mg oral
dose of XL184 (L-malate salt) containing 100 pCi [14C1-XL184; (2) to determine
the
recovery of 14C radioactivity as a percentage of the administered dose; (3) to
determine the
percentage of 14C radioactivity present as XL184 in plasma and urine at
selected time points
following administration of the study drug; and (4) to assess the safety of a
single dose of 175
mg of XL184 (L-malate salt) containing 100 pCi [14C1-XL184 in healthy male
subjects. The
secondary objectives of the study were: (1) to determine the plasma
pharmaco*kinetics of 14C
radioactivity and XL184 in healthy male subjects following a single oral dose
of study drug;
(2) to determine the percentage of 14C radioactivity associated with
erythrocytes in whole
blood over time; and (3) to estimate the amount and probable structure of any
significant
metabolites or degradation products of XL184 in plasma and urine.
[0084] The following PK objectives listed above will not be addressed in
this example:
[0085] Primary objective (3): to determine the percentage of 14C
radioactivity present as
XL184 in plasma and urine at selected time points following administration of
the study drug;
[0086] Secondary objective (3): to estimate the amount and probable
structure of any
significant metabolites or degradation products of XL184 in plasma and urine.
[0087] The study was completed as planned.
[0088] Methodology: This was an open-label, single-dose, single-center,
mass balance,
Phase 1 study in healthy male volunteers. There were two study periods: a
Screening Period,
during which subjects underwent assessments to determine their eligibility for
the study, and
an On-study Period, which started on Day -1 (check-in' day) when the subject
was admitted
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to the Celerion clinic. Subjects received a single calculated oral dose
intended to contain a
total of 175 mg of XL184 (L-malate salt) and 100 Ci of I-4C at Hour 0 on Day
1; initially
they were to remain in the clinic through to the completion of all scheduled
post-dose
procedures on the morning of Day 28. Alternatively, if scintillation counts
were available,
subjects, on an individual basis, could be discharged prior to Day 28 if
either of the following
conditions were met: (1)? 90% of the administered radioactivity was recovered
in the urine
and feces (accounting for radioactivity in vomitus if applicable); or (2) the
daily total
excreted radioactivity was 1% or less of the administered dose on 2
consecutive days and?
85% of the administered radioactivity had been recovered. However, subjects
who were
discharged from the clinic before Day 28 were required to return to the clinic
for all
remaining scheduled pharmaco*kinetic blood sampling and the Day 28 safety
assessments.
Subjects not meeting radioactivity release criteria by Day 28 could be asked
to remain
confined in the clinic or continue collection of urine and feces at home
(returning samples to
the clinic daily) for up to an additional 7 days (through to Day 35). Due to
the fact that by
Day 35 subjects had still not met release criteria, subjects were given the
option of
withdrawing from the study or completing the additional 14-day collection
period (either in
the clinic or as a daily visitor) with urine and feces collections and daily
adverse event (AE)
inquiries. All urine and fecal collections for all subjects stopped following
the conclusion of
the Day 49 scheduled events regardless of percentage of total radioactive dose
recovered.
[0089] Number of subjects (planned and analyzed): 8 planned and 8 analyzed
[0090] Diagnosis and main criteria for eligibility: Healthy male adults,
aged 19 to 55
years of age, with screening and check in amylase or lipase levels below the
upper limit of
normal, a minimum of one bowel movement a day, and no evidence of urinary
obstruction or
difficulty in voiding urine at screening.
[0091] Test product, dose and mode of administration, and batch numbers:
XL184 (L-
malate salt) containing [1-4C1_
XL184 (100 Ci dose) was prepared as a dosing solution. Each
dosing solution was analyzed for radioactivity content (scintillation
counting), radiochemical
purity, and XL184 concentration. A single dose oral solution was administered
at Hour 0 on
Day 1 by the clinic staff The dose was given via the scintillation vial.
Following dosing, the
scintillation vial was rinsed 3 times with room temperature distilled water,
and the rinsate
was administered to the subject. Residual radioactivity was determined for
each dosing vial.
The total volume of liquid administered including radiolabelled study drug,
rinses, and water
given for dosing (in addition to the rinses) was the same for each subject.
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[0092] Duration of treatment: Each subject was dosed with a single 175 mg
oral solution
dose of XL184 (L-malate salt) containing [14C1-XL184 (100 p.Ci).
[0093] Reference therapy, dose and mode of administration, and batch
numbers: Not
applicable.
[0094] Criteria for evaluation:
[0095] Efficacy: Not applicable (efficacy was not measured in this study)
[0096] Pharmaco*kinetics: Serial blood, urine, and feces were collected at
specified times
following dosing. As data allowed, standard noncompartmental pharmaco*kinetic
parameters,
including area under the concentration-time curve calculated using linear
trapezoidal
summation from time zero to time t, where t is the time of the last measurable
concentration
(AUCO-t), area under the concentration-time curve calculated using linear
trapezoidal
summation from time zero to time 24 hours (AUC0_24), area under the
concentration-time
curve calculated using linear trapezoidal summation from time zero to time 72
hours (AUCo_
72), area under the concentration-time curve from time zero to infinity,
AUCo_mf= AUCo-t +
Ct/kel, where kel is the terminal elimination rate constant and Ct is the last
measurable
concentration (AUCo_tm), maximum observed concentration (Cmax), time of
maximum
concentration (tmax), apparent terminal elimination rate constant calculated
by linear
regression of the terminal linear portion of the log concentration vs. time
curve (ket), and
apparent terminal elimination half-life calculated as ln(2)/ket (t1/2) were
calculated from
radioactivity data in plasma and whole blood, and standard noncompartmental
pharmaco*kinetic parameters, including AUCo-t, AUC0-24, AUCo-mf, Cmax, truax,
kel, and t1/2, were
calculated from XL184 and/or metabolite concentrations in plasma.
[0097] As data allowed, pharmaco*kinetic parameters, including urine
concentration
(Curine), amount excreted during each collection interval, calculated as Comte
x urine volume,
renal clearance, cumulative amount of dose excreted in urine, percentage
recovered in urine
over the collection interval, and cumulative percent of dose recovered in
urine, were
calculated from XL184 and metabolites concentrations in urine. Fecal
concentration (C feces), feces,,,
amount excreted during each collection interval, calculated as Cfeces x fecal
weight,
cumulative amount of dose excreted in feces, percentage of dose recovered in
feces over the
collection interval, and cumulative percent of dose recovered in feces, were
also calculated
from XL184 and metabolites concentrations in feces.
[0098] Mass balance was calculated as the percent of total administered
radioactivity
recovered in urine and feces. For the purpose of calculating mass balance, the
amount of

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administered radioactivity was defined as the total radioactivity in the
dosing solution minus
any radioactivity lost due to emesis (if any occurred), adsorption to the
dosing vial, etc.
[0099] To determine the percentage of radioactivity associated with
erythrocytes in whole
blood over time (ETR; calculated only for time points that whole blood is
collected), the
following was calculated:
[00100] The amount of I-4C radioactivity in plasma versus whole blood,
adjusted for the
hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1-[Cp * (1-
Hct)/Cb1,
where Xe and Xb stands for amount of radioactivity in erythrocyte or whole
blood,
respectively. Hematocrit values for Days -1, 2, and 4 were averaged for use in
this
calculation.
[00101] Safety: Safety evaluations included assessments of AEs, vital
signs,
electrocardiogram (ECG), laboratory tests, and concomitant medications.
Adverse event
seriousness, severity grade, and relationship to study treatment were assessed
by the
investigator. Severity grade was defined by the National Cancer Institute
Common
Terminology Criteria for Adverse Events (CTCAE) version 4Ø
[00102] Adverse event terms were standardized using the Medical Dictionary for
Regulatory Activities and tabulated by system organ class and preferred term.
[00103] Metabolic Profiling: Details regarding metabolic profiling were
prepared under
separate cover by QPS, LLC. The results will be reported separately.
[00104] Statistical methods:
[00105] Efficacy: Not applicable (efficacy was not measured in this study).
[00106] Pharmaco*kinetics: The pharmaco*kinetic parameters identified above were
summarized using descriptive statistics (e.g., mean, median, standard
deviation [SD],
coefficient of variation (CV), standard error of the mean, geometric mean,
minimum,
maximum, and sample size). No inferential statistics were calculated. The
radiocarbon
concentration over each collection period was determined for plasma, whole
blood, urine, and
feces. To determine the percentage of radioactivity associated with
erythrocytes in whole
blood over time (calculated only for time points that whole blood is
collected) the following
was calculated: the amount of radioactivity in plasma versus whole blood,
adjusted for the
hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1-[Cp * (1-
Hct)/Cb1,
where Xe and Xb stands for amount of radioactivity in erythrocyte or whole
blood,
respectively. Hematocrit values for Days -1, 2, and 4 were averaged for use in
this
calculation.
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[00107] Safety: AEs and other safety data were summarized and listed as
appropriate.
Laboratory values were presented to allow evaluation of changes after
baseline. No safety
data were formally analyzed.
[00108] No interim analyses were performed.
[00109] Summary of Results:
[00110] Disposition of subjects:
[00111] Eight subjects were dosed; one subject was followed for 37 days then
withdrew
consent while seven subjects were followed for 49 days for urine and feces
collection, and
one of the seven opted for home collection for the final 14 day extension.
[00112] Pharmaco*kinetic results:
[00113] Radioactivity recovery
[00114] A summary of cumulative recovery of total radioactivity (as percent of
dose) in
the urine and feces following a single 175 mg oral administration of XL184 (L-
malate salt)
containing [14C] XL184 (100 [tCi) to the healthy male subjects is presented in
the following
table.
[00115] Summary (mean SD and %CV) of cumulative recovery of total
radioactivity (as
percent of dose) in urine and feces following a single 175 mg oral
administration of XL184
(L-malate salt) containing [14C] XL184 (100 1,1Ci) to healthy male subjects as
shown below in
Table 6.
[00116] Table 6. Cumulative recovery of total radioactivity.
Cumulative Recovery of Total Radioactivity
(as Percent of Dose) (n=8)
Urine Feces Total
27.29 4.65 (17 %) 53.79 4.52 (8%) 81.09 1.56 (2%)
[00117] The mean recovery of radioactivity of 81.09% was achieved within 48
days, and
the radioactivity was mainly eliminated in feces (53.79%) and the remainder in
urine
(27.29%). Less than 1% total mean radioactivity was recovered in feces and
urine after Day
28 post dose.
[00118] Radioactivity in plasma and whole blood
[00119] A summary of plasma and whole blood pharmaco*kinetic parameters for
total
radioactivity following a single 175 mg oral administration of XL184 (L-malate
salt)
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containing [14C1 XL184 (100 [tCi) ) to healthy male subjects is presented in
the following
table.
[00120] Summary (mean SD and %CV) of plasma and whole blood pharmaco*kinetic
parameters for total radioactivity following a single 175 mg oral
administration of XL184 (L-
malate salt) containing [14C] XL184 (100 [tCi) to healthy male subjects as
shown below in
Table 7.
[00121] Table 7. Plasma and whole blood pharmaco*kinetic parameters for total
radioactivity following a single 175 mg oral administration of XL184
%Ratio of Plasma to Whole
Parameters Plasma Whole Blood Blood
C., ngEq/mL 2000 429 (21) 1200 243 (20) 167 12.4 (7)
t., ha 2.00 (1.00, 4.00) 2.00 (1.98, 2.00) NA
AUCo_t, h=ng,Eq/mL 259000 42700 (16) 54100 10300
(19) 487 73.3 (15)
AUC0_24, h=ng,Eq/mL 31400 6380 (20) 19600 3780
(19) 160 6.65 (4)
AUC0_72, h=ng,Eq/mL 89700 19000 (21) 54100 10300
(19) 165 11.1 (7)
AUCo_ta, h=ng,Eq/mL 306000 59500 (19) NR NA
kelt 1/h 0.00308 0.00182 (59) NR NA
t1/2, h 269 93.2 (35) NR NA
a: median (range); NR: Not Reportable (since AUCo_t/ AUCo_ta ratio < 0.80);
NA: Not Applicable
C., maximum observed concentration; T., time of the maximum concentration;
AUCo_t, area under the
concentration-time curve from time zero to the time of the last measurable
concentration; AUC0_24, area under
the concentration-time curve from time zero to 24 hours post XL184 dose;
AUC0_72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo_ta,
area under the concentration-
time curve from time zero to infinity; ng,Eq, an equivalent amount of XL184
freebase required to produce a
measured or calculated amount of total radioactivity; ket, apparent terminal
elimination rate constant; ti/2,
apparent terminal elimination half-life.
[00122] Following a single oral dose, the peak radioactivity in plasma and
whole blood
was achieved at approximately 2 hours (median) with a mean C. of 2000 and 1200
ngEq/mL, respectively. The mean elimination half-life value for the total
radioactivity in
plasma was 269 hours. The mean values of systemic exposures (AUC0_24 and
AUC0_72) in
plasma were around 1.6 times higher than those in whole blood.
[00123] Radioactivity present in erythrocytes and whole blood
[00124] The percent total mean radioactivity concentration present in
erythrocytes relative
to whole blood ranged from 0.174 4.51 to 12.3 3.71 within 72 hours after
single dosing,
indicating that radioactivity was present primarily in plasma and not markedly
associated
with red blood cells.
[00125] Pharmaco*kinetic parameters of XL184 and its metabolites in plasma
[00126] XL184 and metabolites XL184 half-dimer, XL184-N-oxide, XL184-sulfate,
and
para fluoroaniline (p-FA) were measured in plasma samples from healthy male
subjects
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following a single 175 mg oral administration of XL184 containing [14C1XL184
(100 Ci) by
a validated LC/MS/MS method. The p-FA concentrations were below the lower
limit of
quantification at all time points for all subjects. A summary of plasma
pharmaco*kinetic
parameters for XL184 and metabolites XL184 half-dimer, XL184-N-oxide, and
XL184
sulfate is presented in the following table.
[00127] Summary (mean SD, and %CV) of plasma pharmaco*kinetic parameters for
XL184 and selected metabolites following a single 175 mg oral administration
of XL184 (L
malate salt) containing [14C1 XL184 (100 Ci) to healthy male subjects
determined by a
validated LC/MS/MS method as shown below in Table 8.
[00128] Table 8. Plasma pharmaco*kinetic parameters for XL184 and selected
metabolites following a single 175 mg oral administration of XL184
Parameters XL184
XL184-Half-Dimer XL184-N-Oxide XL184-Sulfate
C., ng/mL 1250 238 (19) 52.9 17.3 (33) 118 33.7
(28) 236 66.7 (28)
Tmax, ha1.49 (1.00, 3.00) 18.99 (5.00, 24.10) 13.50 (2.00, 24.30)
24.00 (3.00, 48.00)
AUC0_24, h=ngimL 14300 2600 (18) 1080 341 (32) 2030 682
(34) 3970 1350 (34)
AUC0_72, h=ngimL 35000 6770 (19) 3120 976
(31) 5610 1940 (35) 12600 4180 (33)
AUCo_t, h=ngimL 67200 6880 (10) 6540 1680 (26) 10100 3210 (32)
28900 10700 (37)
Ratio b, % NA 9.93 3.20 (32) 15.0 3.80 (25) 42.9 14.4
(33)
Ratio, % 60.2 7.05 (12) 5.97 1.91 (32) 8.82 1.48
(17) 25.0 6.60 (26)
h=ngimL 68000 6910 (10) 6770 1700 (25) 10300 3170 (31)
29500 10600 (36)
kei 1/h 0.00712 0.00176 0.00807 0.00218 0.00846
0.00256 0.00859 0.0022
(25) (27) (30) (26)
t112, h 102 23.3 (23) 91.8 25.4 (28) 89.2 29.2
(33) 86.0 24.3 (28)
a: median (range); b: ratio of AUCo_t (metabolite)/AUCo-t (parent);
e: ratio of AUCo_t (each analyte)/ AUCo_t (parent+3 measured metabolites); NA:
Not Applicable;
C., maximum observed concentration; T., time of the maximum concentration;
AUCo_t, area under the
concentration-time curve from time zero to the time of the last measurable
concentration; AUC0_24, area under
the concentration-time curve from time zero to 24 hours post XL184 dose;
AUC0_72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo,
area under the concentration-
time curve from time zero to infinity; Ica apparent terminal elimination rate
constant; tin., apparent terminal
elimination half-life.
[00129] The main circulating compound in plasma was XL184, which was rapidly
absorbed after oral administration and eliminated relatively slowly. Following
a single oral
dose, the mean peak concentrations of XL184, XL184-half-dimer, XL184-N-oxide,
and
XL184-sulfate in plasma were achieved at approximately 1.49, 18.99, 13.50, and
24.00 hours
(median) with a mean Cmax of 1250, 52.9, 118 and 236 ng/mL, respectively. The
mean
estimated elimination half-lives of XL184, XL184-half-dimer, XL184-N-oxide,
and XL184-
sulfate were 102, 91.8, 89.2, and 86.0 hours, respectively.
[00130] For metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate,
the mean
metabolite exposure ratios relative to parent XL184 (AUCO-t (metabolite)/ AUCO-
t (parent))
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were 9.93%, 15.0%, and 42.9%, respectively. Mean exposure ratios for parent
and
metabolites XL184 half dimer, XL184-N-oxide and XL184-sulfate relative to
total exposure
(AUCO-t (each analyte)/AUCO-t (parent+3 measured metabolites)) were 60.2%
5.97%,
8.82%, and 25.0%, respectively.
[00131] Safety results:
[00132] There were no deaths, other SAEs, discontinuations due to AEs, or
other
significant AEs reported during the study. No subject vomited within 4 hours
of dosing. Six
subjects (75%) reported a total of 36 TEAEs, the majority of which were mild
in severity
(CTCAE grade 1). The exception was one event of treatment related dizziness,
which was
moderate (CTCAE grade 2) in severity. Most TEAEs (31/36, 86%) resolved within
1 to 3
days.
[00133] Apart from the preferred terms 'headache' and 'flatulence,' which were
both
reported in three (37.5%) subjects, all other preferred terms were reported in
only one subject
each. Five subjects (62.5%) reported TEAEs that were assessed as related to
the study
treatment.
[00134] There were no clinically significant changes from baseline in any
laboratory
values. No remarkable on study results were noted for vital signs or ECG
evaluations.
[00135] Conclusion: Every attempt was made to keep the subjects in the clinic
to obtain
90% recovery of the administered radioactivity.
[00136] Following oral administration of a single 175 mg dose of XL184 (L-
malate salt)
containing 100 pEi [14C1-XL184, a mean recovery of total radioactivity of
81.09% was
achieved within 48 days. Less than 1% total mean radioactivity was recovered
in feces and
urine after Day 28 post-dose. The radioactivity was mainly eliminated in
feces: (53.79%) and
the remainder in urine (27.29%). The peak radioactivity in plasma and whole
blood was
achieved at approximately 2 hours (median) with a mean C. of 2000 and 1200
ngEq/mL,
respectively. The elimination half life of the total radioactivity in plasma
was determined
with a mean value of 269 hours. The mean values of systemic exposures (AUC0-24
and AUC0-
72) in plasma were around 1.6 times higher than those in whole blood. The mean
percent total
radioactivity concentrations associated with erythrocytes relative to whole
blood indicated
that radioactivity was present primarily in plasma and not markedly associated
with red blood
cells.
[00137] The main circulating compound in plasma was XL184, which was rapidly
absorbed after oral administration and eliminated relatively slowly. Following
a single oral
dose, the mean peak concentrations of XL184 and metabolites XL184-half-dimer,
XL184-N-

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oxide, and XL184 sulfate in plasma were achieved at approximately 1.49, 18.99,
13.50, and
24.00 hours (median) with a mean C. of 1250, 52.9, 118, and 236 ng/mL,
respectively; the
mean estimated elimination half-lives were 102, 91.8, 89.2, and 86.0 hours,
respectively.
[00138] For metabolites XL184-half-dimer, XL184-N-oxide, and XL184-sulfate,
the mean
metabolite exposure ratios relative to parent XL184 (AUCO-t (metabolite)/ AUCO-
t (parent))
were 9.93%, 15.0%, and 42.9%, respectively. Mean exposure ratios for parent
and
metabolites XL184 half dimer, XL184-N-oxide, and XL184-sulfate relative to
total exposure
(AUCO-t (each analyte)/ AUCO-t (parent+3 measured metabolites)) were 60.2%,
5.97%,
8.82%, and 25.0%, respectively.
[00139] The treatment was well tolerated. There were no deaths, other SAEs,
discontinuations due to AEs, or other significant AEs. Six subjects (75%)
reported a total of
36 TEAEs, the majority of which were mild in severity (CTCAE grade 1); none
were severe.
Apart from the preferred terms 'headache' and 'flatulence,' which were both
reported in three
(37.5%) subjects, all other preferred terms were reported in only one subject
each. Most
TEAEs were transient and resolved within 1 to 3 days. There were no notable
clinical
laboratory findings, or other safety concerns.
[00140] Embodiments
[00141] The invention is further defined by the following non-limiting
embodiments.
[00142] Embodiment 1. A liquid pharmaceutical formulation comprising a
compound
of formula I:
H IX( H
kyN N
OR2
)o-5
0 0
CH3 0
\(R1)04
0
'1'
H3c ¨0
Formula I
or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable
excipient, wherein:
Rl is halo;
R2 is halo; and
Q is CH or N.
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[00143] Embodiment 2. The liquid pharmaceutical composition according to
embodiment
1, wherein the compound of formula I is compound 1, or a pharmaceutically
acceptable salt
thereof
H IX( H
NO ON 101
CH-a 0
I
0
H3C-0
Compound 1
[00144] Embodiment 3. The liquid pharmaceutical composition according to
embodiment 2, wherein compound 1 is the L-malate salt (or S-malate salt).
[00145] Embodiment 4. The liquid pharmaceutical composition according to
embodiment 2, wherein compound 1 is the D-malate salt (or R-malate salt).
[00146] Embodiment 5. The liquid formulation composition according to any one
of
embodiments 1-4, wherein the amount of the compound of Formula I or compound
1, or a
pharmaceutically acceptable salt thereof present in the liquid formulation,
ranges from about
1 mg to about 200 mg.
[00147] Embodiment 6. The liquid pharmaceutical composition according to
embodiment 5, wherein the amount of the compound of Formula I or compound 1,
or a
pharmaceutically acceptable salt thereof present in the liquid formulation is
about 60 mg, or
about 40 mg, or about 20 mg of the compound of formula I or compound 1, or a
pharmaceutically acceptable salt thereof
[00148] Embodiment 7. The liquid pharmaceutical composition according to
embodiment 1, wherein the liquid formulation provides a smaller inter-subject
variability in
exposure (%CV of about 10% for AUC 04 and AUC o_mi.; reference: Lacy et al,
2015 DMD
43:1190-1207) relative to the tablet formulation ((%CV of about 44% for AUC04
and about
46% for AUCo_mi. ; reference: Nguyen et al, 2016 Anticancer Drugs 27:669-78)
upon
administration of a single dose of the liquid pharmaceutical composition.
[00149] Embodiment 8. A method of treating locally advanced or metastatic
solid
tumors, comprising administering a patient in need of such treatment, a liquid
pharmaceutical
composition comprising a compound of formula I:
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H XrH
k)N
41R2)0-5
0 0
CH3 0
\(1R1)
0 0-4
Q
I
H3C-0
Formula I
or a pharmaceutically acceptable salt thereof or a liquid pharmaceutical
composition comprising the compound of formula I or the pharmaceutically
acceptable salt
thereof, and a pharmaceutically acceptable carrier, wherein:
Rl is halo;
R2 is halo; and
Q is CH or N,
and wherein administration of a single dose of the liquid pharmaceutical
composition
to the patient, provides a smaller inter-subject variability in exposure (%CV
of about 10% for
AUC 04 and AUC o_mf; reference: Lacy et al, 2015 DMD 43:1190-1207) relative to
the tablet
formulation ((%CV of about 44% for AUC04 and about 46% for AUC0-11r;
reference: Nguyen
et al, 2016 Anticancer Drugs 27:669-78).
[00150] Embodiment 9. The method according to embodiment 8, wherein the
compound of formula I is compound 1, or a pharmaceutically acceptable salt
thereof
H H
N N
0 0
CH-a 0
I
0
H3C-0
Compound 1
[00151] Embodiment 10. The method according to embodiment 9, wherein compound
1
is administered as the L-malate salt (or S-malate salt).
[00152] Embodiment 11. The method according to embodiment 9, wherein compound
1
is administered as the D-malate salt (or R-malate salt).
[00153] Embodiment 12. The method according to any one of embodiments 8-11,
wherein the locally advanced or metastatic solid tumors is advanced UC or RCC.
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[00154] Embodiment 13. The method according to embodiment 9, wherein compound
1,
or a pharmaceutically acceptable salt thereof is administered to the patient
in a liquid
pharmaceutical composition once daily with fasting in an amount of 100 mg, 95
mg, 90 mg,
85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg,
30 mg, 25
mg, 20 mg, 15 mg, 10 mg, or 5 mg.
[00155] Embodiment 14. The method according to embodiment 13, wherein compound
1, or a pharmaceutically acceptable salt thereof is administered to the
patient in a liquid
pharmaceutical composition once daily with fasting in an amount of 60 mg, 40
mg, or 20 mg.
[00156] Embodiment 15. The method according to any one of embodiments 9-14,
wherein a complete serological response is observed in patients being treated
with the liquid
pharmaceutical composition comprising compound 1, or a pharmaceutically
acceptable salt
thereof
[00157] Embodiment 16. The method according to any one of embodiments 9-14,
wherein a serological partial response is observed in patients being treated
with compound 1,
or a pharmaceutically acceptable salt thereof
[00158] Embodiment 17. The method according to any one of embodiments 9-14,
wherein stable disease is observed in patients being treated with compound 1,
or a
pharmaceutically acceptable salt thereof
[00159] Preparation of Compound 1
Preparation of 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid
(Compound
A-1)
0 0
F
HO N =
[00160] The starting 1,1-cyclopropanedicarboxylic acid was treated with
thionyl chloride
(1.05 equivalents) in approximately 8 volumes of isopropyl acetate at 25 C
for 5 hours. The
resulting mixture was then treated with a solution of 4-fluoroaniline (1.1
equivalents) and
triethylamine (1.1 equivalents) in isopropyl acetate (2 volumes) over 1 hour.
The product
slurry was quenched with 5N NaOH solution (5 volumes), and the aqueous phase
was
discarded. The organic phase was extracted with 0.5N NaOH solution (10
volumes), and the
basic extract was washed with heptane (5 volumes) and subsequently acidified
with 30% HC1
solution to give a slurry. Compound A-1 was isolated by filtration.
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[00161] Compound A-1 was prepared on a 1.00 kg scale using 1,1-
cyclopropanedicarboxylic acid as the limiting reagent to furnish 1.32 kg of
Compound A-1
(77% isolated yield; 84% mass balance) with 99.92% purity (HPLC) and 100.3%
assay.
[00162] Preparation of N-(4-{16,7-bis(methyloxy)quinolin-4-yl]oxy}pheny1)-N'-
(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) and the (L)-malate
salt
thereof
[00163] A synthetic route that can be used for the preparation of N-(4-1[6,7-
bis(methyloxy)quinolin-4-ylloxylpheny1)-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 1.
Scheme 1
NH, NH,
OH
CI
--0 0
O
POCI3/CH3CN -- 01 OH
0
0
40Na' , DMA
or sodium tea pentoxide, DMA
K,CO3
H20
THF
0 0 1) SOCl2, Etpl
THF 0 0 Oxalyl chloride 0 0 F
HO OH
H2N
N THF
[CIAK11. --O 0140 'N I
F
=
DMF TOT TO 140
THF HO
I
0
(L)-Malic acid
MEK
0So g id 40
--O .C4H605

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[00164] Another synthetic route that can be used for the preparation of N-(4-
1[6,7-
bis (methyloxy)quinolin-4-yl] oxylpheny1)-N' -(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 2.
Scheme 2
NH2 NH2
OH CI 140
_0 40 1
0 0
___________________ -- #0 =
1 POCI3/CH3CN
40 I , OH ..--0 01 \
0 N \ 0 N
0 N
40Na. , DMA
or sodium tert pentoxide, DMA
XF12C003
/
THE
0 0 ........\\\\,
1) 50C12, IPAc 0 0 .. a F
H0)1X11-0H __ ^=
2) Et3N, I PAc HO'IV-N ... 1110
IRIININI am
H
0 0 VI
, cr
0 F
H2N --0 0
I
,
0 N
(1)-Malic acid
N INRII am MEK
40 0 0 WI
0 P
--O 0I
, .C4H603
0 N
[00165] Preparation of 4¨Chloro-6,7¨dimethoxy¨quinolone
[00166] A reactor was charged sequentially with 6,7¨dimethoxy¨quinoline-4¨ol
(47.0 kg)
and acetonitrile (318.8 kg). The resulting mixture was heated to approximately
60 C, and
phosphorus oxychloride (POC13, 130.6 kg) was added. After the addition of
POC13, the
temperature of the reaction mixture was raised to approximately 77 C. The
reaction was
deemed complete (approximately 13 hours) when less than 3% of the starting
material
remained, as measured by in-process high-performance liquid chromatography
[HPLC]
analysis. The reaction mixture was cooled to approximately 2 to 7 C and then
quenched into
a chilled solution of dichloromethane (DCM, 482.8 kg), 26 % NH4OH (251.3 kg),
and water
(900 L). The resulting mixture was warmed to approximately 20 to 25 C, and
phases were
separated. The organic phase was filtered through a bed of AW hyflo super-cel
NF (Celite;
5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined
organic phase
was washed with brine (282.9 kg) and mixed with water (120 L). The phases were
separated,
and the organic phase was concentrated by vacuum distillation with the removal
of solvent
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(approximately 95 L residual volume). DCM (686.5 kg) was charged to the
reactor
containing organic phase and concentrated by vacuum distillation with the
removal of solvent
(approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg)
was then
charged, and the temperature of the mixture was adjusted to ¨ 20 to ¨ 25 C
and held for 2.5
hours resulting in solid precipitate, which was then filtered, washed with n-
heptane (92.0 kg),
and dried on a filter at approximately 25 C under nitrogen to afford the
title compound
(35.6 kg).
[00167] Preparation of 4¨(6, 7 ¨Dimethoxy¨quinoline-4¨yloxy)¨phenylamine
[00168] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3
kg)
was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg),
sodium t-
butoxide (21.4 kg), and DMA (167.2 kg) at 20 ¨ 25 C. This mixture was then
heated to 100
¨ 105 C for approximately 13 hours. After the reaction was deemed complete as
determined
using in-process HPLC analysis (less than 2% starting material remaining), the
reactor
contents were cooled at 15 to 20 C, and water (pre-cooled, 2 to 7 C, 587 L)
was charged at a
rate to maintain 15 to 30 C temperature. The resulting solid precipitate was
filtered, washed
with a mixture of water (47 L) and DMA (89.1 kg), and finally washed with
water (214 L).
The filter cake was then dried at approximately 25 C on filter to yield crude
4¨(6, 7 ¨
dimethoxy¨quinoline-4¨yloxy)¨phenylamine (59.4 kg wet, 41.6 kg dry calculated
based on
LOD). Crude 4¨(6, 7 ¨dimethoxy¨quinoline-4¨yloxy)¨phenylamine was refluxed
(approximately 75 C) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA
(108.8 kg)
for approximately 1 hour, then cooled to 0 to 5 C, and aged for approximately
1 hour, after
which time the solid was filtered, washed with THF (147.6 kg), and dried on a
filter under
vacuum at approximately 25 C to yield 4¨(6, 7 ¨dimethoxy¨quinoline-4¨yloxy)¨
phenylamine (34.0 kg).
[00169] Alternative Preparation of 4¨(6, 7 ¨Dimethoxy¨quinoline-4¨yloxy)¨
phenylamine
[00170] 4-chloro-6,7-dimethoxyquinoline (34.8 kg), 4-Aminophenol (30.8 kg),
and
sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF)
were charged to a
reactor, followed by N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was
then heated
to 105 to 115 C for approximately 9 hours. After the reaction was deemed
complete as
determined using in-process HPLC analysis (less than 2% starting material
remaining), the
reactor contents were cooled at 15 to 25 C, and water (315 kg) was added over
a two hour
period while maintaining the temperature between 20 and 30 C. The reaction
mixture was
then agitated for an additional hour at 20 to 25 C. The crude product was
collected by
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filtration and washed with a mixture of 88 kg water and 82.1 kg DMA, followed
by 175 kg
water. The product was dried on a filter drier for 53 hours. The LOD showed
less than 1%
w/w.
[00171] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide
were used,
and the reaction temperature was increased from 110 to 120 C. In addition,
the cool down
temperature was increased to 35 to 40 C, and the starting temperature of the
water addition
was adjusted to 35 to 40 C, with an allowed exotherm to 45 C.
[00172] Preparation of 1¨(4¨Fluoro¨phenylcarbamoy1)¨cyclopropanecarbonyl
chloride
[00173] Oxalyl chloride (12.6 kg) was added to a solution of 1¨(4¨fluoro¨
phenylcarbamoy1)¨cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF
(96.1 kg) and
N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch
temperature did not
exceed 25 C. This solution was used in the next step without further
processing.
[00174] Alternative Preparation of 1¨(4¨Fluoro¨phenylcarbamoy1)¨
cyclopropanecarbonyl chloride
[00175] A reactor was charged with 1¨(4¨fluoro¨phenylcarbamoy1)¨
cyclopropanecarboxylic acid (35 kg), DMF (344 g), and THF (175kg). The
reaction mixture
was adjusted to 12 to 17 C, and then to the reaction mixture was charged 19.9
kg of oxalyl
chloride over a period of 1 hour. The reaction mixture was left stirring at 12
to 17 C for 3 to
8 hours. This solution was used in the next step without further processing.
[00176] Preparation of cyclopropane-1,1¨dicarboxylic acid 14¨(6,7¨dimethoxy¨
quinoline-4¨yloxy)¨phenylFamide (4¨fluoro¨phenyl)¨amide
[00177] The solution from the previous step containing
1¨(4¨fluoro¨phenylcarbamoy1)¨
cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-
dimethoxy-
quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in
THF (245.7
kg) and water (116 L) at a rate such that the batch temperature did not exceed
30 C. When
the reaction was complete (in approximately 20 minutes), water (653 L) was
added. The
mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted
in the
precipitation of the product. The product was recovered by filtration, washed
with a pre-made
solution of THF (68.6 kg) and water (256 L), and dried first on a filter under
nitrogen at
approximately 25 C and then at approximately 45 C under vacuum to afford the
title
compound (41.0 kg, 38.1 kg, calculated based on LOD).
[00178] Alternative Preparation of cyclopropane-1,1¨dicarboxylic acid 1446,7¨
dimethoxy¨ quinoline-4¨yloxy)¨phenylFamide (4¨fluoro¨phenyl)¨amide
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[00179] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-
phenylamine
(35.7 kg, 1 equivalent), followed by THF (412.9 kg). To the reaction mixture
was charged a
solution of K2CO3 (48.3 kg) in water (169 kg). The acid chloride solution of
described in the
Alternative Preparation of 1¨(4¨Fluoro¨phenylcarbamoy1)¨cyclopropanecarbonyl
chloride
above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-
yloxy)-
phenylamine while maintaining the temperature between 20 to 30 C over a
minimum of two
hours. The reaction mixture was stirred at 20 to 25 C for a minimum of three
hours. The
reaction temperature was then adjusted to 30 to 25 C, and the mixture was
agitated. The
agitation was stopped, and the phases of the mixture were allowed to separate.
The lower
aqueous phase was removed and discarded. To the remaining upper organic phase
was added
water (804 kg). The reaction was left stirring at 15 to 25 C for a minimum of
16 hours.
[00180] The product precipitated. The product was filtered and washed with a
mixture of
water (179 kg) and THF (157.9 kg) in two portions. The crude product was dried
under a
vacuum for at least two hours. The dried product was then taken up in THF
(285.1 kg). The
resulting suspension was transferred to reaction vessel and agitated until the
suspension
became a clear (dissolved) solution, which required heating to 30 to 35 C for
approximately
30 minutes. Water (456 kg) was then added to the solution, as well as SDAG-1
ethanol (20
kg, ethanol denatured with methanol over two hours). The mixture was agitated
at 15 to 25
C for at least 16 hours. The product was filtered and washed with a mixture of
water (143 kg
and 126.7 kg THF (143 kg) in two portions. The product was dried at a maximum
temperature set point of 40 C.
[00181] In an alternative procedure, the reaction temperature during acid
chloride
formation was adjusted to 10 to 15 C. The recrystallization temperature was
changed from
15 to 25 C to 45 to 50 C for 1 hour and then cooled to 15 to 25 C over 2
hours.
[00182] Preparation of cyclopropane-1,1¨dicarboxylic acid 14¨(6,7¨dimethoxy¨
quinoline-4¨yloxy)¨phenylFamide (4¨fluoro¨phenyl)¨amide, cabozantinib (L)
malate
salt
[00183] Cyclopropane-1,1¨dicarboxylic acid [4¨(6,7¨dimethoxy¨ quinoline-
4¨yloxy)¨
phenyll¨amide (4¨fluoro¨phenyl)¨amide (13.3 kg), L-malic acid (4.96 kg),
methyl ethyl
ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor, and the
mixture was
heated to reflux (approximately 74 C) for approximately 2 hours. The reactor
temperature
was reduced to 50 to 55 C, and the reactor contents were filtered. These
sequential steps
described above were repeated two more times starting with similar amounts of
cyclopropane-1,1¨dicarboxylic acid [4¨(6,7¨dimethoxy¨ quinoline-
4¨yloxy)¨phenyll-
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amide (4¨fluoro¨phenyl)¨amide (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6
kg), and
water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric
pressure using
MEK (1133.2 kg) (approximate residual volume 711 L; KF <0.5 % w/w) at
approximately
74 C. The temperature of the reactor contents was reduced to 20 to 25 C and
held for
approximately 4 hours, resulting in solid precipitate which was filtered,
washed with MEK
(448 kg), and dried under vacuum at 50 C to afford the title compound (45.5
kg).
[00184] Alternative Preparation of cyclopropane-1,1¨dicarboxylic acid 1446,7¨
dimethoxy¨ quinoline-4¨yloxy)¨phenylFamide (4¨fluoro¨phenyl)¨amide, (L) malate
salt
[00185] Cyclopropane-1,1¨dicarboxylic acid [4¨(6,7¨dimethoxy¨ quinoline-
4¨yloxy)¨
phenyll¨amide (4¨fluoro¨phenyl)¨amide (47.9 kg), L-malic acid (17.2 kg),
methyl ethyl
ketone (658.2 kg), and water (129.1 kg) were charged to a reactor, and the
mixture was
heated 50 to 55 C for approximately 1 to 3 hours and then at 55 to 60 C for
an additional 4
to 5 hours. The mixture was clarified by filtration through a 1 p.m cartridge.
The reactor
temperature was adjusted to 20 to 25 C and vacuum distilled with a vacuum at
150 to 200
mm Hg with a maximum jacket temperature of 55 C to the volume range of 558 to
731 L.
[00186] The vacuum distillation was performed two more times with the charge
of 380 kg
and 380.2 kg methyl ethyl ketone, respectively. After the third distillation,
the volume of the
batch was adjusted to 18 v/w of Cyclopropane-1,1¨dicarboxylic acid
[4¨(6,7¨dimethoxy¨
quinoline-4¨yloxy)¨phenyll¨amide (4¨fluoro¨phenyl)¨amide by charging methyl
ethyl
ketone (159.9 kg) to give a total volume of 880 L. An additional vacuum
distillation was
carried out by adjusting methyl ethyl ketone (245.7 kg). The reaction mixture
was left with
moderate agitation at 20 to 25 C for at least 24 hours. The product was
filtered and washed
with methyl ethyl ketone (415.1 kg) in three portions. The product was dried
under a vacuum
with the jacket temperature set point at 45 C.
[00187] In an alternative procedure, the order of addition was changes so that
a solution of
L-malic acid (17.7 kg) dissolved in water (129.9 kg) was added to Cyclopropane-
1,1¨
dicarboxylic acid [4¨(6,7¨dimethoxy¨ quinoline-4¨yloxy)¨phenyll¨amide
(4¨fluoro¨
pheny1)¨amide (48.7 kg) in methyl ethyl ketone (673.3 kg).
[00188] Example 1. Phase I Study of Mass Balance Study Of Cabozantinib (L-
malate
salt) Following a Single 175 mg Oral Administration of 114C1- Cabozantinib
(100 pCi) in
healthy male subjects
[00189] 1. BACKGROUND AND RATIONALE
[00190] 1.1 Background

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[00191] Multi-targeted tyrosine kinase inhibitors (TKIs) and checkpoint
inhibiting
immunotherapies represent two systemic modalities that have been instrumental
in the recent
advancements of anticancer treatment over the past several years. Both classes
of therapies
have demonstrated broad clinical effects leading to new approved treatment
options across
multiple tumor types including renal cell carcinoma (RCC), urothelial
carcinoma (UC),
melanoma, non-small-cell lung cancer (NSCLC), and others. The success of these
therapy
types as single agents with distinct mechanisms of action has naturally led to
interest in
evaluating combinations of TKIs with checkpoint inhibitors in search of
further, possibly
synergistic, anticancer clinical effects.
[00192] XL184 is a new chemical entity that inhibits multiple receptor
tyrosine kinases
implicated in tumor growth and neoangiogenesis. The primary targets of XL184
are
hepatocyte growth factor receptor protein (MET), vascular endothelial growth
factor
receptor 2 (VEGFR2), and rearranged during transfection (RET) proto-oncogene.
[00193] XL184 is orally bioavailable as demonstrated by pharmaco*kinetic (PK)
studies in
rodent and non-rodent models. In in vivo target modulation studies,
administration of XL184
to mice resulted in dose-dependent inhibition of MET, VEGFR2, and RET (Yakes,
et al.
2011). Immunohistochemistry studies demonstrate rapid effects on the
endothelium, vascular
breakdown, and tumor cell death within 24 hours after administration of XL184.
This effect
translates into significant tumor growth inhibition after XL184 treatment in
multiple tumor
models. Additionally, in the models tested (human medullary thyroid cancer,
human breast
cancer, and rat glioma), marked tumor regression was observed.
[00194] Clinical activity with the use of XL184 in a variety of tumor settings
has been
reported and the drug is currently being developed for use in oncology.
[00195] 1. Introduction
[00196] The pharmaco*kinetic (PK) and statistical analyses of plasma, whole
blood, urine
and feces concentration, and total radioactivity data were performed and
reported in the
Clinical Pharmaco*kinetic Report for the Study XL184-012.
[00197] 2. Study Objectives
[00198] The objectives of the study were:
[00199] (1) To determine the time-course for excretion of 14C radioactivity in
urine in
healthy male subjects following a single oral dose of the study drug.
[00200] (2) To determine the time-course for excretion of 14C radioactivity in
feces in
healthy male subjects following a single oral dose of the study drug.
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[00201] (3) To determine the recovery of 14C radioactivity as a percentage of
administered
dose.
[00202] (4) To determine the plasma pharmaco*kinetics (PK) of 14C radioactivity
in healthy
male subjects following a single oral dose of the study drug.
[00203] (5) To determine the whole blood pharmaco*kinetics (PK) of 14C
radioactivity in
healthy male subjects following a single oral dose of the study drug.
[00204] (6) To determine the percentage of 14C radioactivity associated with
erythrocytes
in whole blood over time.
[00205] (7) To determine the plasma pharmaco*kinetics (PK) of XL184 and its
metabolites
by LC/MS/MS in healthy male subjects following a single oral dose of the study
drug.
[00206] (8) To determine the urine pharmaco*kinetics (PK) of XL184 and its
metabolites in
healthy male subjects using a radio-quantitative method following a single
oral dose of the
study drug.
[00207] (9) To determine the feces pharmaco*kinetics (PK) of XL184 and its
metabolites in
healthy male subjects using a radio-quantitative method following a single
oral dose of the
study drug.
[00208] (10) To determine the plasma pharmaco*kinetics (PK) of XL184 and its
metabolites in healthy male subjects using a radio-quantitative method
following a single oral
dose of the study drug.
[00209] 3. INVESTIGATION PLAN
[00210] 3.1 Summary of Study Design
[00211] The clinical phase of the study was conducted from 15 March 2011,
through 07
June 2011. This study was designed as an open-label, single-dose, mass balance
study
conducted in 8 healthy male subjects at one study center in the US. Additional
subjects would
be enrolled only to replace any dosed subjects who drop out of the study prior
to recovery of
at least 85% of the radioactive dose in the subject's vomitus, urine, and
feces. The primary
endpoints of the study were time course for excretion of 14C radioactivity in
urine and feces;
the recovered percentage of the total dose of 14C radioactivity; and the
percentage of 14C
radioactivity present as XL184 in plasma and whole blood at selected time
points.
[00212] Subjects received a single calculated oral dose intended to contain
a total of
175 mg of XL184 (L-Malate Salt) containing 100 [10 of 14C.
[00213] 3.1.1 Identity of Investigational Product(s)
Name: XL184
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Active Compound: XL184
Activity: Cancers
Route of Administration: Oral
Dose/Solution: 175 mg XL184 (L-Malate Salt) Containing HC XL184
(100 nCi )
[00214] 3.2 Pharmaco*kinetic Evaluations and Metabolic Profiling Samples
[00215] 3.2.1 Blood Sample Collections
[00216] Plasma
[00217] Blood samples for plasma for analysis of total radioactivity (10 mL
each) and for
PK analysis of XL184 and/or metabolite concentrations (3 mL each) were
collected predose
(within the 15 minutes prior to dose) and at 0.5, 1, 2, 3, 4, 5, 8, 14, 24,
48, 72, 120, 144, 168,
240, 336, 408, 504, and 648 hours post-dose. Blood samples for plasma for
possible
metabolic profiling (10 mL each) were collected pre-dose (within the 15
minutes prior to
dose) and at 0.5, 1, 2, 3, 4, 5, 8, 14, 24, 72, 168, 336, 504, and 648 hours
post-dose. Prior to
study initiation, the Celerion Scintillation Laboratory and the laboratory
performing the
XL184/metabolite analysis and metabolic profiling (QPS, LLC) supplied to the
Celerion
clinic complete written instructions for collection, aliquot volume required
for analysis,
handling, processing, and shipping (if applicable) of samples. All samples
collected for
radioactivity analysis were analyzed for total radioactivity.
[00218] If radioactivity was present in the plasma samples, individual samples
at selected
time points were analyzed for XL184 and/or metabolites content and metabolic
profiling as
determined by the sponsor.
[00219] Whole Blood
[00220] Blood samples (4 mL) for whole blood analysis of total radioactivity
were
collected within 15 minutes pre-dose and at 1, 2, 4, 8, 14, 24, and 72 hours
post-dose. Prior to
study initiation, the Celerion Scintillation Laboratory supplied to the
Celerion clinic complete
written instructions for collection, handling, and processing of samples.
Samples collected
were used to determine the percentage of radioactivity associated with
erythrocytes in whole
blood over time (calculated only for time points that whole blood was
collected).
[00221] 3.2.2 Urine
[00222] Urine samples were collected for the analysis of total radioactivity
and for
possible analysis for XL184 and/or metabolites and possible metabolic
profiling. Subjects
were asked to empty their bladders within approximately 60 minutes prior to
dosing for the
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pre-dose sample. Samples were collected during the 0 to 8 hours and 8 to 24
hours post-dose
intervals, and then continuing in 24-hour intervals through Day 49. For
subjects who met
early release criteria, sampling could cease upon discharge from the clinic.
Six subjects were
contained in the clinic through 1152 hours (Day 49). One subject was released
from the clinic
following the 816 hour interval (Day 35) collection and was allowed to home-
collect excreta
through 1152 hours. One subject was released from the clinic following the 864
hour interval
(Day 37) collection and no longer provided excreta samples.
[00223] Urine was refrigerated during the collection intervals. Subjects were
instructed to
urinate at the end of each collection period, if possible. The total volume
collected for each
interval was recorded. At the end of each collection interval, the urine was
mixed to suspend
any sediment and the appropriate aliquots were removed. After preparing the
necessary
aliquots, the remaining samples were destroyed.
[00224] Prior to study initiation, the Celerion Scintillation Laboratory and
the laboratory
performing the XL184/metabolite analysis and metabolic profiling (QPS, LLC)
supplied to
the Celerion clinic complete written instructions for collection, aliquot
volume required for
analysis, handling, processing, and shipping (if applicable) of samples. All
samples collected
for radioactivity were analyzed. If radioactivity was present in the urine
samples, individual
samples at selected time points might be analyzed for XL184 and/or metabolites
content and
metabolic profiling as determined by the sponsor.
[00225] 3.2.3 Feces
[00226] Subjects were asked to bring a pre-dose stool sample with them at
check-in
(produced within 24 hours of check-in). Stools produced between subject check-
in and
dosing were collected for the pre-dose sample as well, and the sample produced
nearest to
dosing was used as the pre-dose sample. Post-dose stools were collected in 24-
hour intervals
through the morning of Day 49. For subjects who met early release criteria,
sampling could
cease upon discharge from the clinic. Six subjects were contained in the
clinic through 1152
hours (Day 49). One subject was released from the clinic following the 816
hour interval
(Day 35) collection and was allowed to home-collect excreta through 1152
hours. One
subject was released from the clinic following the 864 hour interval (Day 37)
collection and
no longer provided excreta samples.
[00227] For each subject, multiple fecal specimens from each 24-hour interval
were
combined into a pre-weighed wide mouth polypropylene/polyethylene container
and
appropriately labeled. For each interval, the fecal sample was weighed to
determine the final
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fecal weight. Each sample was hom*ogenized into a slurry (approximately 20%
suspension in
water) from which the necessary aliquots were taken.
[00228] Prior to study initiation, the Celerion Scintillation Laboratory and
the laboratory
performing the XL184/metabolite analysis and metabolic profiling (QPS, LLC)
supplied to
the Celerion clinic complete written instructions for collection, aliquot
volume required for
analysis, handling, processing, and shipping (if applicable) of samples. All
samples collected
for radioactivity were analyzed. If radioactivity was present in the fecal
samples, individual
samples at selected time points might have been analyzed for XL184 and/or
metabolites
content and metabolic profiling as determined by the sponsor.
[00229] 3.2.4 Emesis
[00230] If emesis occurred within 4 hours following dosing, it was collected
(if possible)
and stored for potential scintillation counting. The vomitus should have been
weighed (the
weight recorded in the CRF); labeled with subject number, time, and date; and
placed in a
freezer set at -20 C 10 C until it could be analyzed for radioactivity.
[00231] If emesis occurred within 4 hours of dose administration, the subject
was replaced
and no re-dosing of the same subject was permitted. If radioactivity recovered
in vomitus in
such subject was 85% of total administered radioactivity, the subject would
have been
discharged. However, if radioactivity recovered in vomitus was < 85% of total
administered
radioactivity, the radioactivity in urine and feces produced by this subject
might have been
measured and monitored throughout the study upon discretion of the sponsor. A
new subject
might have been enrolled in the study to replace such a subject.
[00232] 3.3 Drug Concentration Measurements
[00233] 3.3.1 Scintillation Counting
[00234] The Celerion Scintillation Laboratory, 621 Rose Street, Lincoln,
Nebraska,
performed sample analysis for radioactivity. All analyses were conducted in
accordance with
GLP.
[00235] Individual dosing containers (including the dosage form) were analyzed
pre-dose
and post-dose for radioactivity, with the (post-dose - pre-dose) difference
being the
administered dose. Whole blood, plasma, urine, feces, and emesis (if
applicable) were
analyzed for radioactivity content by liquid scintillation counting
procedures. Whole blood
and fecal samples were dried and oxidized prior to counting. Detailed reports
of scintillation
counting method and results for total radioactivity accompany the clinical
study report.

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[00236] 3.3.2 Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-
MS/MS) and Radio-quantitative Method for XL184 and/or Metabolite Content
[00237] Plasma concentrations of XL184 and metabolites XL184-Half-Dimer, XL184-
N-
Oxide, and XL184-Sulfate were measured using a validated LC/MS/MS method by
QPS,
LLC, 3 Innovation Way, Suite 240, Newark, DE 19711, USA. Detailed reports of
the
bioanalytical methodologies and results accompany the clinical study report.
Analyses of
XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were
conducted in accordance with GLP. However, the newly identified metabolite, 6-
Demethyl
Half-Dimer Sulfate, was measured using a non-validated method by QPS, LLC and
was not
conducted in accordance with GLP.
[00238] The other minor metabolite in plasma, p-Fluoroaniline, was analyzed by
Exelixis
using a validated LC/MS/MS method. The values of p-Fluoroaniline
concentrations for all
the plasma samples were below the lower limit of quantitation (2.0 ng/mL).
Therefore, no
data will be listed for p-Fluoroaniline concentrations in this study report.
[00239] The newly identified metabolite, 6-Demethyl Half-Dimer Sulfate, was
measured
using non-validated method by QPS, LLC.
[00240] In addition, the plasma concentration of XL184 and metabolites XL184-
Half-
Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, P2,
and P7
were determined using a non-GLP radio-quantitative method by QPS, LLC, 3
Innovation
Way, Suite 240, Newark, DE 19711, USA. Detailed reports of the radio-
quantitative method
and results can be found in the DMPK report.
[00241] 3.4 Pharmaco*kinetic Parameters Estimation
[00242] 3.4.1 Mass Balance and Blood-to-Plasma Distribution
[00243] Mass balance was calculated as the percent of total administered
radioactivity
recovered in urine and feces. For the purpose of calculating mass balance, the
amount of
administered radioactivity was defined as the total radioactivity in the
dosing solution minus
any radioactivity lost due to emesis (if any occurred), adsorption to the
dosing cup, etc.
[00244] To determine the percentage of radioactivity associated with
erythrocytes in whole
blood over time (calculated only for time points where whole blood was
collected), the
following was calculated: the amount of radioactivity in plasma versus whole
blood, adjusted
for the hematocrit, at the specific time points of comparison (ETR=Xe/Xb=1-[Cp
* (1-
HcO/Cb], where Cp stands for amount of radioactivity in plasma and Cb stands
for the
amount of radioactivity in blood and Hct stands for hematocrit value.
Hematocrit values for
Days -1, 2, and 4 were averaged for use in this calculation.
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[00245] 3.4.2 Plasma and Whole Blood
[00246] As appropriate, the PK parameters were calculated as data allowed for
XL184
and/or metabolite concentrations in plasma and for radioactivity in plasma and
whole blood
(i.e., nanogram equivalents from radioactivity) using noncompai [mental
approaches. PK
variables were computed using WinNonlin Professional, version 5.2. The
definition for each
PK variable is listed in the following table. Actual elapsed sampling times
relative to
[14C1¨XL184 (100 põCi) oral administration were used for the estimation of PK
metrics.
[00247] Table 9. PK Variable Definitions.
Cmax Maximum observed concentration
tmax Time of the maximum concentration
AUCo-t Area under the concentration-time curve calculated using
linear trapezoidal
summation from time zero to time t, where t was the time of the last
measurable concentration (Ct)
AUC0-24 Area under the concentration-time curve calculated using
linear trapezoidal
summation from time zero to time 24 hours
AUC0-72 Area under the concentration-time curve calculated using
linear trapezoidal
summation from time zero to time 72 hours
AUCo-olf Area under the concentration-time curve from time zero to
infinity,
AUCo_inf = AUCo-t + Ct/ket, where kei was the terminal elimination rate
constant
kei Apparent terminal elimination rate constant calculated by
linear regression
of the terminal linear portion of the log concentration vs. time curve
t1/2 Apparent terminal elimination half-life calculated as
ln(2)/kei
%Ratio of %Ratio of AUCmet/AUCXL184 = %(AUCO-t of
metabolite)/(AUCo_t of XL184)
AUCmet/AUCXL 184
%Ratio of %Ratio of AUCanalyte/AUC XL 184 +Metabolites ¨ %(AUCO-t of
XL184 or
AUCana1yte/AUCXL184+Meta1o1ites metabolite)/(AUCo_t of XL184 and metabolites)
[00248] The C. and time to peak concentration (t.) were directly determined
from the
observed blood/plasma concentrations data. AUC0_24, AUC0_72, and AUCo_t, the
area under the
concentration-time curve from time zero to 24 hours post dose, to 72 hours
postdose, and to
the time of the last measurable concentration (Ct), were calculated using the
linear trapezoidal
method.
[00249] The area under the blood/plasma concentration time curve from time
zero to 24
hours postdose, to 72 hours postdose, or up to the last quantifiable
concentration (AUCo_t)
was estimated by numerical integration using the linear trapezoidal rule
(Equation 1):
AUC = 0.5 = (C, + C,_,) = (t, ¨ t,_,) Eq. 1
2
47

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where Ci was the blood / plasma concentration at the corresponding sampling
time point of
24, 72 hours or tt, and n was the number of time points up to and including
the last
quantifiable concentration.
[00250] Estimates of half-life (tv2) were calculated using the following
(Equation 2):
Eq. 2
t1/2 = 0.693
kei
where the value of the terminal-phase disposition rate constant (kei) of the
apparent phase
were determined by a non-compartmental analysis using WinNonlin. A regression
analysis
was performed on the terminal linear phase of the semi-logarithmic plots of
individual blood/
plasma concentration time data. During the analysis, WinNonlin repeated
regressions using
the last three points with non-zero concentrations, then the last four points,
and the last five,
etc. Points prior to C. were not used. Points with a value of zero for the
dependent variable
were excluded. For each regression, an adjusted R2 was computed:
Adjusted R2=1-(1- R2)*(n-1)/(n-2) Eq. 3
where n was the number of data points in the regression, and R2 was the square
of the
correlation coefficient. WinNonlin estimates kei using the regression with the
largest adjusted
R2, and, if the adjusted R2 did not improve but was within 0.0001 of the
largest adjusted R2
value, the regression with the larger number of points was used. kei had to be
positive and
calculated from at least three data points.
[00251] If the terminal phase for any individual subject failed to meet the
stated criteria,
the t112 were considered to be not reportable.
[00252] The area under the plasma concentration time curve up to time infinity
(AUCo)
was computed using the following (Equation 4):
Ct Eq. 4
AUC = AUC +
0-mf 0-t kei
where Ct was the last measurable concentration.
[00253] 3.5 Some Data Handling Procedures
[00254] If a PK profile did not contain more than five consecutive data points
with a
quantifiable concentration value, this PK profile was considered not evaluable
by the
pharmaco*kineticist.
[00255] Only subjects included in the pharmaco*kinetic analysis were included
in the
summary statistics.
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[00256] Below the Quantification Limit (BQL):
[00257] Plasma, blood, urine, and feces concentrations below quantifiable
limits (BQL)
were imputed with a value of zero for the calculation of PK metrics.
[00258] The area under the concentration time curve up to time infinity (AUCo)
[00259] AUCo_inf was considered reportable if the following criteria were met:
= t112 was estimable according to Section [00241].
= AUC04/ AUC0-i11f ratio 0.80.
[00260] If AUCo_inf for an individual subject fails any of the above criteria,
the value was
reported as NE or NR, where
= NE: could not be estimated.
= NR: AUC04/ AUCof ratio <0.80; therefore, AUCof and t112 were not
reportable.
[00261] Data Format (significant figures and decimal points):
[00262] Pharmaco*kinetic parameters were reported to 3 significant figures for
individual
parameters and summary statistics, with the exception of t. (2 decimal places)
and CV%
and N, which were whole numbers (0 decimal places).
[00263] 3.6 Statistical Evaluations of PK parameters
[00264] Descriptive statistics [sample size, mean, standard deviation (SD),
standard error
of the mean (SEM), minimum, median, maximum, coefficient of variation, and
geometric
mean] were calculated for those PK parameters identified in the section
describing
Pharmaco*kinetic Parameters Estimation. No inferential statistics were
calculated.
[00265] 4. PHARMAco*kINETICS RESULTS
[00266] 4.1 Data Set Analyzed
[00267] Eight subjects were enrolled and completed the study. No subject was
withdrawn
from the study and experienced the emesis. The statistical analysis
population, therefore,
consists of 8 subjects.
[00268] 4.2 Pharmaco*kinetic Results
[00269] 4.2.1 Mass Balance Results
[00270] The actual total amounts of the dose of XL184 with ['CI-radioactivity
for
individual subjects are listed in Table 10. The individual cumulative percent
excretion of
[14¨,u]_
radioactivity in the urine and feces based on total radioactivity after a
single oral dose
administration of XL184 (L-Malate Salt) containing [14C1-XL184 solution in
eight healthy
male subjects are presented in Table 16 and 17, respectively. The total
cumulative percent
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recoveries of [14g-radioactivity in the urine and feces based on total
radioactivity after a
single 175 mg oral dose administration of XL184 (L-Malate Salt) containing 100
[iCi [14C1-
XL184 formulated as a solution in eight healthy male subjects is listed in
Table 19.
[00271] Individual subject urine and feces cumulative excretion of total
radioactivity
versus time plots following a single 175 mg oral administration of XL184 (L-
Malate Salt)
containing 100 Ci [14C] XL184 was tracked.
[00272] Mean ( SD) cumulative excretion versus time plots of total
radioactivity in urine
and feces following a single 175 mg oral administration of XL184 (L-Malate
Salt) containing
100 [10 [14C] XL184 to healthy male subjects are shown in FIG. 1.
[00273] Table 10. Dosing Record.
XL184 Total
Radioactivity
Subject (mg) ([1.Ci)
1444-1010 192.01 104.74
1444-1023 189.97 103.63
1444-1040 191.81 104.63
1444-1042 189.59 103.42
1444-1051 188.35 102.74
1444-1052 187.93 102.51
1444-1057 188.41 102.77
1444-1058 189.57 103.41
[00274] A summary of cumulative recovery of total radioactivity (as percent of
dose) in
the urine and feces following a single 175 mg oral administration of XL184 (L-
Malate Salt)
containing 100 Ci [14C] XL184 to the healthy male subjects is presented in
Table 11.
[00275] Table 11. Summary (Mean SD and %CV) of Cumulative Recovery of Total
Radioactivity (as Percent of Dose) in Urine and Feces Following a Single 175
mg Oral
Administration of XL184 (L-Malate Salt) containing 100 luCi 114C1-XL184 to
Healthy
Male Subjects.
Cumulative Recovery of Total Radioactivity
(as Percent of Dose) (n=8)
Urine Feces Total
27.29 4.65 (17 %) 53.79 4.52 (8%) 81.09 1.56 (2%)

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[00276] An average 27.29% (ranged from 19.78% to 34.88% based on Table 19) and
53.79% (ranged from 46.54% to 61.89% based on Table 19) of the dose was
excreted in the
urine and feces following the oral administration of the 175 mg XL184
containing 100 tCi
[14C,_
XL184 to eight male healthy volunteers, respectively. An average of 81.09%
(ranged
from 78.14% to 83.38% based on Table 19) of the dose was excreted in total in
the urine and
feces through 48 days post dose. Approximately 1% total mean radioactivity was
recovered
in feces and urine after Day 28 post-dose. In human radiolabel studies, total
cumulative
recovery of radioactivity in excreta above 80% may be considered acceptable
for mass
balance evaluation and sufficient recovery of radioactivity. The total
recovery was considered
satisfactory (81.09%), with a predominant fecal excretion of 53.79% and urine
excretion of
27.29%.
[00277] 4.2.2 Pharmaco*kinetic Results
[00278] 4.2.2.1 Pharmaco*kinetic Parameters for Total Radioactivity in
Plasma and
Whole Blood
[00279] The individual and mean plasma and whole blood concentration data for
[14C1-
radioactivity after single dose administration of 175 mg of XL184 (L-Malate
Salt) containing
100 p..Ci [14C1-XL184 formulated as a solution in healthy male subjects are
presented in
Tables 22 and 23, respectively. The individual and mean hematocrit values are
listed in Table
22. The individual and descriptive statistics of the percentage of 14C
radioactivity associated
with erythrocytes in whole blood (ETR) over time are included in Table 26. The
individual
actual blood sampling times of total radioactivity for plasma and whole blood
are listed in
Table 27.
[00280] The individual subject 14C total radioactivity in plasma and whole
blood and
plasma XL184 concentration (by LC/MS/MS method) versus time plots following a
single
175 mg oral administration of 175 mg of XL184 (L-Malate Salt) containing 100
p..Ci [14C1-
XL184 are presented in the figures herein (linear axes) and (semi-logarithmic
axes). The
individual percentage of 14C radioactivity associated with erythrocytes in
whole blood (ETR)
over time graphs following a single oral administration of 175 mg of XL184 (L-
Malate Salt)
containing 100 Ci [14C1-XL184 to healthy male subjects are shown in the
figures and tables
herein.
[00281] The individual subject and descriptive statistics for pharmaco*kinetic
parameters of
['4C1-radioactivity in plasma and whole blood are included in Table 26 and
Table 27,
respectively.
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[00282] WinNonlin outputs of pharmaco*kinetic analyses of total radioactivity
in plasma
and whole blood data are included in the Figures and Tables herein.
[00283] FIGS. 2 and 3 (linear axes) and FIGS. 4 and 5 (semi-logarithmic axes)
illustrate
the mean ( SD) 14C total radioactivity in plasma and whole blood and plasma
XL184
concentration (by LC/MS/MS method) versus time plots after administration of
single
175 mg dose of XL184 (L-Malate Salt) containing 100 uCi [14C1-XL184 formulated
as an
oral solution, respectively. FIG. 6 demonstrates the mean ( SD) plots of
percentage of 14C
radioactivity associated with erythrocytes in whole blood over time following
a single
175 mg oral administration of XL184 (L-Malate Salt) containing 100 uCi [14C1-
XL184 to
healthy male subjects.
[00284] A summary of plasma and whole blood pharmaco*kinetic parameters for
total
radioactivity following a single 175 mg oral administration of XL184 (L-Malate
Salt)
containing 100 uCi [14C1-XL184 to healthy male subjects is presented in Table
12.
[00285] A summary (mean SD) of the percentage of 14C radioactivity associated
with
erythrocytes in whole blood (ETR) over time following a single 175 mg oral
administration
of XL184 (L-Malate Salt) containing 100 uCi [14C1-XL184 to healthy male
subjects is
presented in Table 13.
[00286] Following a single oral dose, the peak radioactivity in plasma and
whole blood
were achieved at approximately 2 hours (median) with a mean maximum value
(C.,,) of 2000
and 1200 ngEq/mL, respectively. The elimination half-life (t1/2) of the total
radioactivity in
plasma was determined with a mean value of 269 hours. However, the t112,
AUCo_mf, and
AUC0_72 of the total radioactivity in whole blood were not reportable since
AUC04/ AUC0-Ear
ratio were less than 0.80 for those eight subjects. The mean values of
systemic exposures
(AUC0_24 and AUC0_72) in plasma were around 1.6 times higher than those in
whole blood
(Table 12).
[00287] Table 12. Summary (Mean SD and %CV) of Plasma and Whole Blood
Pharmaco*kinetic Parameters for Total Radioactivity following a Single 175 mg
Oral
Administration of XL184 (L-Malate Salt) containing 100 Ci 114C1-XL184 to
Healthy
Male Subjects.
%Ratio of Plasma to
Parameters
Plasma Whole Blood Whole blood
C., ngEq/mL 2000 429 (21) 1200 243 (20) 167 12.4 (7)
t, ha 2.00 (1.00, 4.00) 2.00 (1.98, 2.00) NA
AUC0_1, h.ngEq/mL 259000 42700 (16) 54100 10300 (19)
487 73.3 (15)
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AUC0_24, h=ngEq/mL 31400 6380 (20) 19600 3780 (19) 160 6.65 (4)
AUC0_72, h=ngEq/mL 89700 19000 (21) 54100 10300 (19)
165 11.1 (7)
AUCo, h=ngEq/mL 306000 59500 (19) NR NA
kel, 1/h 0.00308 0.00182 (59) NR NA
h 269 93.2 (35) NR NA
a: median (range); NR: Not Reportable, since AUCo_t/ AUCof ratio < 0.80 ; NA:
Not
Applicable;
C., maximum observed concentration; Tmax, time of the maximum concentration;
AUCo-t,
area under the concentration-time curve from time zero to the time of the last
measurable
concentration; AUC0_24, area under the concentration-time curve from time zero
to 24 hours
post XL184 dose; AUC0_72, area under the concentration-time curve from time
zero to
72 hours post XL184 dose; AUCo, area under the concentration-time curve from
time zero
to infinity; kei apparent terminal elimination rate constant; t112, apparent
terminal elimination
half-life; CL/F, apparent total body clearance; V/F, apparent total volume of
distribution;
ngEq, an equivalent amount of XL184 freebase required to produce a measured or
calculated amount of
total radioactivity.
[00288] The total radioactivity in whole blood and plasma was detectable in
all subjects
following single dosing. One of the purposes of this measurement was to
characterize the
partitioning of [14q-XL184 in erythrocytes and whole blood. Erythrocyte to
whole blood
concentration ratios were examined after single dosing. The details of
calculation used to
determine the erythrocyte-to-whole blood total radioactivity concentration
ratios are
described in Section 3.4.1.
[00289] The mean percent of total radioactivity concentrations associated with
erythrocytes based on the concentration of total radioactive concentrations in
plasma and
whole blood ranged from 0.174 4.51 to 12.3 3.71 within 72 hours after
single dosing,
indicating that radioactivity was present primarily in plasma and not markedly
associated
with red blood cells (Table 13).
[00290] Table 13. Summary (Mean SD and %CV) of Percentage of "C Radioactivity
Associated with Erythrocytes in Whole Blood (ETR) over Time following a Single
175 mg Oral Administration of XL184 (L-Malate Salt) containing 100 pCi 1"C1-
XL184
to Healthy Male Subjects.
Time (hr) Percentage (%)
1 7.08 5.93 (84)
2 7.85 3.27 (42)
4 6.40 2.05 (32)
8 12.2 5.00 (41)
14 12.3 3.71 (30)
24 0.174 4.51 (2595)
72 3.89 5.58 (143)
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[00291] 4.2.2.2 Plasma Pharmaco*kinetic Parameters for XL184 and its
metabolites by
LC/MS/MS method
[00292] The individual and mean plasma concentration data for XL184 and
metabolites
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer
Sulfate
by LC/MS/MS method after single dose administration of 175 mg of XL184 (L-
Malate Salt)
containing 100 u.Ci [14C1-XL184 formulated as an oral solution in healthy male
subjects are
presented in Tables 28 to 32A. Para-fluoroaniline (pFA) metabolite
concentrations were
below the LLOQ for all subjects. The individual actual plasma sampling times
are listed in
Table 23. The individual subject and descriptive statistics plasma
pharmaco*kinetic
parameters of XL184 and metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-
Sulfate,
and 6-Demethyl Half-Dimer Sulfate by LC/MS/MS method are included in Tables 33
to 36.
[00293] FIGS. 7 and 8 (linear axes) and FIGS. 9 and 10 (semi-logarithmic axes)
illustrate
the mean ( SD) plasma concentrations versus time plots of XL184 and
metabolites XL184-
Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate,
respectively, measured by LC/MS/MS method after administration of single 175
mg dose of
XL184 (L-Malate Salt) containing 100 u.Ci ['4C1-XL184 as an oral solution.
[00294] A summary of plasma pharmaco*kinetic parameters of XL184 and
metabolites
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer
Sulfate
measured by LC/MS/MS method following a single 175 mg oral administration of
XL184 (L-
Malate Salt) containing 100 uCi ['4C1-XL184 to healthy male subjects is
presented in Table
14.
[00295] The parent compound, XL184, was rapidly absorbed after oral
administration and
eliminated relatively slowly. The main circulating metabolite in plasma was 6-
Demethyl
Half-Dimer Sulfate. Following a single oral dose, the mean peak concentrations
of XL184,
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer
Sulfate in
plasma were achieved at approximately 1.49, 18.99, 13.50, 24.00, and 168.00
hours (median)
with a mean maximum concentration value (C.) of 1250, 52.9, 118, 236 and 230
ng/mL,
respectively. The mean estimated elimination half-lives of XL184, XL184-Half-
Dimer,
XL184-N-Oxide, and XL184-Sulfate were 102, 91.8, 89.2, and 86.0 hours,
respectively
(FIGS. 7, 8, 9, and 10 and Table 14). However, the elimination half-lives of 6-
Demethyl
Half-Dimer Sulfate for all the subjects could not be determined.
[00296] For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-
Demethyl Half-Dimer Sulfate, the mean metabolite exposure ratios relative to
parent XL184
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(AUC04 (metabolite)/ AUCo4 (parent)) were 9.93%, 15.0%, 42.9%, and 150%,
respectively.
Mean exposure ratios for parent and metabolites XL184-Half-Dimer, XL184-N-
Oxide,
XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate relative to total exposure,
(AUCo4 (each
analyte)/ AUCo4 (parent+4 measured metabolites)) were 32.4%, 3.09%, 4.90%,
13.8%, and
45.9%, respectively.
[00297] Table 14. Summary (Mean SD and %CV) of Plasma Pharmaco*kinetic
Parameters for XL184 and Selected Metabolites by LC/MS/MS Method Following a
Single 175 mg Oral Administration of XL184 (L-Malate Salt) Containing 114C1-
XL184
(100 pCi) to Healthy Male Subjects.
XL184-Half- 6-
Demethyl Half-
Parameters XL184 XL184-N-Oxide XL184-Sulfate
Dimer Dimer
Sulfate*
1250 238 52.9 17.3 118 33.7 236 66.7 230 91.2
Cmax, ng/mL
(19)e (33) (28) (28) (40)
T h 1.49 18.99 13.50 24.00 168.00
max , a
(1.00, 3.00) (5.00, 24.10) (2.00, 24.30) (3.00, 48.00)
(71.97, 240.00)
AUC0-24, 14300 2600 1080 341 2030 682 3970 1350
951 377
h= ngimL (18) (32) (34) (34) (40)
AUC0-72, 35000 6770 3120 976 5610 1940 12600 4180
7530 3200
h= ngimL (19) (31) (35) (33) (42)
AUCo-t, 67200 6880 6540 1680 10100 3210 28900 10700 99500
34500
h= ngimL (10) (26) (32) (37) (35)
9.93 3.20 15.0 3.80 42.9 14.4 150 51.5
Ratio b , 04 NA
(32) (25) (33) (34)
Rat C % 32.4 6.07 3.09 0.689 4.90 2.01
13.8 5.63 45.9 11.2
io ,
(19) (22) (41) (41) (24)
AUC0-mr, 68000 6910 6770 1700 10300 3170 29500 10600 NA
h= ngimL (10) (25) (31) (36)
Ica, 1/h 0.00712 0.00176 0.00807
0.00218 0.00846 0.00256 0.00859 0.0022 NA
(25) (27) (30) (26)
t112, h 102 23.3 91.8 25.4 89.2 29.2 86.0
24.3 NA
(23) (28) (33) (28)
a: median (range); b: ratio of AUCo-t (metabolite)/ AUCo-t (parent); c: ratio
of AUCo-t (each analyte)/ AUCo-t ( parent+4 measured
metabolites); NA: Not Applicable; C., maximum observed concentration; Tmax,
time of the maximum concentration; AUCo-t,
area under the concentration-time curve from time zero to the time of the last
measurable concentration; AUG-24, area under the
concentration-time curve from time zero to 24 hours post XL184 dose;
AUC0-72, area under the concentration-time curve from time zero to 72 hours
post XL184 dose; AUC0-,ff, area under the
concentration-time curve from time zero to infinity; Lc-) apparent terminal
elimination rate constant; biz, apparent terminal
elimination half-life; *: The LC/MS/MS analytical method for 6-demethy half-
dimer sulfate is not validated.
[00298] 4.2.2.3 Plasma
Pharmaco*kinetic Parameters for XL184 and its Metabolites
using a Radio-Quantitation Method
[00299] Samples for 2 subjects were used for the investigation study.
Therefore, only 6
subjects' PK profiles were determined using a radio-quantitation method. Due
to the low
radioactivity after 336 hours, the samples for 504 hours and 648 hours were
not analyzed.
The individual and mean plasma concentration data for XL184 and metabolites
XL184-Half-
Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5, P2,
and P7
using a radio-quantitative method after single dose administration of 175 mg
of XL184 (L-

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Malate Salt) containing 100 Ci [14C1-XL184 formulated as an oral solution in
healthy male
subjects are presented in Table 15.
[00300] The individual actual plasma sampling times are listed in Table 23.
The individual
subject and descriptive statistics plasma pharmaco*kinetic parameters of XL184
and
metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-
Dimer
Sulfate, P5, P2, and P7 using a radio-quantitative method are included in
Table 45. app
[00301] FIGS. 11 and 12 (linear axes) and FIGS. 13 and 14 (semi-logarithmic
axes)
illustrate the mean ( SD) plasma concentrations versus time plots of XL184 and
metabolites
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate,
P5,
and P7, respectively, measured by a radio-quantitative method after
administration of single
175 mg dose of XL184 (L-Malate Salt) containing 100 Ci ['4C1-XL184 as an oral
solution.
[00302] A summary of plasma pharmaco*kinetic parameters of XL184 and
metabolites
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate,
P5,
and P7, measured by a radio-quantitative method following a single 175 mg oral
administration of XL184 (L-Malate Salt) containing 100 Ci [14C1-XL184 to
healthy male
subjects is presented in Table 15. Since no subjects had more than five
consecutive data
points with a quantifiable P2 concentration value, there is no pharmaco*kinetic
parameter
information included in Table 15. The proposed major biotransformation
products of XL184
are displayed in Scheme 3.
56

CA 03065560 2019-11-28
WO 2018/227119
PCT/US2018/036703
Scheme 3.
A oso3H
411 0 0 0 IP 40 Li Li SI
XL184 N-Oxide
XL184 Monohydroxy Sulfate
0.- EXEL-04625162; EXEL-5162
N EXEL-04621646; EXEL-1646
00
yyj
SI 0 0 10
0
XL184 (Cabozantinib)
Amide Cleavage
NyKrOH H2N io
4110 0 0
0
0
4-Fluoroaniline
N-' XL184 Amide Cleavage Product
EXEL-04615366; EXEL5366
410 0 0 0
H03s0
-0 XL184 Desmethyl Amide Cleavage Product
sulfate
EXEL-04621644; EXEL-1644
[00303] The parent compound, XL184, was rapidly absorbed after oral
administration and
was eliminated relatively slowly. Following a single oral dose, the median
peak
concentrations of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-
Demethyl
Half-Dimer Sulfate, P5, and P7 in plasma were achieved at approximately 1.99,
1.49, 3.00,
4.50, 71.99, 2.00, and 2.00 hours with a mean maximum concentration value (C.)
of 1080,
210, 299, 649, 379, 194, and 95.3 ngEq/mL, respectively. The mean estimated
elimination
half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and P5
were
70.5, 57.9, 73.1, 79.2, and 73.4 hours, respectively (FIGS. 11, 12, 13, and 14
and Table 15).
However, the elimination half-lives of 6-Demethyl Half-Dimer Sulfate and P7
for all the
subjects were not reportable.
57

CA 03065560 2019-11-28
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[00304] For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-
Demethyl Half-Dimer Sulfate, P5, and P7, the mean metabolite exposure ratios
relative to
parent XL184 (AUC04 (metabolite)/ AUC04 (parent)) were 34.4%, 34.1%, 188%,
283%,
24.5%, and 1.54%, respectively. Mean exposure ratios for parent and
metabolites XL184-
Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5,
and P7
relative to total exposure (AUC04 (each analyte)/ AUC04 (parent + measured
metabolites)
were 20.0%, 6.25%, 7.16%, 37.6%, 40.3%, 4.10%, and 0.386%, respectively.
[00305] The results of the mean metabolite exposure ratios relative to parent
XL184
(AUC04 (metabolite)/ AUC04 (parent)) and the mean exposure ratios for parent
and
metabolites relative to total exposure (AUC04 (each analyte)/ AUC04 (parent +
measured
metabolites) between LC/MS/MS and the radio-quantitative method are different
since they
are two different methods. LC/MS/MS was a validated method (except for 6-
Demethyl Half-
Dimer Sulfate) and was run under the GLP environment in this study. On the
contrary, the
radio-quantitative method was not a validated method and was run under the non-
GLP
environment in this study.
58

[00306] Table 15. Summary (Mean SD and %CV) of Plasma
Pharmaco*kinetic Parameters for XL184 and
Selected Metabolites Using a Radio-Quantitative Method* Following a Single 175
mg Oral Administration of XL184 (L- 0
Malate Salt) Containing 1HC1-XL184 (100 pCi) to Healthy Male Subjects (N=6).
tµ.)
o
,-,
oe
n.)
XL184-Half-
6-Demethyl
-4
Parameters XL184
XL184-N-Oxide XL184-Sulfate Half-Dimer P5 P7
Dimer
1¨,
Sulfate
vo
Cmax, 1080 234 210 73 299 56
649 132 379 151 194 51.1 95.3i
ngEq/mL (22) (35) (19) (20)
(40)g (26)h
Ti.õ, ha 1.99 1.49 3.00 4.50 71.99
2.00 2.001
(1.00, 4.00) (1.00, 24.08) (2.00, 4.00) (1.98, 24.08)
(24.00, 168.00)g (1.98, 5.00)11
AUG-24, 10700 3170 3610 1350 4300 1460 11300
2360 2520 1370 2470 1290 625i
h=ngEq/mL (30) (37) (34) (21)
(54)g (52)h
AUG-72, 23800 9340 8680 3980 10600 3490 33200
7940 17400 7000 5950 2870 625i
h=ngEq/mL (39) (46) (33) (24)
(40)g (48)h P
AUC0-1, 38100 12800 11100 5890 13300 8360 69900
22000 89000 32000 7660 442 5101
h=ngEq/mL (34) (53) (63) (31)
(36)g (6)h u,
u,
un
Ratio I), % NA 34.4 24.7 (72) 34.1 15.4 (45) 188
29.1 (15) 283 200 (71) 24.5 11.4 (47) 1.54
r.,
Ratio, % 20.0 6.24 (31) 6.25 3.76 (60) 7.16
4.20 (59) 37.6 13.9 (37) 40.3 15.9 (40) 4.10 1.19 (29) 0.386
,
AUC0, 40300 12300 16400+1770 20800 7640
74500 22900 NA 87201 NA ,-
,-
,
h=ngEq/mL (30) (11)d (37) e (31)
'
kel, 1/h 0.0112 0.0053 0.0136 0.00672 0.00976
0.00212 0.00923 0.00221 NA 0.009451 NA
(47) (49) d (22) e (24)
t112, h 70.5 23.2 57.9 28.4 73.1 14.0
79.2 21.4 NA 73.41 NA
(33) (49) d (19) e (27)
a: median (range); b: ratio of AUCo-t (metabolite)/ AUCo-t (parent); e: ratio
of AUCo-t (each analyte)/ AUCo-t ( parent+6 measured metabolites); NA: Not
Applicable; d: N=2;
e: N=3; NR: Not reportable. g: N=4; h:N=3; 1: N=1; C., maximum observed
concentration; T., time of the maximum concentration; AUCo-t, area under the
concentration-
time curve from time zero to the time of the last measurable concentration;
AUCo-24, area under the concentration-time curve from time zero to 24 hours
post XL184 dose; IV
n
Auc0_72, area under the concentration-time curve from time zero to 72 hours
post XL184 dose; AUCo, area under the concentration-time curve from time zero
to infinity; 1-3
kel, apparent terminal elimination rate constant; tin, apparent terminal
elimination half-life. *: The radio-quantitative method was not performed
according to GLP regulations.
cp
n.)
o
1¨,
oe
-a-,
-4
=
c,.,

CA 03065560 2019-11-28
WO 2018/227119 PCT/US2018/036703
[00307] 5. Conclusions
[00308] Following oral administration of the 175 mg dose of XL184 (L-Malate
Salt)
containing 100 [tCi [14Q-XL184 to eight male healthy volunteers, a mean
recovery of total
radioactivity of 81.09% was achieved within 48 days. Approximately 1% total
mean
radioactivity was recovered in feces and urine after Day 28 post-dose. The
radioactivity was
mainly eliminated in feces (53.79%) and the remainder in urine (27.29%).
[00309] Following a single oral dose, the peak radioactivity in plasma and
whole blood
was achieved at approximately 2 hours (median) with a mean maximum value
(Cmax) of 2000
and 1200 ngEq/mL, respectively. The elimination half-life of the total
radioactivity in plasma
was determined with a mean value of 269 hours. The mean values of systemic
exposures
(AUC0_24 and AUC0_72) in plasma were around 1.6 times higher than those in
whole blood.
[00310] The mean percent total radioactivity concentrations associated with
erythrocytes
relative to whole blood ranged from 0.174 4.51 to 12.3 3.71 within 72
hours after single
dosing, indicating that radioactivity was present primarily in plasma and not
markedly
associated with red blood cells.
[00311] XL184 was rapidly absorbed after oral administration and eliminated
relatively
slowly. The main circulating metabolite in plasma was 6-Demethyl Half-Dimer
Sulfate.
Following a single oral dose, the mean peak concentrations of XL184 and
metabolites
XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer
Sulfate in
plasma by LC/MS/MS method were achieved at approximately 1.49, 18.99, 13.50,
24.00, and
168.00 hours (median) with a mean maximum concentration value (Cmax) of 1250,
52.9, 118,
236, and 230 ng/mL, respectively. The mean estimated elimination half-lives of
XL184,
XL184-Half-Dimer, XL184-N-Oxide, and XL184-Sulfate were 102, 91.8, 89.2, and
86.0
hours, respectively. However, the elimination half-lives of 6-Demethyl Half-
Dimer Sulfate
for all the subjects could not be determined. Para-fluoroaniline (pFA)
metabolite
concentrations were below the LLOQ for all subjects.
[00312] For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-
Demethyl Half-Dimer Sulfate, the mean metabolite exposure ratios relative to
parent XL184
(AUCot (metabolite)/ AUCot (parent)) by LC/MS/MS method were 9.93%, 15.0%,
42.9%,
and 150%, respectively. Mean exposure ratios for parent and metabolites XL184-
Half-

CA 03065560 2019-11-28
WO 2018/227119 PCT/US2018/036703
Dimer, XL184-N-Oxide, XL184-Sulfate, and 6-Demethyl Half-Dimer Sulfate
relative to total
exposure (AUCot (each analyte)/ AUC04 (parent+4 measured metabolites)) were
32.4%,
3.09%, 4.90%, 13.8%, and 45.9%, respectively.
[00313] Following a single oral dose, the median peak concentrations of XL184,
XL184-
Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5,
and P7 in
plasma using a radio-quantitative method were achieved at approximately 1.99,
1.49, 2.00,
4.50, 71.99, 2.00, and 2.00 hours with a mean maximum concentration value (C.)
of 1080,
210, 299, 649, 379, 194, and 95.3 ngEq/mL, respectively. The mean estimated
elimination
half-lives of XL184, XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, and P5
were
70.5, 57.9, 73.1, 79.2, and 73.4 hours, respectively
[00314] For metabolites XL184-Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-
Demethyl Half-Dimer Sulfate, P5, and P7, the mean metabolite exposure ratios
relative to
parent XL184 (AUCot (metabolite)/ AUCot (parent)) were 34.4%, 34.1%, 188%,
283%,
24.5%, and 1.54%, respectively. Mean exposure ratios for parent and
metabolites XL184-
Half-Dimer, XL184-N-Oxide, XL184-Sulfate, 6-Demethyl Half-Dimer Sulfate, P5,
and P7
relative to total exposure (AUCot (each analyte)/ AUC04 (parent + measured
metabolites)
were 20.0%, 6.25%, 7.16%, 37.6%, 40.3%, 4.10%, and 0.386%, respectively.
[00315] The results of the mean metabolite exposure ratios relative to parent
XL184
(AUCot (metabolite)/ AUCot (parent)) and the mean exposure ratios for parent
and
metabolites relative to total exposure (AUCot (each analyte)/ AUC04 (parent +
measured
metabolites) between LC/MS/MS and the radio-quantitative method are different
since they
are two different methods. LC/MS/MS was a validated method (except for 6-
Demethyl Half-
Dimer Sulfate) and was run under the GLP environment in this study. On the
contrary, the
radio-quantitative method was not a validated method and was run under the non-
GLP
environment in this study.
61

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[00316] Table 16. Individual Urine Cumulative Excretion of "C Total
Radioactivity
Following Administration of a Single 175 mg Oral Administration of XL184 (L-
Malate
Salt) Containing 1'4C1-XL184 (100 luCi) to Healthy Male Subjects
Subject
Summary Statistics
Time Time
Post-dose Interval 1444- 1444- 1444- 1444- 1444- 1444- 1444-
(Day) (hrs) 1010 1444-1023 1040 1042 1051 1052
1057 1058 Mean SD CV%
0.33 8 0.75 1.29 1.08 2.31 1.56 1.08 1.38
1.24 1.34 0.46 34
1 24 2.32 4.30 3.22 7.81 3.81 3.89 4.78
3.38 4.19 1.64 39
2 48
4.70 8.75 6.39 14.86 7.68 8.34 9.68 7.07 8.43 3.01 36
3 72
7.26 13.09 9.22 20.34 11.00 12.23 13.67 9.75 12.07 3.96 33
4 96
9.65 16.19 11.53 24.39 13.47 15.11 16.57 12.11 14.88 4.52 30
120 11.74 18.60 13.44 27.04 15.59 17.46 18.91 13.86 17.08 4.77 28
6 144
13.48 20.51 14.81 28.88 16.94 19.11 20.68 15.33 18.72 4.90 26
7 168
15.03 22.11 15.82 30.27 18.00 20.49 22.01 16.62 20.04 4.95 25
8 192
16.27 23.34 16.60 31.32 19.36 21.56 23.11 18.17 21.22 4.91 23
9 216
17.35 24.24 17.22 32.02 20.33 22.44 23.99 19.02 22.08 4.86 22
240 18.26
25.17 17.67 32.59 21.12 23.24 24.71 19.68 22.81 4.85 21
11 264
19.07 25.95 18.05 32.99 21.78 24.03 25.27 20.23 23.42 4.82 21
12 288
19.85 26.61 18.34 33.28 22.27 24.73 25.73 20.71 23.94 4.77 20
13 312
20.51 27.11 18.55 33.54 22.61 25.24 26.07 21.05 24.34 4.75 20
14 336
21.13 27.58 18.73 33.74 23.12 25.70 26.34 21.33 24.71 4.72 19
360 21.69
27.98 18.88 33.91 23.45 26.14 26.60 21.59 25.03 4.70 19
16 384
22.15 28.33 18.98 34.05 23.85 26.49 26.82 21.79 25.31 4.69 19
17 408
22.54 28.64 19.08 34.16 24.21 26.80 26.99 21.96 25.55 4.67 18
18 432
22.89 28.85 19.16 34.24 24.52 27.05 27.13 22.12 25.75 4.65 18
19 456
23.22 29.10 19.23 34.32 24.81 27.28 27.25 22.24 25.93 4.65 18
480 23.48
29.30 19.29 34.38 25.04 27.46 27.34 22.34 26.08 4.64 18
23 504 - 552 24.15 29.80 19.40 34.51 25.59
27.94 27.56 22.57 26.44 4.64 18
26 576 -624 24.69 30.14 19.49 34.62 25.98
28.27 27.71 22.74 26.71 4.63 17
29 648 -696 25.11 30.38 19.55 34.68 26.26 28.49
27.81 22.85 26.89 4.63 17
32 720 - 768 25.36 30.54 19.59 34.73 26.46
28.64 27.88 22.93 27.02 4.63 17
35 792 - 840 25.52 30.67 19.61 34.77 26.61 28.77
27.94 22.99 27.11 4.64 17
38 864 - 912 25.56 30.76 19.63 34.81 26.72
28.86 27.98 23.04 27.17 4.65 17
41 936 - 984 25.56 30.84 19.65 34.83 26.80
28.92 28.02 23.07 27.21 4.66 17
44 1008 - 1056 25.56 30.90 19.78 34.85
26.86 28.98 28.04 23.11 27.26 4.64 17
47 1080 - 1128 25.56 30.95 19.78 34.88
26.91 29.02 28.07 23.13 27.29 4.65 17
48
1152 25.56 30.97 19.78 34.88 26.92 29.03 28.07 23.14 27.29 4.65 17
62

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[00317] Table 17. Individual Feces Cumulative Excretion of "C Total
Radioactivity
Following Administration of a Single 175 mg Oral Administration of 1"C1-XL184
(100 pCi) to Healthy Male Subjects
Summary
Subject
Statistics
Time Time
Post-dose Interval 1444- 1444- 1444- 1444- 1444- 1444- 1444- 1444-
(Day) (hrs) 1010 1023 1040 1042 1051 1052 1057 1058 Mean SD CV%
1 24.00 0.00 1.51 0.00 0.00 7.27 0.00 0.00 6.55
1.92 3.13 163
2 48.00 2.41 4.69 6.21 13.42 13.75 0.00 0.00
23.82 8.04 8.33 104
3 72.00
17.54 11.89 19.42 23.50 19.09 6.71 20.02 27.89 18.26 6.54 36
4 96.00
29.54 15.75 26.66 23.50 24.06 21.44 20.02 33.67 24.33 5.62 23
120.00 29.54 26.82 38.33 33.66 30.04 21.44 32.13 38.11 31.26 5.66 18
6 144.00
29.54 32.95 42.31 33.66 32.58 34.95 32.13 40.73 34.86 4.41 13
7 168.00
37.33 35.74 46.15 37.83 35.24 34.95 39.21 42.53 38.62 3.92 10
8 192.00
37.33 38.12 50.16 37.83 35.24 42.36 39.21 46.78 40.88 5.17 13
9 216.00
38.43 40.65 52.52 41.88 39.09 42.36 44.88 47.60 43.43 4.74 11
240.00 40.55 40.97 53.88 41.88 40.04 42.36 44.88 49.11 44.21 4.90 11
11 264.00
40.55 42.16 56.19 44.05 41.53 42.36 47.81 51.46 45.76 5.58 12
12 288.00
43.16 45.59 57.02 44.05 43.34 46.17 47.81 51.70 47.36 4.81 10
13 312.00
43.16 45.85 58.37 44.65 43.60 46.17 49.96 53.34 48.14 5.37 11
14 336.00
44.52 46.96 58.62 44.65 45.13 47.75 49.96 54.31 48.99 5.09 10
360.00 46.60 47.74 59.19 44.65 45.47 47.75 50.79 54.76 49.62 5.03 10
16 384.00
48.10 48.28 59.83 45.48 46.43 47.75 50.79 55.20 50.23 4.91 10
17 408.00
49.60 48.83 60.27 45.48 46.79 49.42 51.79 55.60 50.97 4.86 10
18 432.00
49.60 49.07 60.38 45.89 47.53 49.42 51.79 55.93 51.20 4.76 9
19 456.00
50.94 49.54 60.68 45.89 47.53 50.45 52.32 56.14 51.69 4.76 9
480.00 51.52 49.81 60.90 46.07 48.35 50.45 52.32 56.50 51.99 4.71 9
21 504.00
51.52 50.21 61.01 46.07 48.80 50.89 52.62 56.69 52.23 4.68 9
24 528 -576 52.49 50.91 61.34 46.17 49.60 51.46
52.95 57.04 52.75 4.64 9
27 600 -648 52.58 51.55 61.60 46.35 49.90 51.79
53.09 57.29 53.02 4.63 9
672 -720 53.58 51.77 61.75 46.44 50.45 52.07 53.29
57.46 53.35 4.60 9
33 744 -792 54.17 52.00 61.82 46.48 50.76 52.56
53.41 57.56 53.60 4.57 9
36 816 - 864 54.27 52.19 61.89 46.48 50.95 52.56
53.45 57.67 53.68 4.57 9
39 888 -936 54.27 52.30 61.89 46.54 51.11 52.71
53.45 57.67 53.74 4.54 8
42 960- 1008 54.27 52.41 61.89 46.54 51.22 52.81
53.45 57.67 53.78 4.52 8
45 1032 -1080 54.27 52.41 61.89 46.54 51.22 52.89
53.45 57.67 53.79 4.52 8
48 1104 -1152 54.27 52.41 61.89 46.54 51.22 52.89
53.45 57.67 53.79 4.52 8
63

CA 03065560 2019-11-28
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[00318] Table 18. Individual and Mean ( SD) Total Cumulative Recoveries of
XL184 Following Administration of a Single 175 mg Oral Administration of XL184
(L-
Malate Salt) Containing 1'4C1-XL184 (100 ftCi) to Healthy Male Subjects
%Dose Administered
Subject Urine Feces Total
1444-1010 25.56 54.27 79.83
1444-1023 30.97 52.41 83.38
1444-1040 19.78 61.89 81.67
1444-1042 34.88 46.54 81.42
1444-1051 26.92 51.22 78.14
1444-1052 29.03 52.89 81.92
1444-1057 28.07 53.45 81.52
1444-1058 23.14 57.67 80.81
8 8 8
Mean 27.29 53.79 81.09
SD 4.65 4.52 1.56
SE 1.65 1.60 0.55
Min 19.78 46.54 78.14
Median 27.50 53.17 81.47
Max 34.88 61.89 83.38
CV% 17 8 2
Geometric Mean 26.94 53.63 81.07
64

[00319] Table 19. Individual and Mean Plasma "C Total
Radioactivity (ngEq/mL) Following a Single 175 mg Oral
Administration of XL184 (L-Malate Salt) Containing 114C1-XL184 (100 pCi) to
Healthy Male Subjects 0
Time (hours) n.)
o
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00 1--,
00
1444-1010 0.00 575.58 1170.98 1151.99 957.10
1166.03 828.28 562.37 625.13 1156.95
n.)
1444-1023 0.00 637.52 1307.24 1619.39 1679.68
1583.06 1398.91 1100.79 1072.71 1415.42 --.1
1--,
1--,
1444-1040 0.00 552.46 1494.70 2134.69 2072.76
2093.40 1824.19 1334.49 1493.87 1889.43 o
1444-1042 0.00 145.34 1165.20 2318.85 2358.48
2384.91 1938.98 1178.42 1366.70 2109.92
1444-1051 0.00 733.31 1703.63 1744.92 1535.99
1426.16 1209.80 926.55 949.67 1166.03
1444-1052 0.00 477.31 1296.51 2113.22 2389.04
1850.62 1538.47 1157.77 1204.02 1458.36
1444-1057 0.00 1003.35 2068.63 2189.20 1814.28
1859.70 1397.25 1177.59 1267.60 1455.06
1444-1058 0.00 677.98 1797.77 2277.56 1733.35
1788.68 1136.30 1383.22 1077.67 1461.67
N 8 8 8 8 8 8
8 8 8 8
Mean 0.00 600.36 1500.58 1943.73 1817.59
1769.07 1409.02 1102.65 1132.17 1514.11
SD 0.00 242.77 327.85 405.18 467.53
380.89 362.84 259.06 268.92 330.29
SEM 0.00 85.83 115.91 143.25 165.30 134.67
128.28 91.59 95.08 116.78 P
Min 0.00 145.34 1165.20 1151.99 957.10
1166.03 828.28 562.37 625.13 1156.95 .
Median 0.00 606.55 1400.97 2123.96 1773.82
1819.65 1398.08 1167.68 1140.85 1456.71 u,
u,
o .
vi Max 0.00 1003.35 2068.63 2318.85 2389.04
2384.91 1938.98 1383.22 1493.87 2109.92 .
%CV NA 40 22 21 26 22
26 23 24 22
,
GM NA 537.97 1470.80 1899.92 1756.69
1731.81 1365.83 1068.66 1099.67 1484.70 .
,
,
,
, GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL! 84
freebase required to produce a measured or calculated amount of total
radioactivity;
.3
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00320] Table 19A. Individual and Mean Plasma "C Total
Radioactivity (ngEq/mL) Following a Single 175 mg
0
Oral Administration of XL184 (L-Malate Salt) Containing 114C1-XL184 (100 pCi)
to Healthy Male Subjects t..)
o
,-,
oe
Time (hours)
n.)
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00 --4
1-,
1-,
1444-1010 663.12 694.50 539.25 470.71 454.19
305.55 245.26 206.45 156.90 99.10 vD
1444-1023 1130.52 861.31 610.27 561.54
516.95 317.93 202.32 165.16 125.52 94.14
1444-1040 1401.38 919.12 572.28 540.07
478.14 223.79 132.95 0.00 0.00 0.00
1444-1042 1689.59 1305.59 665.59 580.54
528.51 351.79 205.62 177.55 144.52 111.48
1444-1051 1131.35 913.33 618.52 537.60
535.94 371.61 248.57 206.45 146.99 130.48
1444-1052 1080.15 861.31 606.96 579.71
494.65 402.16 307.20 227.92 184.15 151.95
1444-1057 986.01 858.83 580.54 518.60 443.45
289.86 200.67 144.52 114.79 91.66
1444-1058 1392.30 1414.60 888.56 796.90
644.12 430.24 317.11 237.83 199.84 149.47
N 8 8 8 8 8 8
8 8 8 8
Mean 1184.30 978.57 635.25 573.21 511.99 336.62
232.46 170.74 134.09 103.54 P
SD 310.11 247.09 108.87 97.19 63.04
66.27 60.61 75.82 61.00 48.12
SEM 109.64 87.36 38.49 34.36 22.29 23.43 21.43 26.81
21.57 17.01 u,
u,
o,
.
o, Min 663.12 694.50 539.25 470.71 443.45
223.79 132.95 0.00 0.00 0.00 .
r.,
Median 1130.94 887.32 608.62 550.81
505.80 334.86 225.44 192.00 145.76 105.29 .
,
Max 1689.59 1414.60 888.56 796.90 644.12 430.24
317.11 237.83 199.84 151.95 ,
,
,
%CV 26 25 17 17 12 20 26 44
45 46 ,
r.,
.3
GM 1146.14 953.99 628.27 566.94
508.82 330.55 225.10 NA NA NA
GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL184
freebase required to produce a measured or calculated amount of total
radioactivity.
IV
n
,-i
cp
t..)
=
oe
-a,
c,
-4
=
c,.,

CA 03065560 2019-11-28
WO 2018/227119
PCT/US2018/036703
[00321] Table
20. Individual and Mean Whole Blood 14C Total Radioactivity
(ngEq/mL) Following a Single 175 mg Oral Administration of XL184 (L-Malate
Salt)
Containing 114C1-XL184 (100 ftCi) to Healthy Male Subjects
Time (hours)
Subject 0.00 1.00 2.00 4.00 8.00 14.00 24.00 72.00
1444-1010 0.00 717.47 763.98 742.45 395.34 432.38 701.11 452.19
1444-1023 0.00 839.78 998.26 928.49 647.70 695.94 764.84 503.00
1444-1040 0.00 916.43 1309.19 1303.16 873.37 908.68 986.20 540.04
1444-1042 0.00 776.04 1536.58 1458.20 813.08 941.41 1196.36 845.81
1444-1051 0.00 952.61 1077.50 879.40 620.14 624.45 692.49 562.44
1444-1052 0.00 817.38 1260.96 1162.77 799.30 744.17 883.70 510.76
1444-1057 0.00 1137.79 1222.20 1056.83 708.86 769.15 786.38 450.46
1444-1058 0.00 1136.07 1389.29 1048.21 821.69 720.05 854.42 764.84
8 8 8 8 8 8 8 8
Mean 0.00 911.70 1194.75 1072.44 709.94 729.53 858.19 578.69
SD 0.00 157.37 242.26 232.35 155.26 160.06 167.93 146.65
SEM 0.00 55.64 85.65 82.15 54.89 56.59 59.37 51.85
Min 0.00 717.47 763.98 742.45 395.34 432.38 692.49 450.46
Median 0.00 878.11 1241.58 1052.52 754.08 732.11 820.40 525.40
Max 0.00 1137.79 1536.58 1458.20 873.37 941.41 1196.36 845.81
%CV NA 17 20 22 22 22 20 25
GM NA 900.21 1171.16 1050.57 691.86 712.27 845.09 564.30
GM: Geometric Mean; NA: not applicable; ngEq, an equivalent amount of XL184
freebase required to
produce a measured or calculated amount of total radioactivity
67

[00322] Table 21. Individual and Mean Hematocrit Value
0
cio
Hematocrit
CYO
Subject Day -1 Day 2 Day 4
Mean
1444-1010 40.8 41.1 39.7
40.5
1444-1023 44.6 45.7 44.2
44.8
1444-1040 41.8 44.3 42.5
42.9
1444-1042 41.7 42.0 44.6
42.8
1444-1051 42.6 41.9 42.2
42.2
1444-1052 43.9 42.5 42.0
42.8
1444-1057 48.2 46.6 46.3
47.0 P
1444-1058 42.6 41.9 42.2
42.2
1444-1010 43.5 41.8 42.4
42.6
cioo

[00323] Table 22. Individual and Descriptive Statistics of the
Percentage of "C Radioactivity Associated with
Erythrocytes in Whole Blood (ETR) over Time Following a Single 175 mg Oral
Administration of XL184 (L-Malate Salt) 0
tµ.)
Containing 114C1-XL184 (100 uCi) to Healthy Male Subjects
o
,-,
oe
Time (hours)
t.)
Subject 1.00 2.00 4.00 8.00
14.00 24.00 72.00 -4
1-,
1-,
1444-1010 2.89 10.3 6.55 15.4
14.0 1.81 8.62
1444-1023 14.1 10.5 5.88 6.19
14.9 -2.15 5.48
1444-1040 6.87 6.90 8.27 12.8
6.13 -9.40 2.82
1444-1042 14.1 13.7 6.45 17.1
17.0 -0.88 11.7
1444-1051 -3.37 6.40 6.26 13.6
12.1 2.68 6.14
1444-1052 9.27 4.14 8.96 17.2
7.45 5.60 3.54
1444-1057 3.64 5.07 6.74 12.0
12.7 1.93 -1.05
1444-1058 9.17 5.90 2.05 3.37
14.1 1.80 -6.16
N 8 8 8 8 8
8 8 P
Mean 7.08 7.85 6.40 12.2
12.3 0.174 3.89 2
.9
SD 5.93 3.27 2.05 5.00
3.71 4.51 5.58 &
c:
SEM 2.10 1.16 0.725 1.77
1.31 1.59 1.97 o'
Min -3.4 4.1 2.1 3.4
6.1 -9.4 -6.2
Median 8.0 6.7 6.5 13 13
1.8 4.5 ,
,
Max 14 14 9.0 17 17
5.6 12
%CV 84 42 32 41 30
2595 143
GM NA 7.30 5.96 10.9
11.7 NA NA
ETR=Xe/Xb=1-[Cpx(1-Hct)/Cb], where Cp stands for concentration of
radioactivity in plasma, Cb stands for concentration of radioactivity in blood
and Hct
stands for hemocrit value.
Hematocrit values for Days -1, 2, and 4 were averaged for use in this
calculation. GM: geometric me
IV
n
,-i
cp
,..,
=
c,
-a-,
c,
-4
=
,,,

[00324] Table 23. Individual Subject Actual Blood Sampling
Times for Plasma for Total Radioactivity and for
Pharmaco*kinetic Analysis of XL184 and Its Metabolites Following a Single 175
mg Oral Administration of XL184 (L-Malate 0
t..)
Salt) Containing 1'4C1-XL184 (100 pCi) to Healthy Male Subjects o
,-,
cio
t..)
0-24 hrs
-4
,-,
,-,
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00
1444-1010 0.00 0.50 1.00 2.00 3.00 4.00
5.00 7.98 13.98 24.00
1444-1023 0.00 0.50 1.00 1.98 3.00 4.00
5.00 7.98 13.98 24.00
1444-1040 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.03
1444-1042 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 13.98 24.03
1444-1051 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 13.98 24.08
1444-1052 0.00 0.50 1.00 1.98 3.00 4.00
5.00 8.00 14.00 24.10
1444-1057 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.08 P
1444-1058 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 23.68
u,
u,
o .
r.,
48-648 hrs
,
,
,
,
,
Time (hours)
.3
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00
1444-1010 48.03 72.00 120.00 144.00 168.00
240.00 336.00 407.98 504.00 648.00
1444-1023 48.00 72.00 120.00 144.00 168.00
239.98 336.00 407.98 504.00 648.00
1444-1040 48.00 72.00 120.00 143.98 168.00
240.00 336.00 408.00 503.98 648.00
1444-1042 48.00 71.97 120.00 143.98 168.00
240.00 336.00 407.98 503.98 648.00
1444-1051 48.00 71.98 120.00 144.00 167.98
240.00 336.00 407.98 503.98 647.98
1444-1052 48.00 71.98 120.00 143.98 168.00
240.00 335.87 407.98 503.98 648.00
Iv
1444-1057 48.00 71.98 120.00 144.00 168.00
240.00 335.95 407.98 503.98 647.98 n
1444-1058 48.00 72.00 119.98 143.98 168.00
240.00 336.00 407.98 503.98 648.00 1-3
cp
i.)
o
1-,
cio
-a,
-4
=
c,.,

[00325] Table 24. Individual Subject Actual Blood Sampling
Times for Whole Blood Analysis of Total
Radioactivity Following a Single 175 mg Oral Administration of XL184 (L-Malate
Salt) Containing 1'4C1-XL184 (100 uCi) to 0
t..)
Healthy Male Subjects
o
,-,
cio
t..)
Time (hours)
--.1
1--,
Subject 0.00 1.00 2.00 4.00 8.00
14.00 24.00 72.00 1--,
o
1444-1010 0.00 1.00 2.00 4.00 7.98
13.98 24.00 72.00
1444-1023 0.00 1.00 1.98 4.00 7.98
13.98 24.00 72.00
1444-1040 0.00 1.00 2.00 4.00 8.00
14.00 24.03 72.00
1444-1042 0.00 1.00 2.00 4.00 8.00
13.98 24.03 71.97
1444-1051 0.00 1.00 2.00 4.00 8.00
13.98 24.08 71.98
1444-1052 0.00 1.00 1.98 4.00 8.00
14.00 24.10 71.98
1444-1057 0.00 1.00 2.00 4.00 8.00
14.00 24.08 71.98
1444-1058 0.00 1.00 2.00 4.00 8.00
14.00 23.68 72.00
P
.
.
--4
.
,-, [00326] Table 25. Individual Subject Actual Blood Sampling
Times for Plasma for Possible Metabolic .
rõ
Profiling Following a Single 175 mg Oral Administration of XL184 (L-Malate
Salt) Containing 1HC1-XL184 (100 uCi) to ,
,
Healthy Male Subjects
,
,
,
rõ
.3
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.00 72.00 168.00
336.00 504.00 648.00
1444-1010 0.00 0.50 1.00 2.00 3.00 4.00 5.00 7.98 13.98 24.00 72.00 168.00
336.00 504.00 648.00
1444-1023 0.00 0.50 1.00 1.98 3.00 4.00 5.00 7.98 13.98 24.00 72.00 168.00
336.00 504.00 648.00
1444-1040 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.03 72.00 168.00
336.00 503.98 648.00
1444-1042 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.03 71.97 168.00
336.00 503.98 648.00
1444-1051 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 13.98 24.08 71.98 167.98
336.00 503.98 647.98 IV
1444-1052 0.00 0.50 1.00 1.98 3.00 4.00 5.00 8.00 14.00 24.10 71.98 168.00
335.87 503.98 648.00 n
1-3
1444-1057 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 24.08 71.98 168.00
335.95 503.98 647.98
1444-1058 0.00 0.50 1.00 2.00 3.00 4.00 5.00 8.00 14.00 23.68 72.00 168.00
336.00 503.98 648.00 cp
n.)
o
1--,
oo
-a,
-4
=
c,.,

CA 03065560 2019-11-28
WO 2018/227119 PCT/US2018/036703
[00327] Table 26. Individual and Descriptive Statistics of Plasma
Pharmaco*kinetic
Parameters of Total Radioactivity Following a Single 175 mg Oral
Administration of
XL184 (L-Malate Salt) Containing 114C1-XL184 (100 uCi) to Healthy Male
Subjects
Cmax tmax AUC0-1 AUC0-24 AUC0-72 AUCO-inf kel
tVa
Subject _ID (ngEq/mL) (h) (h=ngEq/mL) (h=ngEq/mL) (h=ngEq/mL) (h=ngEq/mL)
(1/h) (h)
1444-1010 1170 1.00 216000 19400 57600 249000 0.00307
226
1444-1023 1680 3.00 244000 29600 84000 283000 0.00246
282
1444-1040 2130 2.00 210000 38700 106000 228000 0.00741
93.5
1444-1042 2380 4.00 302000 38700 120000 359000 0.00197
352
1444-1051 1740 2.00 258000 26400 78500 299000 0.00317
218
1444-1052 2390 3.00 278000 32800 86500 333000 0.00278
250
1444-1057 2190 2.00 234000 33400 84900 283000 0.00187
371
1444-1058 2280 2.00 333000 32000 99900 410000 0.00194
357
N 8 8 8 8 8 8 8
8
Mean 2000 2.38 259000 31400 89700 306000 0.00308
269
SD 429 0.92 42700 6380 19000 59500 0.00182
93.2
SEM 152 0.32 15100 2260 6720
21000 0.000644 33.0
Min 1170 1.00 210000 19400 57600 228000 0.00187
93.5
Median 2160 2.00 251000 32400 85700 291000 0.00262
266
Max 2390 4.00 333000 38700 120000 410000 0.00741
371
%CV 21 39 16 20 21 19 59
35
GM 1950 2.21 256000 30700 87900 301000 0.00278
250
GM: Geometric Mean; C., maximum observed concentration; T., time of the
maximum
concentration;
AUCo-t, area under the concentration-time curve from time zero to the time of
the last measurable
concentration; AUCo-24, area under the concentration-time curve from time zero
to 24 hours post XL184
dose; AUC0_72, area under the concentration-time curve from time zero to 72
hours post XL184 dose;
AUCo.f, area under the concentration-time curve from time zero to infinity;
Ica apparent terminal
elimination rate constant; tin, apparent terminal elimination half-life; CL/F,
apparent total body clearance;
V/F, apparent total volume of distribution; ngEq, an equivalent amount of
XL184 freebase required to
produce a measured or calculated amount of total radioactivity.
72

[00328] Table 27. Individual and Descriptive Statistics of Whole Blood
Pharmaco*kinetic Parameters of Total
Radioactivity following a Single 175 mg Oral Administration of XL184 (L-Malate
Salt) Containing 1'4C1-XL184 (100 uCi) to 0
t,..)
Healthy Male Subjects
o
,-,
oe
iz..1
n.)
C max tmax AUC0-1 AUC0-24 AUC0-72
Ratio' Ratio' Ratio' Ratio' --.1
1¨,
Subject (ngEq/mL) (h) (IpngEq/mL) (IpngEq/mL) (IpngEq/mL)
(%) (%) (%) (%)
o
1444-1010 764 2.00 40700 13000 40700 153
531 149 142
1444-1023 998 1.98 48200 17800 48200 168
506 166 174
1444-1040 1310 2.00 60000 23400 60000 163
350 165 177
1444-1042 1540 2.00 74000 25000 74000 155
408 155 162
1444-1051 1080 2.00 46900 16800 46900 161
550 157 167
1444-1052 1260 1.98 54000 20600 54000 190
515 159 160
1444-1057 1220 2.00 49500 19800 49500 180
473 169 172
1444-1058 1390 2.00 59400 20500 59400 164
561 156 168
N 8 8 8 8 8 8
8 8 8 P
Mean 1200 2.00 54100 19600 54100 167
487 160 165 .
L.
SD 243 0.01 10300 3780 10300
12.4 73.3 6.65 11.1 .
SEM 85.9 0.00 3650 1340 3660
4.39 25.9 2.35 3.92 .
Min 764 1.98 40700 13000 40700 153
350 149 142
,
Median 1240 2.00 51800 20100 51800 163
511 158 168 .
,
,
Max 1540 2.00 74000 25000 74000 190
561 169 177 ,
,
r.,
%CV 20 0 19 19 19 7
15 4 7 .3
GM 1170 1.99 53300 19300 53300 166
481 159 165
GM: Geometric Mean; AUCo_inf, kel and t1/2 were not reportable since the value
of AUCO-t / AUCo_mfratio for each subject was <0.80; a, b, c and d: % ratio of
plasma to whole blood for C., AUCO-t, AUC0_24and AUG-72, respectively. C.,
maximum observed concentration; Tmax, time of the maximum
concentration; AUCO-t, area under the concentration-time curve from time zero
to the time of the last measurable concentration; AUCO-24, area under the
concentration-time curve from time zero to 24 hours post XL184 dose; AUG-72,
area under the concentration-time curve from time zero to 72 hours post
XL184 dose; AUCO-inf, area under the concentration-time curve from time zero
to infinity; kel, apparent terminal elimination rate constant; t1/2, apparent
terminal elimination half-life; CL/F, apparent total body clearance; V/F,
apparent total volume of distribution; ngEq, an equivalent amount of XL184
freebase
required to produce a measured or calculated amount of total radioactivity.
IV
r)
,-i
cp
t..,
=
1¨,
oe
C-5
o
--.1
o
c,.)

[00329] Table 28. Individual and Mean Plasma Concentrations
(ng/mL) of XL184 by LCAVISAVIS Method 0
Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to Healthy Male
cio
Subjects
0-24 hrs
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00
8.00 14.00 24.00
1444-1010 0.000 377.055 777.766 703.373 459.276 682.206 409.319 266.879
335.869 681.961
1444-1023 0.000 410.653 988.621 1026.742 1024.476 902.898 697.894 386.419
417.208 434.009
1444-1040 0.000 328.704 998.065 1441.786 1095.197 1063.173 970.873 687.933
487.884 860.448
1444-1042 0.000 59.305 914.945 1482.359 1310.794 1158.537 978.352 504.541
600.449 788.240
1444-1051 0.000 509.883 1240.897 953.447 793.118
732.686 547.741 382.217 366.964 435.770
1444-1052 0.000 350.200 841.426 1093.027 1319.899 1019.020 729.002 529.976
486.724 504.273
1444-1057 0.000 760.436 1403.846 1237.637 902.344 1025.043 700.088 531.908
523.762 547.776
1444-1058 0.000 488.450 1344.723 1241.830 889.579 844.899 513.445 700.302
397.419 534.139
8 8 8 8 8 8 8
8 8 8
Mean 0.000 410.586 1063.786 1147.525 974.335 928.558
693.339 498.772 452.035 598.327
SD 0.000 197.553 235.829 258.626 282.901
166.997 204.878 150.468 88.307 160.675
SEM 0.000 69.846 83.378 91.438 100.021 59.042
72.435 53.198 31.221 56.807
Min 0.000 59.305 777.766 703.373 459.276 682.206
409.319 266.879 335.869 434.009
Median 0.000 393.854 993.343 1165.332 963.410
960.959 698.991 517.259 451.966 540.958
Max 0.000 760.436 1403.846 1482.359 1319.899
1158.537 978.352 700.302 600.449 860.448
%CV NA 48 22 23 29 18 30 30
20 27
GM NA 344.890 1041.459 1119.787 931.654
914.828 666.511 477.461 444.581 580.567
NA: Not Applicable; GM: Geometric Mean

[00330] Table 28A. Individual and Mean Plasma Concentrations
(ng/mL) of XL184 by LCAVISAVIS Method
Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to Healthy Male 0
Subjects
48-648 hrs
Time (hours)
Subject 48.00 72.00 120.00 144.00 168.00 240.00
336.00 408.00 504.00 648.00
1444-1010 283.853 254.530 156.488 122.688 163.095
90.153 65.102 43.328 27.834 10.464
1444-1023 333.638 255.041 147.087 145.915 135.606
49.766 35.903 21.636 13.009 6.311
1444-1040 489.217 246.732 179.421 172.821 134.168
55.790 24.788 10.908 5.771 2.424
1444-1042 614.498 411.177 148.076 107.202 75.695
39.898 10.711 4.879 1.968 0.000
1444-1051 424.868 305.315 154.063 125.163 121.433
71.462 39.049 25.305 14.396 8.189
1444-1052 352.213 255.189 118.584 114.427 97.118
65.257 38.068 17.412 11.462 3.790
1444-1057 307.958 244.280 113.195 116.918 92.425
44.384 19.250 10.002 3.954 2.050
1444-1058 516.059 418.464 184.363 162.622 115.395
61.247 24.467 10.756 6.704 2.270
8 8 8 8 8 8 8
8 8 8
Mean 415.288 298.841 150.160 133.470 116.867
59.745 32.167 18.028 10.637 4.437
SD 116.396 74.114 25.238 24.098 28.013 16.211
16.569 12.232 8.239 3.555
SEM 41.152 26.203 8.923 8.520 9.904 5.732
5.858 4.325 2.913 1.257
Min 283.853 244.280 113.195 107.202 75.695 39.898
10.711 4.879 1.968 0.000
Median 388.541 255.115 151.070 123.926 118.414
58.519 30.346 14.160 9.083 3.107
Max 614.498 418.464 184.363 172.821 163.095 90.153
65.102 43.328 27.834 10.464
%CV 28 25 17 18 24 27 52
68 77 80
GM 401.634 291.722 148.236 131.665 113.863 57.917
28.494 14.850 8.070 NA
NA: Not Applicable; GM: Geometric Mean
oe

[00331] Table 29. Individual and Mean Plasma
Concentrations (ng/mL) of XL184 Half-Dimer by LCAVISAVIS
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to 0
t..)
o
Healthy Male Subjects
,--,
cio
i:.)=-=
t..)
0-24 hrs
-4
,-,
,-,
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00
1444-1010 0.000 4.846 13.450 23.314 24.221
27.171 24.260 22.875 31.511 35.627
1444-1023 0.000 4.593 17.564 31.523 33.843
34.651 35.617 38.445 37.909 37.924
1444-1040 0.000 4.531 14.478 27.120 29.439
32.345 32.584 28.090 34.054 35.050
1444-1042 0.000 0.000 17.132 43.143 52.416
54.336 76.749 63.237 68.777 75.680
1444-1051 0.000 4.356 17.489 28.961 31.495
36.085 36.373 38.175 40.841 35.055
1444-1052 0.000 4.261 21.194 35.430 44.061
49.890 55.705 63.530 65.263 67.985
1444-1057 0.000 8.367 24.937 37.927 38.602
51.831 50.493 57.434 69.700 69.776 P
1444-1058 0.000 6.794 23.881 35.764 38.359
42.571 43.260 58.592 47.769 56.247
N 8 8 8 8 8 8
8 8 8 8 u,
u,
o, Mean 0.000 4.719 18.766 32.898 36.555
41.110 44.380 46.297 49.478 51.668 .
r.,
SD 0.000 2.399 4.184 6.409 8.873 10.051
16.473 16.331 16.047 17.688 .
,
, SEM 0.000 0.848 1.479 2.266 3.137 3.554 5.824 5.774
5.674 6.254 ,
,
, Min 0.000 0.000 13.450 23.314 24.221 27.171 24.260
22.875 31.511 35.050
.3
Median 0.000 4.562 17.527 33.477 36.101
39.328 39.817 47.940 44.305 47.086
Max 0.000 8.367 24.937 43.143 52.416 54.336 76.749
63.530 69.700 75.680
%CV NA 51 22 19 24 24 37 35
32 34
GM NA NA 18.364 32.341 35.633 40.015 41.935
43.470 47.247 49.053
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00332] Table 29A. Individual and Mean Plasma
Concentrations (ng/mL) of XL184 Half-Dimer by LCAVISAVIS
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to 0
t..)
Healthy Male Subjects
o
,-,
cio
i:.)=-=
t..)
48-648 hrs
-4
,-,
,-,
Time (hours)
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00
1444-1010 30.648 24.554 18.190 14.057 11.729
7.495 5.228 2.998 2.084 0.000
1444-1023 36.546 24.587 16.438 15.153 12.065
5.903 2.034 1.806 1.083 0.000
1444-1040 26.242 19.464 11.095 9.729 8.353
2.927 1.209 0.000 0.000 0.000
1444-1042 56.997 42.700 17.753 13.747 9.922
4.398 1.547 0.000 0.000 0.000
1444-1051 33.055 23.197 13.375 11.927 12.076
7.066 3.887 2.509 1.813 0.000
1444-1052 56.829 46.257 21.732 19.455 16.224
8.332 5.513 2.769 1.445 0.000
1444-1057 53.673 44.053 23.839 20.401 17.365
7.257 3.352 2.045 0.000 0.000 P
1444-1058 48.913 35.430 25.809 23.143 16.260
8.677 3.578 1.740 0.000 0.000
N 8 8 8 8 8 8
8 8 8 8 u,
u,
--.1
.
--.1 Mean 42.863 32.530 18.529 15.952 12.999
6.507 3.294 1.733 0.803 0.000 .
r.,
SD 12.592 10.807 5.048 4.595 3.262 1.983
1.607 1.158 0.905 0.000 .
,
, SEM 4.452 3.821 1.785 1.625 1.153 0.701 0.568
0.409 0.320 0.000 ,
,
, Min 26.242 19.464 11.095 9.729 8.353 2.927 1.209
0.000 0.000 0.000
.3
Median 42.730 30.009 17.972 14.605 12.071
7.162 3.465 1.926 0.542 0.000
Max 56.997 46.257 25.809 23.143 17.365 8.677 5.513
2.998 2.084 0.000
%CV 29 33 27 29 25 30 49 67
113 NA
GM 41.175 30.943 17.899 15.374 12.633
6.174 2.908 NA NA NA
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00333] Table 30. Individual and Mean Plasma
Concentrations (ng/mL) of XL184-N-Oxide by LCAVISAVIS 0
t..)
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to
,-,
cio
Healthy Male Subjects
t..)
-4
,-,
0-24 hrs
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00
1444-1010 0.000 11.529 42.306 49.777 46.221
57.466 38.445 33.122 25.454 64.769
1444-1023 0.000 15.944 47.387 65.128 82.005
78.375 78.220 67.430 63.633 101.490
1444-1040 0.000 17.041 82.525 149.634 167.092
150.220 135.223 125.712 140.835 178.702
1444-1042 0.000 1.789 40.311 104.019 108.484
115.106 103.517 66.642 73.090 129.577
1444-1051 0.000 13.441 67.257 94.858 92.250
91.248 79.258 68.805 66.930 84.372
1444-1052 0.000 14.585 67.753 103.201 134.615
124.375 89.247 85.963 71.593 84.326 P
1444-1057 0.000 27.247 92.619 113.541 90.538
111.017 86.573 79.003 80.870 93.700
1444-1058 0.000 20.854 97.364 128.577 118.153
125.842 88.903 115.660 68.937 113.468 u,
u,
--.1
.
cee N 8 8 8 8 8 8
8 8 8 8
r.,
Mean 0.000 15.304 67.190 101.092 104.920
106.706 87.423 80.292 73.918 106.301
,
' SD 0.000 7.346 22.445 32.172 36.397 29.586 26.993
29.414 31.759 35.266 ,
,
' SEM 0.000 2.597 7.935 11.375 12.868 10.460 9.543
10.400 11.229 12.468
.3
Min 0.000 1.789 40.311 49.777 46.221 57.466 38.445
33.122 25.454 64.769
Median 0.000 15.265 67.505 103.610 100.367
113.062 87.738 73.904 70.265 97.595
Max 0.000 27.247 97.364 149.634 167.092 150.220
135.223 125.712 140.835 178.702
%CV NA 48 33 32 35 28 31 37
43 33
GM NA 12.572 63.787 95.996 98.865 102.671 83.180
75.094 67.779 101.778
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00334] Table 30A. Individual and Mean Plasma
Concentrations (ng/mL) of XL184-N-Oxide by LCAVISAVIS
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to 0
t..)
o
Healthy Male Subjects
cio
i:.)=-=
t..)
48-648 hrs
-4
,-,
,-,
Time (hours)
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00
1444-1010 29.036 28.612 21.842 13.355 13.351
7.415 4.583 3.326 1.817 1.062
1444-1023 64.132 40.828 19.980 19.507 14.871
5.771 2.530 1.964 0.000 0.000
1444-1040 116.958 82.612 51.850 35.583
26.090 10.327 4.459 1.674 1.094 0.000
1444-1042 90.059 63.663 20.037 13.485 10.109
4.830 1.199 0.000 0.000 0.000
1444-1051 69.537 47.911 25.291 19.696 18.011
9.570 5.079 3.200 2.005 0.000
1444-1052 50.889 33.767 16.002 11.804 9.229
6.267 2.973 1.678 1.052 0.000
1444-1057 49.764 40.895 21.335 17.057 14.433
5.546 2.390 1.382 0.000 0.000 P
1444-1058 89.002 76.099 31.817 30.113 19.166
9.684 4.176 1.946 1.237 0.000
N 8 8 8 8 8 8
8 8 8 8 u,
u,
--4
.
vD Mean 69.922 51.798 26.019 20.075 15.658
7.426 3.424 1.896 0.901 0.133 .
r.,
SD 27.918 19.992 11.423 8.517 5.428
2.154 1.349 1.049 0.816 0.375 .
,
, SEM 9.870 7.068 4.039 3.011 1.919 0.761 0.477
0.371 0.289 0.133 ,
,
, Min 29.036 28.612 16.002 11.804 9.229 4.830 1.199
0.000 0.000 0.000
.3
Median 66.835 44.403 21.589 18.282 14.652
6.841 3.575 1.812 1.073 0.000
Max 116.958 82.612 51.850 35.583 26.090 10.327
5.079 3.326 2.005 1.062
%CV 40 39 44 42 35 29 39 55
91 283
GM 64.709 48.563 24.374 18.696 14.883 7.156 3.136
NA NA NA
NA: Not Applicable; GM: Geometric Mean
Iv
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00335] Table 31. Individual and Mean Plasma
Concentrations (ng/mL) of XL184-Sulfate by LCAVISAVIS 0
t..)
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to
,-,
cio
Healthy Male Subjects
t..)
-4
,-,
0-24 hrs
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00
1444-1010 0.000 26.136 53.208 75.013 69.493
92.232 65.650 37.746 34.395 112.189
1444-1023 0.000 39.062 88.742 138.826 158.824
179.491 172.724 130.798 131.091 233.292
1444-1040 0.000 45.896 145.829 249.626 310.748
267.057 283.604 197.270 268.052 306.497
1444-1042 0.000 6.360 78.291 157.511 203.331
205.443 243.196 98.885 127.544 287.276
1444-1051 0.000 29.730 96.816 126.368 141.682
148.181 125.679 108.976 133.704 174.720
1444-1052 0.000 32.267 120.212 157.200 194.021
215.476 174.760 143.215 153.538 205.532 P
1444-1057 0.000 59.658 156.410 180.378 187.282
226.697 174.947 159.230 198.553 262.691
1444-1058 0.000 43.796 143.662 181.953 231.546
216.139 162.694 204.329 153.379 289.913 u,
u,
oo
.
= N 8 8 8 8 8 8
8 8 8 8
r.,
Mean 0.000 35.363 110.396 158.359 187.116
193.840 175.407 135.056 150.032 234.014
,
' SD 0.000 15.828 36.898 50.320 69.969 53.659 66.538
54.506 66.343 66.769 ,
,
' SEM 0.000 5.596 13.045 17.791 24.738 18.971 23.525
19.271 23.456 23.606
.3
Min 0.000 6.360 53.208 75.013 69.493 92.232 65.650
37.746 34.395 112.189
Median 0.000 35.665 108.514 157.356 190.652
210.460 173.742 137.007 143.542 247.992
Max 0.000 59.658 156.410 249.626 310.748 267.057
283.604 204.329 268.052 306.497
%CV NA 45 33 32 37 28 38 40
44 29
GM NA 30.490 104.387 150.767 173.768 185.812
162.613 121.946 132.738 223.841
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00337] Table 31A. Individual and Mean Plasma
Concentrations (ng/mL) of XL184-Sulfate by LCAVISAVIS
Method Following a Single 175 mg Oral Administration of XL184 (L-Malate Salt)
Containing 1HC1-XL184 (100 pCi) to 0
t..)
o
Healthy Male Subjects
cio
i:.)=-=
t..)
48-648 hrs
-4
,-,
,-,
Time (hrs)
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00
1444-1010 45.563 50.547 46.211 27.744 23.691
11.649 8.367 5.228 0.000 0.000
1444-1023 146.630 132.711 90.680 85.890
73.594 26.053 9.824 5.311 0.000 0.000
1444-1040 230.932 198.580 156.507 125.712
112.019 47.012 18.863 9.010 4.723 0.000
1444-1042 220.082 185.825 81.561 61.841
46.492 21.297 5.717 0.000 0.000 0.000
1444-1051 176.870 152.441 95.518 73.454
73.048 36.170 20.502 13.626 7.874 4.167
1444-1052 130.352 106.815 47.419 37.916
27.883 16.190 10.596 4.971 0.000 0.000
1444-1057 147.459 151.276 89.982 80.113
61.829 30.106 11.580 6.347 0.000 0.000 P
1444-1058 258.933 211.280 149.901 151.619
97.444 49.589 22.349 8.128 4.996 0.000
N 8 8 8 8 8 8
8 8 8 8 u,
u,
1--, Mean 169.603 148.684 94.722 80.536
64.500 29.758 13.475 6.578 2.199 0.521
r.,
SD 67.915 52.708 40.823 41.620 31.252
13.782 6.195 3.916 3.175 1.473
,
' SEM 24.011 18.635 14.433 14.715 11.049 4.873 2.190
1.384 1.123 0.521 ,
,
' Min 45.563 50.547 46.211 27.744 23.691 11.649
5.717 0.000 0.000 0.000 N,
.3
Median 162.165 151.859 90.331 76.784
67.439 28.080 11.088 5.829 0.000 0.000
Max 258.933 211.280 156.507 151.619 112.019 49.589
22.349 13.626 7.874 4.167
%CV 40 35 43 52 48 46 46 60
144 283
GM 152.912 137.642 86.953 70.735 57.000 26.794 12.223
NA NA NA
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00338] Table 32. Individual and Mean Plasma
Concentrations (ng/mL) of 6-Demethyl Half-Dimer Sulfate by
LCAVISAVIS Method Following a Single 175 mg Oral Administration of XL184 (L-
Malate Salt) Containing 1HC1-XL184 0
t..)
(100 pCi) to Healthy Male Subjects
o
,-,
oe
i:.)=-=
t..)
0-24 hrs
-4
,-,
,-,
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00
5.00 8.00 14.00 24.00
1444-1010 0.000 0.000 0.000 0.000 3.386 5.641
8.608 15.507 34.150 51.405
1444-1023 0.000 0.000 0.000 2.592 6.599 11.121
15.479 32.187 47.455 99.900
1444-1040 0.000 0.000 0.000 0.000 2.692 3.416
6.003 10.485 18.220 27.408
1444-1042 0.000 0.000 0.000 2.376 6.406 11.906
19.210 40.794 76.906 141.432
1444-1051 0.000 0.000 0.000 2.132 5.610 8.166
12.887 24.346 50.905 71.492
1444-1052 0.000 0.000 0.000 0.000 3.763 6.466
10.265 23.612 54.607 79.917
1444-1057 0.000 0.000 0.000 0.000 3.139 5.576
8.199 17.826 44.580 71.085 P
1444-1058 0.000 0.000 0.000 2.672 6.542 10.442
16.258 31.365 69.308 107.045
N 8 8 8 8 8 8
8 8 8 8 u,
u,
oe
.
n.) Mean 0.000 0.000 0.000 1.222 4.767 7.842
12.114 24.515 49.516 81.211 .
r.,
SD 0.000 0.000 0.000 1.315 1.681 3.061
4.595 9.960 18.570 35.102 .
,
, SEM 0.000 0.000 0.000 0.465 0.594 1.082 1.625
3.521 6.566 12.410 ,
,
, Min 0.000 0.000 0.000 0.000 2.692 3.416 6.003
10.485 18.220 27.408
.3
Median 0.000 0.000 0.000 1.066 4.687 7.316
11.576 23.979 49.180 75.705
Max 0.000 0.000 0.000 2.672 6.599 11.906 19.210 40.794
76.906 141.432
%CV NA NA NA 108 35 39 38 41
38 43
GM NA NA NA NA 4.496 7.275 11.327 22.623
45.842 73.647
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
c,
-4
=
c,.,

[00339] Table 32A. Individual and Mean Plasma
Concentrations (ng/mL) of 6-Demethyl Half-Dimer Sulfate
by LCAVISAVIS Method Following a Single 175 mg Oral Administration of XL184 (L-
Malate Salt) Containing 1'4C1-XL184 0
t..)
(100 pCi) to Healthy Male Subjects
o
,-,
cio
i:.)=-=
t..)
48-648 hrs
-4
,-,
,-,
Time (hrs)
Subject 48.00 72.00 120.00 144.00 168.00
240.00 336.00 408.00 504.00 648.00
1444-1010 84.732 122.418 164.550 168.502 174.221 159.028 158.082 144.822
127.233 97.753
1444-1023 141.710 176.888 212.151 207.554 215.785 198.217 177.675 135.964
125.529 108.334
1444-1040 49.742 59.747 72.988 67.894 85.113
66.807 59.122 46.038 39.328 29.436
1444-1042 223.640 323.165 247.344 250.230 267.533 212.848 186.228 150.688
141.540 107.324
1444-1051 146.757 146.869 154.952 157.981 173.296 176.893 133.908 136.789
121.149 105.230
1444-1052 149.399 208.455 242.883 243.269 274.906 245.792 222.108 179.242
162.042 157.284
1444-1057 117.309 162.565 179.245 188.012 215.041 170.955 150.313 120.915
121.615 104.173 P
1444-1058 218.918 271.897 311.399 288.310 371.830 297.836 225.057 208.293
202.228 143.171
N 8 8 8 8 8 8
8 8 8 8 u,
u,
oo
.
Mean
141.526 184.001 198.189 196.469 222.216 191.047
164.062 140.344 130.083 106.588 .
r.,
SD 59.831 83.504 72.171 68.143 85.190
67.604 53.336 47.147 45.942 37.702 .
,
, SEM 21.153 29.523 25.516 24.092 30.119 23.902
18.857 16.669 16.243 13.330 ,
,
, Min 49.742 59.747 72.988 67.894 85.113 66.807
59.122 46.038 39.328 29.436
.3
Median
144.234 169.727 195.698 197.783 215.413 187.555
167.879 140.806 126.381 106.277
Max
223.640 323.165 311.399 288.310 371.830 297.836 225.057 208.293
202.228 157.284
%CV 42 45 36 35 38 35 33 34
35 35
GM
128.687 165.608 184.175 182.634 206.142 177.656 153.681 130.546
119.974 97.637
NA: Not Applicable; GM: Geometric Mean
IV
n
,-i
cp
t..)
=
oe
-a,
-4
=
c,.,

[00340] Table 33. Individual and Descriptive Statistics of
XL184 Plasma Pharmaco*kinetic Parameters by
LCAVISAVIS Method Following a Single 175 mg Oral Administration of XL184 (L-
Malate Salt) Containing 1HC1-XL184
0
(100 uCi) to Healthy Male Subjects
o
,..,
oe
Subject Cmax tmax AUC0-24 AUC0-72 AUC0-1
AUCO-inf kel tVa Ratioa
r..)
--.1
(ng/mL) (h) (Ipng/mL) (Ipng/mL) (Ipng/mL)
(Ipng/mL) (1/h) (h) (%)
1-,
1444-1010 778 1.00 10700 28800 72100
73900 0.0058 119 39.5
1444-1023 1030 1.98 12500 28800 61300
62500 0.00512 135 30.2
1444-1040 1440 2.00 17800 42800 74300
74700 0.00625 111 43.3
1444-1042 1480 2.00 17600 46800 72900
73100 0.0101 69.0 30.7
1444-1051 1240 1.00 11600 30700 66100
67500 0.00575 121 33.0
1444-1052 1320 3.00 14500 32100 61700
62200 0.00675 103 27.6
1444-1057 1400 1.00 15300 32200 56200
56400 0.00862 80.4 29.2
1444-1058 1340 1.00 14300 38100 73300
73500 0.00856 81.0 25.6
N 8 8 8 8 8
8 8 8 8
Mean 1250 1.62 14300 35000 67200
68000 0.00712 102 32.4 P
SD 238 0.74 2600 6770 6880
6910 0.00176 23.3 6.07 L.
SEM 84.1 0.26 919 2390 2430
2440 0.000623 8.25 2.15
oe
.
.6. Min 778 1.00 10700 28800 56200
56400 0.00512 69.0 25.6
r.,
Median 1330 1.49 14400 32100 69100
70300 0.0065 107 30.4 ,
Max 1480 3.00 17800 46800 74300
74700 0.0101 135 43.3 ' ,
,
%CV 19 46 18 19 10
10 25 23 19
.3
GM 1230 1.49 14100 34500 66900
67700 0.00694 100 31.9
GM: Geometric Mean; a: ratio of AUCo-t (each analyte)/ AUCo-t (parent + 4
measured metabolites);
C., maximum observed concentration; T., time of the maximum concentration;
AUCo-t, area under the concentration-time curve from time zero to the time
of the last measurable concentration; AUCo-24, area under the concentration-
time curve from time zero to 24 hours post XL184 dose; AUG-72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo_mf,
area under the concentration-time curve from time zero to infinity; kel,
apparent terminal elimination rate constant; ti/2, apparent terminal
elimination half-life; CL/F, apparent total body clearance; V/F, apparent
total volume of
distribution.
IV
n
,-i
cp
t..,
=
oe
C-5
o
--.1
o
c,.)

[00341] Table 33A. Individual and Descriptive Statistics of XL184-Half-
Dimer Plasma Pharmaco*kinetic
Parameters by LCAVISAVIS Method Following a Single 175 mg Oral Administration
of XL184 (L-Malate Salt) Containing 0
ricij_
XL184 (100 uCi) to Healthy Male Subjects
t..)
o
,-,
cio
Subject Cmax tmax AUC0-24 AUC0-72 AUC0-1
Ratioa Ratio") AUCO-inf kel tVa 't:)
N
--1
(ng/mL) (h) (Ipng/mL) (Ipng/mL) (Ipng/mL)
(%) (%) (Ipng/mL) (1/h) (h)
1-,
1444-1010 35.6 24.00 669 2130 5690 7.89
3.11 6080 0.00531 131
1444-1023 38.4 7.98 853 2480 5470 8.92
2.69 5610 0.00786 88.2
1444-1040 35.1 24.03 741 2030 3830 5.15
2.23 3940 0.0108 64.2
1444-1042 76.7 5.00 1530 4320 7230 9.92
3.05 7370 0.0111 62.7
1444-1051 40.8 13.98 859 2350 5470 8.28
2.73 5800 0.00557 124
1444-1052 68.0 24.10 1410 4140 8740 14.2
3.90 8950 0.00708 97.9
1444-1057 69.8 24.08 1420 4070 8270 14.7
4.30 8550 0.00757 91.6
1444-1058 58.6 8.00 1150 3430 7630 10.4
2.66 7820 0.0093 74.5
N 8 8 8 8 8 8 8
8 8 8
Mean 52.9 16.40 1080 3120 6540 9.93
3.09 6770 0.00807 91.8 P
SD 17.3 8.55 341 976 1680 3.20 0.689
1700 0.00218 25.4
SEM 6.10 3.02 120 345 595 1.13 0.244
600 0.000771 9.00 u,
u,
cio
.
vi Min 35.1 5.00 669 2030 3830 5.15
2.23 3940 0.00531 62.7
r.,
Median 49.7 18.99 1010 2950 6460 9.42
2.89 6730 0.00772 89.9 ,
' Max 76.7 24.10 1530 4320 8740 14.7 4.30
8950 0.0111 131 ,
,
' %CV 33 52 32 31 26
32 22 25 27 28
.3
GM 50.4 14.02 1030 2980 6340 9.47 3.02
6560 0.00781 88.8
GM: Geometric Mean; a: ratio of AUCo_t (metabolite)/ AUCo_t (parent); b: ratio
of AUCo_t (each analyte)/ AUCo_t (parent + 4 measured
metabolites); Cõ,õ maximum observed concentration; Tõ,,,õ time of the maximum
concentration; AUCo_t, area under the concentration-time
curve from time zero to the time of the last measurable concentration;
AUC0_24, area under the concentration-time curve from time zero to
24 hours post XL184 dose; AUC0_72, area under the concentration-time curve
from time zero to 72 hours post XL184 dose; AUCo, area under
the concentration-time curve from time zero to infinity; kei, apparent
terminal elimination rate constant; t112, apparent terminal elimination half-
life; CL/F, apparent total body clearance; V/F, apparent total volume of
distribution.
Iv
n
1-i
cp
t..)
=
,-,
oe
(...,
c,
-4
=
(...,

[00342]
Table 34. Individual and Descriptive Statistics of XL184-N-Oxide
Plasma Pharmaco*kinetic
0
Parameters by LCAVISAVIS Method Following a Single 175 mg Oral Administration
of XL184 (L-Malate Salt) Containing
o
114C1-XL184 (100 uCi) to Healthy Male Subjects
,..,
oe
iz..1
n.)
--.1
Subject Cmax tmax AUC0-24 AUC0-72 AUCo-i
Ratio' Ratio') AUCO-inf kel tVa
1-,
(ng/mL) (h) (Ipng/mL) (Ipng/mL)
(1pnWmL) (%) (%) (Ipng/mL) (1/h) (h)
1444-1010 64.8 24.00 945 2760 6780 9.40
3.71 7000 0.00486 143
1444-1023 101 24.00 1750 4990 8640 14.1
4.25 8850 0.00928 74.7
1444-1040 179 24.03 3390 9340 16700 22.5
9.74 16800 0.0109 63.5
1444-1042 130 24.03 2100 6580 10100 13.9
4.26 10200 0.0126 54.8
1444-1051 94.9 2.00 1760 5020 10000 15.1
4.99 10300 0.00596 116
1444-1052 135 3.00 1980 4620 7700 12.5
3.44 7850 0.00684 101
1444-1057 114 2.00 2040 4850 8420 15.0
4.37 8590 0.0083 83.5
1444-1058 129 2.00 2280 6690 12700 17.3
4.44 12800 0.00895 77.4
N 8 8 8 8 8 8
8 8 8 8 P
Mean 118 13.13 2030 5610 10100 15.0
4.90 10300 0.00846 89.2 L.
SD 33.7 11.64 682 1940 3210 3.80 2.01
3170 0.00256 29.2
oe
.
cA SEM 11.9 4.11 241 686 1130 1.34
0.711 1120 0.000905 10.3 .
N)
Min 64.8 2.00 945 2760 6780 9.40 3.44
7000 0.00486 54.8 .
,
Median 122 13.50 2010 5010 9320 14.5
4.31 9530 0.00863 80.5 ,
,
,
Max 179 24.03 3390 9340 16700 22.5 9.74
16800 0.0126 143 ,
r.,
.3
%CV 28 89 34 35 32 25
41 31 30 33
GM 114 7.29 1930 5320 9750 14.6 4.65
9930 0.00811 85.3
GM: Geometric Mean; a: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio
of AUCo-t (each analyte)/ AUCo-t (parent + 4 measured metabolites); C.,
maximum observed concentration; T., time of the maximum concentration; AUCo-t,
area under the concentration-time curve from time zero to the time of the
last measurable concentration; AUCo-24, area under the concentration-time
curve from time zero to 24 hours post XL184 dose; AUG-72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo_mf,
area under the concentration-time curve from time zero to infinity; Ica
apparent terminal elimination rate constant; ti/2, apparent terminal
elimination half-life; CL/F, apparent total body clearance; V/F, apparent
total volume of
distribution.
IV
n
1-i
cp
t.,
=
,-,
oe
C-5
o
--.1
o
c,.)

[00343]
Table 35. Individual and Descriptive Statistics of XL184-
Sulfate Plasma Pharmaco*kinetic Parameters
0
by LCAVISAVIS Method following a Single 175 mg Oral Administration of XL184 (L-
Malate Salt) Containing 1'4C1-XL184
o
(100 uCi) to Healthy Male Subjects
,..,
oe
iz..1
n.)
--.1
Subject Cmax tmax AUC0-24 AUC0-72 AUC0-1
Ratioa Ratio' AUCO-inf kel tVa
1-,
(ng/mL) (h) (Ipng/mL) (Ipng/mL) (Ipng/mL)
(%) (%) (Ipng/mL) (1/h) (h)
1444-1010 112 24.00 1430 4470 11000 15.3
6.02 11900 0.00619 112
1444-1023 233 24.00 3710 11600 26900 43.9
13.2 27400 0.0095 72.9
1444-1040 311 3.00 6090 17700 43000 57.9
25.1 43500 0.00948 73.1
1444-1042 287 24.03 4020 15000 28100 38.5
11.8 28600 0.0122 56.8
1444-1051 177 48.00 3190 11400 30900 46.7
15.4 31700 0.00532 130
1444-1052 215 4.00 3920 10800 19700 31.9
8.80 20400 0.00734 94.4
1444-1057 263 24.08 4710 13200 28700 51.1
14.9 29400 0.00953 72.8
1444-1058 290 23.68 4700 16900 42700 58.3
14.9 43200 0.00913 75.9
N 8 8 8 8 8 8 8
8 8 8 P
Mean 236 21.85 3970 12600 28900 42.9 13.8
29500 0.00859 86.0 L.
SD 66.7 14.04 1350 4180 10700 14.4 5.63
10600 0.00220 24.3
oe
.
--.1 SEM 23.6 4.96 477 1480 3790 5.08
1.99 3750 0.000777 8.61 .
N)
Min 112 3.00 1430 4470 11000 15.3 6.02
11900 0.00532 56.8 .
,
,
Median 248 24.00 3970 12400 28400 45.3
14.1 29000 0.00931 74.5 ,
,
,
Max 311 48.00 6090 17700 43000 58.3 25.1
43500 0.0122 130
.3
%CV 28 64 34 33 37 33 41
36 26 28
GM 226 16.11 3710 11800 26800 40.1
12.8 27600 0.00833 83.2
GM: Geometric Mean; a: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio
of AUCo-t (each analyte)/ AUCo-t (parent + 4 measured metabolites); C.,
maximum observed concentration; T., time of the maximum concentration; AUCo-t,
area under the concentration-time curve from time zero to the time of the
last measurable concentration; AUCo-24, area under the concentration-time
curve from time zero to 24 hours post XL184 dose; AUG-72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo_mf,
area under the concentration-time curve from time zero to infinity;
lcd, apparent terminal elimination rate constant; tin, apparent terminal
elimination half-life; CL/F, apparent total body clearance; V/F, apparent
total volume of
distribution.
IV
n
,-i
cp
t..,
=
oe
C-5
o
--.1
o
c,.)

[00344] Table 36. Individual and Descriptive Statistics of
6-Demethyl Half-Dimer Sulfate Plasma
0
Pharmaco*kinetic Parameters by LCAVISAVIS Method following a Single 175 mg Oral
Administration of XL184 (L-Malate Salt)
o
Containing 114C1-XL184 (100 pCi) to Healthy Male Subjects
oe
iz..1
n.)
--.1
Subject Cmax
tmax AUG-24 AUC0-72 AUC0-1 Ratio' Ratio") AUCo-in( lie'
tv,
1-,
(ng/mL) (h) (h=ng/mL) (h=ng/mL)
(h=ng/mL) (%) (%) (h=ng/mL) (1/h) (h)
1444-1010 174 168.00 627 4750 87100 121 47.7 NR NR NR
1444-1023 216 168.00 1080 7800 101000 165 49.7 NR NR NR
1444-1040 85.1 168.00 348 2590 33600 45.2 19.6 NR NR NR
1444-1042 323 71.97 1570 12500 119000 163 50.1 NR NR NR
1444-1051 177 240.00 916 7060 88000 133 43.9 NR NR NR
1444-1052 275 168.00 972 8020 126000 204 56.3 NR NR NR
1444-1057 215 168.00 816 6430 90900 162 47.2 NR NR NR
1444-1058 372 168.00 1290 11100 150000 205 52.4 NR NR NR
N 8 8 8 8 8 8
8 NA NA NA P
Mean 230 165.00 951 7530 99500 150 45.9 NA NA NA
L.
SD 91.2 45.25 377
3200 34500 51.5 11.2 NA NA NA
oe
.
oe SEM 32.2 16.00 133
1130 12200 18.2 3.97 NA NA NA .
N)
Min 85.1 71.97 348
2590 33600 45.2 19.6 NA NA NA .
,
,
Median 216 168.00 944 7430 96000 162 48.7 NA NA NA
,
,
,
Max 372 240.00 1570 12500 150000 205 56.3 NA NA NA
.3
%CV 40 27 40 42 35 34 24 NA NA NA
GM 212 158.00 875 6850 92400 138 44.1 NA NA NA
GM: Geometric Mean; a: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio
of AUCo-t (each analyte)/ AUCo-t (parent + 4
measured metabolites); C., maximum observed concentration; T., time of the
maximum concentration; AUCo-t, area under the
concentration-time curve from time zero to the time of the last measurable
concentration; AUCo-24, area under the concentration-
time curve from time zero to 24 hours post XL184 dose; AUG-72, area under the
concentration-time curve from time zero to
72 hours post XI. 184 dose; AUCo_mf, area under the concentration-time curve
from time zero to infinity; Ica apparent terminal
elimination rate constant; tin, apparent terminal elimination half-life; CL/F,
apparent total body clearance; V/F, apparent total
IV
volume of distribution; NA: Not applicable; NR: Not reportable.
n
,-i
cp
t..,
=
oe
C-5
cA
--.1
o
c,.)

[00345] Table 37. Individual and Mean Plasma
Concentrations (ngEq/mL) of XL184 using a Radio-
Quantitative Method following a Single 175 mg Oral Administration of 1HC1-
XL184 (100 pCi) to Healthy Male Subjects 0
[00346]
Time (hours)
Subject 0.00 0.50 1.00 2.00 3.00 4.00 5.00
8.00 14.00 24.00 72.00 168.00 336.00
1444-1023 0.0 325.6 706.6 894.9 752.7 675.6 511.9 349.8 251.3 254.6 101.4 51.2
10.3
1444-1040 0.0 282.6 820.7 1132.9 876.2 912.1 806.5 501.4 486.3 573.4 227.6
54.2 12.3
1444-1042 0.0 145.3 674.9 1277.2 1177.6 1493.7 556.5 480.1 525.6 630.4 303.7
30.3 0.0
1444-1051 0.0 366.7 817.9 661.5 557.9 435.3 391.9 268.4 239.9 259.6 144.4 46.0
33.3
1444-1052 0.0 150.9 439.0 880.8 1056.2 755.1 457.2 301.1 233.3 306.3 0.0 23.9
24.1
1444-1057 0.0 429.4 1077.5 1026.3 686.3 733.3 416.1 338.6 297.9 277.5 178.8
53.6 18.3
6 6 6 6 6 6 6 6
6 6 6 6 6
Mean 0.0 283.4 756.1 978.9 851.2 834.2 523.4 373.2 339.1 383.6 159.3 43.2 16.4
SD
0.0 115.5 210.2 215.6 233.3 358.3 151.4 95.7 131.8
171.0 104.7 13.0 11.6
SEM 0.0 47.1 85.8 88.0 95.2 146.3 61.8 39.1 53.8 69.8 42.8 5.3 4.7
Min
0.0 145.3 439.0 661.5 557.9 435.3 391.9 268.4 233.3
254.6 0.0 23.9 0.0
oo
Median 0.0 304.1 762.3 960.6 814.5 744.2 484.6 344.2
274.6 291.9 161.6 48.6 15.3
Max
0.0 429.4 1077.5 1277.2 1177.6 1493.7 806.5 501.4
525.6 630.4 303.7 54.2 33.3
%CV NA 41 28 22 27 43 29 26 39 45 66 30 71
GM NA 261.2 730.1 958.3 824.5 778.1 507.7 363.4 319.9
355.9 NA 41.3 NA
NA: Not Applicable; ND: No Data; GM: Geometric Mean

[00347] Table 38. Individual and Mean Plasma Concentrations
(ngEq/mL) of XL184-Half-Dimer** using a
0
Radio-Quantitative Method following a Single 175 mg Oral Administration of
1'4C1-XL184 (100 pCi) to Healthy Male Subjects
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24 72 168 336
1444-1023 0.0 139.5 166.1 173.5 97.2 162.4 111.4 129.1 109.6 89.2 58.2 0.0 0.0
1444-1040 0.0 81.0 85.9 77.2 76.6 67.1 66.7 52.1 60.2 75.2 0.0 0.0 0.0
1444-1042 0.0 0.0 65.7 136.3 164.3 134.3 210.1 198.0 216.3 295.1 130.0 0.0 0.0
1444-1051 0.0 132.3 213.3 198.6 186.7 138.3 158.0 98.8 154.6 124.1 69.5 31.7
0.0
1444-1052 0.0 140.9 236.4 234.6 203.0 222.9 192.0 190.2 254.7 171.2 0.0 47.7
10.7
1444-1057 0.0 204.9 235.7 160.3 166.6 183.3 137.7 137.8 172.0 175.6 78.7 12.7
0.0
6 6 6 6 6 6 6 6 6 6
6 6 6
Mean 0.0 116.4 167.2 163.4 149.1 151.4 146.0 134.3 161.2
155.1 56.1 15.4 1.8
SD 0.0 69.3 75.5 54.0 50.6 52.6 52.8 55.2 70.4 80.0 49.9
20.1 4.4
SEM 0.0 28.3 30.8 22.0 20.7 21.5 21.5 22.5 28.8 32.6 20.4 8.2 1.8
Min 0.0 0.0 65.7 77.2 76.6 67.1 66.7 52.1 60.2 75.2 0.0 0.0 0.0
Median 0.0 135.9 189.7 166.9 165.5 150.4 147.9 133.5 163.3 147.7 63.9 6.4 0.0
Max 0.0 204.9 236.4 234.6 203.0 222.9 210.1 198.0 254.7
295.1 130.0 47.7 10.7
%CV NA 60 45 33 34 35 36 41 44 52 89 131 245
GM NA NA 149.4 154.6 140.6 142.2 136.7 122.9 146.0 139.5
NA NA NA
** Co-eluted with Demethyl XL184 glueuronide B; NA: Not Applicable; GM:
Geometric Mean
oe

[00348] Table 39. Individual and Mean Plasma Concentrations
(ngEq/mL) of XL184-N-Oxide using a Radio-
Quantitative Method following a Single 175 mg Oral Administration of 1HC1-
XL184 (100 pCi) to Healthy Male Subjects
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1023 0.0 0.0 175.4 224.8 189.5 232.5 183.2 144.4 143.6 140.5 73.8 0.0 8.9
1444-1040 0.0 66.3 217.5 321.2 304.2 327.1 293.7 268.4 319.9 309.6 103.3 38.1
10.7
1444-1042 0.0 0.0 131.0 331.2 344.9 161.7 284.1 110.9 69.4 111.0 100.1 0.0 0.0
1444-1051 0.0 0.0 200.6 221.9 181.3 153.4 137.5 135.2 129.0 208.3 85.1 0.0 0.0
1444-1052 0.0 0.0 132.1 195.6 325.7 235.5 235.9 133.9 104.0 160.6 0.0 0.0
0.0
1444-1057 0.0 87.9 215.0 340.5 252.8 237.0 216.4 167.0 178.6 229.0 60.4 34.2
0.0
6 6 6 6 6 6 6 6 6 6
6 6 6
Mean
0.0 25.7 178.6 272.5 266.4 224.5 225.1 160.0 157.4 193.2 70.5
12.1 3.3
SD 0.0
40.4 39.4 65.1 69.9 63.0 59.7 56.1 87.7 71.6 38.1 18.7 5.1
SEM 0.0 16.5 16.1 26.6 28.5 25.7 24.4 22.9 35.8 29.2 15.5 7.6 2.1
Min 0.0
0.0 131.0 195.6 181.3 153.4 137.5 110.9 69.4 111.0 0.0 0.0 0.0
Median 0.0 0.0 188.0 273.0 278.5 234.0 226.2 139.8 136.3 184.5 79.5 0.0 0.0
Max 0.0
87.9 217.5 340.5 344.9 327.1 293.7 268.4 319.9 309.6 103.3 38.1 10.7
%CV NA 157 22 24 26 28 27 35 56 37 54 155 156
GM NA
NA 174.7 265.9 258.3 217.3 218.0 153.3 140.3 182.5 NA NA NA
NA: Not Applicable; ND: No Data; GM: Geometric Mean
oe

[00349] Table 40. Individual and Mean Plasma Concentrations
(ngEq/mL) of XL184-Sulfate*** using a
0
Radio-Quantitative Method following a Single 175 mg Oral Administration of
1'4C1-XL184 (100 pCi) to Healthy Male Subjects
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1023 0.0 167.5 270.2 350.0 568.8 575.3 543.8 405.8 422.7 381.1 280.7
115.5 41.6
1444-1040 0.0 126.4 426.4 559.5 789.6 740.4 776.3 606.7 571.2 866.9 488.1
252.7 41.0
1444-1042 0.0 0.0 247.5 504.7 589.0 452.6 718.1 207.2 264.6 630.8 418.0 101.1
15.6
1444-1051 0.0 94.8 269.3 458.4 459.9 502.0 389.9 316.1 470.7 515.7 312.6 122.3
75.3
1444-1052 0.0 132.6 362.7 541.6 459.9 535.8 532.0 402.3 366.7 501.3 248.3 0.0
18.5
1444-1057 0.0 282.5 460.4 600.8 588.5 673.9 496.0 435.0 545.0 529.2 311.0
192.8 19.4
6 6 6 6 6 6 6 6 6 6
6 6 6
Mean
0.0 134.0 339.4 502.5 576.0 580.0 576.0 395.5 440.2 570.8 343.1
130.7 35.2
SD
0.0 92.4 90.4 89.0 120.8 108.5 144.4 132.7 114.6 165.4 91.1 86.0
22.8
SEM 0.0 37.7 36.9 36.4 49.3 44.3 59.0 54.2 46.8 67.5 37.2 35.1 9.3
Min
0.0 0.0 247.5 350.0 459.9 452.6 389.9 207.2 264.6 381.1 248.3
0.0 15.6
Median 0.0 129.5 316.5 523.2 578.7 555.6 537.9 404.1 446.7 522.5 311.8 118.9
30.2
Max
0.0 282.5 460.4 600.8 789.6 740.4 776.3 606.7 571.2 866.9 488.1
252.7 75.3
%CV NA 69 27 18 21 19 25 34 26 29 27 66 65
GM
NA NA 329.6 495.2 566.1 571.8 561.0 375.9 426.4 552.7 333.8 NA
29.9
*** Co-eluted with Half-dimer methyl ester; NA: Not Applicable; ND: No Data;
GM: Geometric Mean
oe

[00350] Table 41. Individual and Mean Plasma Concentrations
(ngEq/mL) of Demethyl Half-Dimer Sulfate
0
using a Radio-Quantitative Method following a Single 175 mg Oral
Administration of 1HC1-XL184 (100 pCi) to Healthy Male
Subjects
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14
24 72 168 336
1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 110.2 105.9 182.6 417.5 360.9 313.3 129.8
1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60.1 87.4 172.2 165.5 71.8
1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 127.1 315.2 373.2 391.1 175.0
1444-1052 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 155.6 216.2 532.7 389.9 240.7
4 4 4 4 4 4 4 4 4 4
4 4 4
Mean
0.0 0.0 0.0 0.0 0.0 0.0 27.6 26.5 131.4 259.1 359.8 315.0 154.3
SD 0.0 0.0
0.0 0.0 0.0 0.0 55.1 53.0 52.6 140.9 147.5 106.1 71.4
SEM 0.0 0.0 0.0 0.0 0.0 0.0 27.6 26.5 26.3 70.5 73.8 53.0 35.7
Min 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 60.1 87.4 172.2 165.5 71.8
Median 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 141.4 265.7 367.1 351.6 152.4
Max 0.0 0.0
0.0 0.0 0.0 0.0 110.2 105.9 182.6 417.5 532.7 391.1 240.7
%CV NA NA NA NA NA NA 200 200 40 54 41 34 46
GM NA NA NA NA NA NA NA NA 121.4 223.3 333.4 298.2 140.8
GM: Geometric Mean; NA: Not Applicable
Subjects whose PK profile did not contain more than five consecutive data
points with a quantifiable concentration value.
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14
24 72 168 336
1444-1051 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 113.1 262.0 299.5 143.8
1444-1057 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 142.9 249.6 149.3 157.1
oe

[00351] Table 42. Individual and Mean Plasma Concentrations
(ngEq/mL) of P5 using a Radio-Quantitati
0
Method following a Single 175 mg Oral Administration of 1'4C1-XL184 (100 pCi)
to Healthy Male Subjects
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1042 0.0 0.0 75.0 129.9 150.2 189.8 246.6 173.8 151.8 147.1 0.0 0.0 7.6
1444-1051 0.0 69.2 126.6 144.7 114.6 116.8 106.6 102.2 0.0 0.0 61.8 31.8 0.0
1444-1052 0.0 42.1 76.1 189.6 151.9 144.0 83.4 83.0 84.9 137.1 89.9 0.0 0.0
3 3 3 3 3 3 3 3 3 3
3 3 3
Mean
0.0 37.1 92.6 154.7 138.9 150.2 145.5 119.7 78.9 94.7 50.6 10.6
2.5
SD
0.0 34.9 29.5 31.1 21.1 36.9 88.3 47.9 76.1 82.2 46.0 18.4 4.4
SEM 0.0 20.1 17.0 17.9 12.2 21.3 51.0 27.6 43.9 47.5 26.6 10.6 2.5
Min
0.0 0.0 75.0 129.9 114.6 116.8 83.4 83.0 0.0 0.0 0.0 0.0 0.0
Median 0.0 42.1 76.1 144.7 150.2 144.0 106.6 102.2 84.9 137.1 61.8 0.0 0.0
Max
0.0 69.2 126.6 189.6 151.9 189.8 246.6 173.8 151.8 147.1 89.9
31.8 7.6
%CV NA 94 32 20 15 25 61 40 96 87 91 173 173
GM
NA NA 89.7 152.7 137.8 147.2 129.9 113.8 NA NA NA NA NA
GM: Geometric Mean; NA: Not Applicable
0
Subjects whose PK profile did not contain more than five consecutive data
points with a quantifiable concentration value.
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1023 0.0 0.0 0.0 0.0 146.8 0.0 0.0 0.0 0.0 112.5 0.0 37.7 11.4
1444-1040 0.0 0.0 0.0 126.4 145.3 160.8 0.0 0.0 81.0 103.9 0.0 0.0 0.0
1444-1057 0.0 0.0 0.0 123.7 184.7 0.0 131.9 86.6 128.2 98.7 0.0 21.5 0.0
oe

[00352] Table 43. Individual and Mean Plasma Concentrations
(ngEq/mL) of P7 using a Radio-Quantitative
0
Method following a Single 175 mg Oral Administration of 1'4C1-XL184 (100 pCi)
to Healthy Male Subjects
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1051 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0
1 1 1 1 1 1 1 1 1 1
1 1 1
Mean
0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0
SD
NA NA NA NA NA NA NA NA NA NA NA NA NA
SEM NA NA NA NA NA NA NA NA NA NA NA NA NA
Min
0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0
Median 0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0
Max
0.0 55.4 76.8 95.3 72.7 85.0 57.1 38.4 0.0 0.0 0.0 0.0 0.0
%CV NA NA NA NA NA NA NA NA NA NA NA NA NA
GM
NA 55.4 76.8 95.3 72.7 85.0 57.1 38.4 NA NA NA NA NA
GM: Geometric Mean; NA: Not Applicable
Subjects whose PK profile did not contain more than five consecutive data
points with a quantifiable concentration value.
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1052 0.0 0.0 0.0 110.5 156.0 0.0 87.1 0.0 0.0 0.0 0.0 0.0 0.0
1444-1057 0.0 0.0 106.9 0.0 0.0 106.2 54.2 56.4 0.0 0.0 0.0 0.0 0.0
oe

[00353] Table 44. Individual Plasma Concentrations (ngEq/mL) of P2
using a Radio-quantitative Method
following a Single 175 mg Oral Administration of 1'4C1-XL184 (100 pCi) to
Healthy Male Subjects
Subjects whose PK profile did not contain more than five consecutive data
points with a quantifiable concentration value.
oe
Time (hours)
Subject 0 0.5 1 2 3 4 5 8 14 24
72 168 336
1444-1023 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 41.5 0.0 0.0 0.0
1444-1040 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1042 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1051 0.0 0.0 0.0 0.0 0.0 49.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1444-1052 0.0 0.0 58.7 0.0 74.1 0.0 0.0 72.7 0.0 0.0 0.0 0.0 0.0
1444-1057 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 46.3 0.0 0.0 0.0
oe

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[00354] Table 45. Individual and Descriptive Statistics of Plasma
Pharmaco*kinetic Parameters of XL184 using a Radio-quantitative Method
following a
Single 175 mg Oral Administration of 114C1-XL184 (100 pCi) to Healthy Male
Subjects
Subject Cma. -Gm. AUC04 AUC0-24 AUC0_72 Ratiob AUCo-thr kei t1/2
(ngEq/mL) (h) (h=ngEq/mL) (h=ngEq/mL) (h=ngEq/mL) (%) (h=ngEq/mL) (1/h)
(h)
1444-1023 895 1.98 29900 8890 17400 15.0 31100
0.00876 79.1
1444-1040 1130 2.00 52600 14300 33500 22.5 53700
0.0119 58.0
1444-1042 1490 4.00 53600 15200 37600 20.8 55000
0.0215 32.2
1444-1051 818 1.00 33200 7660 17400 25.1 38000
0.00685 101
1444-1052 1060 3.00 21300 8770 16100 10.2 24000
0.00909 76.2
1444-1057 1080 1.00 37700 9600 20600 26.4 39800
0.00906 76.5
N 6 6 6 6 6 6 6 6 6
Mean 1080 2.16 38100 10700 23800 20.0
40300 0.0112 70.5
SD 234 1.17 12800 3170 9340 6.24 12300
0.0053 23.2
SEM 95.5 0.48 5240 1300 3810 2.55
5010 0.00216 9.48
Min 818 1.00 21300 7660 16100 10.2 24000
0.00685 32.2
Median 1070 1.99 35500 9250 19000 21.7 38900
0.00908 76.4
Max 1490 4.00 53600 15200 37600 26.4 55000
0.0215 101
%CV 22 54 34 30 39 31 30 47 33
GM 1060 1.90 36200 10400 22400 19.0
38700 0.0104 66.6
GM: Geometric Mean; b: ratio of AUCo-t (each analyte)/ AUCo-t (parent + 6
measured metabolites); C.,
maximum observed concentration; Tma., time of the maximum concentration; AUCo-
t, area under the
concentration-time curve from time zero to the time of the last measurable
concentration; AUCo-24, area
under the concentration-time curve from time zero to 24 hours post XL184 dose;
AUCO272, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo,
area under the
concentration-time curve from time zero to infinity; Ica apparent terminal
elimination rate constant; tiu2,
apparent terminal elimination half-life; CL/F, apparent total body clearance;
V/F, apparent total volume of
distribution
97

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[00355] Table 46. Individual and Descriptive Statistics of Plasma
Pharmaco*kinetic Parameters of XL184-Half-dimer** using a Radio-quantitative
Method following a Single 175 mg Oral Administration of 114C1-XL184 (100 Ci)
to
Healthy Male Subjects
Subject Cmax tmax AUC04 AUC0-24 AUC0_72
Ratioa Ratiob AUCo-La kei tz
(ng,Eq/mL) (h) (h. ng,Eq/mL) (h. ng,Eq/mL) (h. ng,Eq/mL) (%) (%) (h. ng,Eq/mL)
(1/h) (h)
1444-1023 174 1.98 6290 2750 6290 21.0
3.15 NR NR NR
1444-1040 85.9 1.00 1550 1550 3360 2.95 0.664
NR NR NR
1444-1042 295 24.03 15200 5000 15200 28.4
5.91 NE NE NE
1444-1051 213 1.00 12900 3370 8020 38.9
9.77 NR NR NR
1444-1052 255 14.00 16400 5050 9160 77.0
7.89 17600 0.00889 77.9
1444-1057 236 1.00 14400 3940 10000
38.2 10.1 15100 0.0184 37.8
N 6 6 6 6 6 6 6 2 2 2
Mean 210 7.17 11100 3610 8680 34.4
6.25 16400 0.0136 57.9
SD 73.0 9.72 5890 1350 3980 24.7
3.76 1770 0.00672 28.4
SEM 29.8 3.97 2400 552 1620 10.1
1.54 1250 0.00476 20.1
Min 85.9 1.00 1550 1550 3360 2.95
0.664 15100 0.00889 37.8
Median 225 1.49 13700 3650 8590 33.3
6.90 16400 0.0136 57.9
Max 295 24.03 16400 5050 15200
77.0 10.1 17600 0.0184 77.9
%CV 35 136 53 37 46 72 60 11 49 49
GM 196 2.96 8760 3360 7870 24.2
4.61 16300 0.0128 54.3
** Co-eluted with Demethyl XL184 glucuronide B; GM: Geometric Mean; a: ratio
of AUCo-t
(metabolite)/ AUCo-t (parent);
b: ratio of AUCo-t (each analyte)/ AUCo-t (parent + 6 measured metabolites);
C., maximum observed
concentration; Tmax, time of the maximum concentration; AUCo-t, area under the
concentration-time
curve from time zero to the time of the last measurable concentration; AUG-24,
area under the
concentration-time curve from time zero to 24 hours post XL184 dose; AUCo-72,
area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo-olf,
area under the
concentration-time curve from time zero to infinity; Ica, apparent terminal
elimination rate constant; 0/2,
apparent terminal elimination half-life; CL/F, apparent total body clearance;
V/F, apparent total volume
of distribution; NE: Not Estimable; NR: Not reportable since AUCo-t/ AUCo-mf
ratio < 0.80
98

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[00356] Table 47. Individual and Descriptive Statistics of
Plasma
Pharmaco*kinetic Parameters of XL184-N-oxide using a Radio-quantitative Method
following a Single 175 mg Oral Administration of 114C1-XL184 (100 Ci) to
Healthy
Male Subjects
Subject Cmax tmax AUCO-t AUC0-24 AUC0_72 Ratio3
Ratiob AUCo-La kei ty,
(ng,Eq/mL) (h) (h=ng,Eq/mL) (h=ng,Eq/mL) (h=ng,Eq/mL) (%) (%)
(h=ng,Eq/mL) (1/h) (h)
1444-1023 233 4.00 13100 3650 8790 43.8 6.55 14100 0.0086 80.6
1444-1040 327 4.00 27900 7050 17000 53.0 12.0 29100 0.00847 81.8
1444-1042 345 3.00 8180 3110 8180 15.3 3.18
NR NR NR
1444-1051 222 2.00 10700 3660 10700 32.2 8.10 NR NR NR
1444-1052 326 3.00 3580 3560 7430 16.8 1.72
NR NR NR
1444-1057 341 2.00 16300 4790 11700 43.2 11.4
19100 0.0122 56.9
N 6 6 6 6 6 6 6 3 3
3
Mean 299 3.00 13300 4300 10600 34.1 7.16 20800 0.00976 73.1
SD 56.0 0.89 8360 1460 3490 15.4 4.20
7640 0.00212 14.0
SEM 22.9 0.37 3410 594 1430 6.30 1.71
4410 0.00122 8.11
Min 222 2.00 3580 3110 7430 15.3 1.72
14100 0.00847 56.9
Median 327 3.00 11900 3650 9750 37.7 7.33 19100 0.0086 80.6
Max 345 4.00 27900 7050 17000 53.0 12.0 29100 0.0122 81.8
%CV 19 30 63 34 33 45 59 37 22 19
GM 294 2.88 11100 4140 10200 30.7 5.84 19900 0.00961 72.1
GM: Geometric Mean; 3: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio
of AUCo-t (each analyte)/
AUCo-t (parent + 6 measured metabolites); C., maximum observed concentration;
T., time of the
maximum concentration; AUCo-t, area under the concentration-time curve from
time zero to the time of
the last measurable concentration; AUC0-24, area under the concentration-time
curve from time zero to
24 hours post XL184 dose; AUC0-72, area under the concentration-time curve
from time zero to 72 hours
post XL184 dose; AUCo-Inf, area under the concentration-time curve from time
zero to infinity;
Lei, apparent terminal elimination rate constant; -0/2, apparent terminal
elimination half-life; CL/F,
apparent total body clearance; V/F, apparent total volume of distribution; NR:
Not reportable since
AUCo-t/ AUCo-Inf ratio <0.80
99

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[00357] Table 48. Individual and Descriptive Statistics of
Plasma
Pharmaco*kinetic Parameters of XL184-Sulfate*** using a Radio-quantitative
Method
following a Single 175 mg Oral Administration of 114C1-XL184 (100 Ci) to
Healthy
Male Subjects
Subject Cmax tmax AUCo-t AUC0_24 AUC0-
72 Ratioa Ratiob AUCo-inf kei ty,
(h. ng,Eq/mL (h. ng,Eq/mL (h. ng,Eq/mL (%) (%)
( 1/h)
(ng,Eq/mL) (h) ) ) ) (h=ng,Eq/mL)
(h)
1444-1023 575 4.00 58100 9980 25900 194 29.1 63800 0.00722 96.0
1444-1040 867 24.03 108000 15700 48200 205 46.3 113000 0.00958 72.3
1444-1042 718 5.00 69300 9370 34500 129 26.9 70500 0.0121 57.2
1444-1051 516 24.08 67600 10200 30100 204 51.2 80000 0.00606 114
1444-1052 542 1.98 41700 10200 28200 196 20.1 43400 0.0103 67.1
1444-1057 674 4.00 74500 12300 32500 198 52.1 76400 0.0101 68.4
N 6 6 6 6 6 6 6 6 6
6
Mean 649 10.52 69900 11300 33200 188 37.6 74500 0.00923 79.2
SD 132 10.53 22000 2360 7940 29.1 13.9 22900 0.00221 21.4
SEM 54.0 4.30 8970 964 3240 11.9 5.67
9330 0.000901 8.73
Min 516 1.98 41700 9370 25900 129 20.1 43400 0.00606 57.2
Median 625 4.50 68500 10200 31300 197 37.7 73500 0.00984 70.4
Max 867 24.08 108000 15700 48200 205 52.1 113000 0.0121 114
%CV 20 100 31 21 24 15 37 31 24 27
GM 638 6.71 67100 11100 32500 185 35.3 71600 0.00899 77.0
*** Co-eluted with Half-dimer methyl ester; GM: Geometric Mean; a: ratio of
AUCo-t (metabolite)/
AUCo-t (parent); b: ratio of AUCo-t (each analyte)/ AUCo-t (parent + 6
measured metabolites); C.,
maximum observed concentration; Tmax, time of the maximum concentration; AUCo-
t, area under the
concentration-time curve from time zero to the time of the last measurable
concentration; AUG-24, area
under the concentration-time curve from time zero to 24 hours post XL184 dose;
AUG-72, area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo-Inf,
area under the
concentration-time curve from time zero to infinity; ice!, apparent terminal
elimination rate constant; 0/2,
apparent terminal elimination half-life; CL/F, apparent total body clearance;
V/F, apparent total volume
of distribution;
100

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[00358] Table 49. Individual and Descriptive Statistics of Plasma
Pharmaco*kinetic Parameters of Demethyl Half-dimer Sulfate using a Radio-
quantitative Method following a Single 175 mg Oral Administration of 114C1-
XL184
(100 Ci) to Healthy Male Subjects
Subject C. 1. AUCo-t AUC0-24 AUC0_72 Ratio3 Ratiob AUCo_inf
Ica ty,
(ng,Eq/mL) (h) (h. ng,Eq/mL) (h. ng,Eq/mL) (h. ng,Eq/mL) (%) (%)
(h. ng,Eq/mL) (1/h) (h)
1444-1023 418 24.00 92500 4250 22900 309
46.3 NR NR NR
1444-1040 172 72.00 43300 917 7150 82.3
18.6 NR NR NR
1444-1042 391 168.00 103000 2590 19100 192
40.0 NE NE NE
1444-1052 533 71.98 117000 2320 20300 549
56.3 NR NR NR
N 4 4 4 4 4 4 4 0 0 0
Mean 379 84.00 89000 2520 17400 283
40.3 NA NA NA
SD 151 60.40 32000 1370
7000 200 15.9 NA NA NA
SEM 75.4 30.20 16000 683 3500 100 7.97
NA NA NA
Min 172 24.00 43300 917
7150 82.3 18.6 NA NA NA
Median 405 71.99 97800 2460 19700 251
43.2 NA NA NA
Max 533 168.00 117000
4250 22900 549 56.3 NA NA NA
%CV 40 72 36 54 40 71 40 NA
NA NA
GM 350 67.61 83400 2200
15900 228 37.3 NA NA NA
GM: Geometric Mean; NR: Not reportable since AUCo_t/ AUCo_inf ratio < 0.80;
NE: Not Estimable; NA: Not Applicable; 3: ratio of AUCo-t (metabolite)/ AUCo-t
(parent); b: ratio of
AUCo-t (each analyte)/ AUCo-t (parent + 6 measured metabolites); C., maximum
observed
concentration; T.x, time of the maximum concentration; AUCo-t, area under the
concentration-time
curve from time zero to the time of the last measurable concentration; AUC0-
24, area under the
concentration-time curve from time zero to 24 hours post XL184 dose; AUC0-72,
area under the
concentration-time curve from time zero to 72 hours post XL184 dose; AUCo-Inf,
area under the
concentration-time curve from time zero to infinity; Ica, apparent terminal
elimination rate constant; 0/2,
apparent terminal elimination half-life; CL/F, apparent total body clearance;
V/F, apparent total volume
of distribution
101

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[00359] Table 50. Individual and Descriptive Statistics of
Plasma
Pharmaco*kinetic Parameters of P5 using a Radio-quantitative Method following a
Single 175 mg Oral Administration of 114C1-XL184 (100 Ci) to Healthy Male
Subjects
Subject C. tin. AUCo-i AUC0_24 AUC0-72
Ratioa Ratiob AUCo_id Ica ty,
(ng,Eq/mL) (h) (h=ng,Eq/mL) (h=ngEq/mL) (h=ng,Eq/mL) (%) (%)
(h=ng,Eq/mL) (1/h) (h)
1444-1042 247 5.00 7920 3750 7280 14.8 3.08 8720
0.00945 73.4
1444-1051 145 2.00 7150 1180 2660 21.5 5.41
NR NR NR
1444-1052 190 1.98 7910 2470 7920 37.1 3.80 NR NR NR
N 3 3 3 3 3 3 3 1 1 1
Mean 194 2.99 7660 2470 5950 24.5 4.10
8720 0.00945 73.4
SD 51.1 1.74 442 1290 2870 11.4 1.19
NA NA NA
SEM 29.5 1.00 255 743 1660 6.61 0.689 NA NA
NA
Min 145 1.98 7150 1180 2660 14.8 3.08 8720
0.00945 73.4
Median 190 2.00 7910 2470 7280 21.5 3.80 8720
0.00945 73.4
Max 247 5.00 7920 3750 7920 37.1 5.41 8720
0.00945 73.4
%CV 26 58 6 52 48
47 29 NA NA NA
GM 189 2.71 7650 2220 5350 22.8 3.99
8720 0.00945 73.4
GM: Geometric Mean; NR: Not reportable since AUCo_t/ AUCor ratio < 0.80; NA:
Not
Applicable; a: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio of AUCo-
t (each analyte)/ AUCo-t
(parent + 6 measured metabolites);
Cmax, maximum observed concentration; Tmax, time of the maximum concentration;
AUCo-t, area under
the concentration-time curve from time zero to the time of the last measurable
concentration; AUC0-24,
area under the concentration-time curve from time zero to 24 hours post XL184
dose; AUC0-72, area
under the concentration-time curve from time zero to 72 hours post XL184 dose;
AUC0-,d, area under the
concentration-time curve from time zero to infinity; ka, apparent terminal
elimination rate constant; tin.,
apparent terminal elimination half-life; CL/F, apparent total body clearance;
V/F, apparent total volume
of distribution
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[00360] Table 51. Individual and Descriptive Statistics of Plasma
Pharmaco*kinetic Parameters of P7 using a Radio-quantitative Method following a
Single 175 mg Oral Administration of 114C1-XL184 (100 Ci) to Healthy Male
Subjects
Subject C. t. AUCo-t
AUC0-24 AUC0_72 Ratio3 Ratiob AUCo_mr Ica ty,
(ng,Eq/mL) (h) (h. ngEq/mL) (h. ng,Eq/mL) (h. ng,Eq/mL) (%) (%)
(h. ngEq/mL) (1/h) (h)
1444-1051 95.3 2.00 510 625 625 1.54
0.386 NR NR NR
N 1 1 1 1 1 1 1 0 0 0
Mean 95.3 2.00 510 625 625 1.54 0.386 NA
NA NA
SD NA NA NA NA NA NA
NA -- NA NA NA
SEM NA NA NA NA NA NA NA
NA NA NA
Min 95.3 2.00 510 625 625
1.54 0.386 NA NA NA
Median 95.3 2.00 510 625 625 1.54
0.386 NA NA NA
Max 95.3 2.00 510 625 625 --
1.54 0.386 NA NA NA
%CV NA NA NA NA NA NA NA
NA NA NA
GM 95.3 2.00 510 625 625 --
1.54 0.386 NA NA NA
GM: Geometric Mean; NR: Not reportable since AUC04/ AUCo_mr ratio < 0.80; NA:
Not
Applicable; 3: ratio of AUCo-t (metabolite)/ AUCo-t (parent); b: ratio of AUCo-
t (each analyte)/ AUCo-t
(parent + 6 measured metabolites); GI., maximum observed concentration; T.x,
time of the maximum
concentration; AUCo-t, area under the concentration-time curve from time zero
to the time of the last
measurable concentration; AUC0-24, area under the concentration-time curve
from time zero to 24 hours
post XL184 dose; AUC0-72, area under the concentration-time curve from time
zero to 72 hours post
XL184 dose; AUCo-Inr, area under the concentration-time curve from time zero
to infinity; kej apparent
terminal elimination rate constant; 6/2, apparent terminal elimination half-
life; CL/F, apparent total body
clearance; V/F, apparent total volume of distribution
[00361] Procedure for Preparation of Vehicle for ['4C1-XL184 for Oral
Solution: PEG-
400/TPGS/Ethanol 85/10/5 w/w/w
Example for 600 g - Scale amounts proportionally for other volumes desired.
1. Heat about 600 g of PEG 400 in an oven set at 50 C.
2. Heat about 100 g of TPGS in an oven set at 50 C. Heat till TPGS has
completely
liquefied.
3. Weigh a 1000 mL glass bottle with cap and record the weight.
4. Tare the balance.
5. Weigh 510 g of warm PEG 400 from step 1 into the glass bottle from step
4.
6. Tare the balance.
7. Weigh 60 g of TPGS from step 2 into the bottle from step 6.
8. Mix the contents of the bottle from step 7 by swirling gently.
9. Place the bottle from step 8 in an oven set at 50 C for about 30
minutes, swirl the
contents intermittently to ensure that the solution is hom*ogenous.
10. Remove the bottle from step 9 from the oven and allow it to cool to RT.
11. Place the bottle on the balance and tare the balance.
12. Weigh 30 g of ethanol into the bottle from step 11, seal the bottle
with the cap, and
mix the contents gently till the solution is hom*ogenous.
13. Label the bottle as follows:
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"Vehicle for ['C(U)]XL184 for Oral Solution"
"Store tightly capped at 25 C to 37 C"
Preparation date and time
Use date and time (use within 24 hours of preparation).
Note: The vehicle must be stored between 25 C and 37 C. The vehicle, when
exposed to
temperatures below 25 C for extended duration (4-6 hours), might become cloudy
due to
precipitation of TPGS. If this happens then the vehicle may be heated to 37 C
to dissolve
any precipitate. Handling to the vehicle at ambient temperature during
preparation of the
formulation is permissible.
[00362] Procedure for Preparation of Oral Solution of [14C1-XL184
[00363] 175 mg/subject (salt basis); 100 uCi/subject; concentration of drug in
vehicle is
about 8 mg/mL (salt basis)
1. Prepare 500 g of vehicle according to instructions; include cinnamon
flavoring
(0.1% v/v).
2. Dispense about 263 mL of vehicle into tared dose prep container (suggest
500 mL
quantity).
3. Add 2100 mg of unlabeled XL184.
4. Add approx. 10 mg of labeled XL184.
5. Dissolve drug in vehicle, according to instructions.
6. Weigh total amount.
7. Withdraw two or three aliquots of about 1 g each and determine
radioactivity per
unit weight, by LSC and drug potency.
8. Dispense about 22 mL aliquots for each subject and obtain accurate
weight for
each aliquot.
9. Administer each aliquot to subject.
[00364] Dose dispensed to each subject will be accurately determined by
multiplying
weight of each aliquot in Step 8 with activity determined in Step 7.
[00365] REFERENCES
[00366] Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R,
Pfister
DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J,
Muller T,
Ratain MJ, Salgia R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase
inhibitor, in
patients with medullary thyroid cancer. J Clin Oncol. 2011; 29(19):2660-6.
104

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[00367] Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib
(XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses
metastasis,
angiogenesis, and tumor growth. Mol Cancer Ther. 2011; 10(12):2298-308.
[00368] The foregoing disclosure has been described in some detail by way of
illustration
and example for purposes of clarity and understanding. The invention has been
described
with reference to various specific and preferred embodiments and techniques.
However, it
should be understood that many variations and modifications can be made while
remaining
within the spirit and scope of the invention. It will be obvious to one of
skill in the art that
changes and modifications can be practiced within the scope of the appended
claims.
Therefore, it is to be understood that the above description is intended to be
illustrative and
not restrictive. The scope of the invention should, therefore, be determined
not with reference
to the above description, but should instead be determined with reference to
the following
appended claims, along with the full scope of equivalents to which such claims
are entitled.
105