Public Disclosure Synopsis
Protocol A4061044 – 27 June 2014 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME® / GENERIC DRUG NAME: Inlyta® / Axitinib
PROTOCOL NO.: A4061044
PROTOCOL TITLE: A Phase 1 Study in Patients With Advanced Solid Tumor to
Evaluate the Pharmacokinetics and Safety of AG-013736 at Single Doses of 5 mg, 7 mg, and10 mg, and at Multiple Doses
Study Center: One study center in Japan took part in the study and enrolled subjects.
Study Initiation Date and Final Completion Date: 29 July 2008 to 26 April 2010

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Phase of Development: Phase 1
Study Objectives:
Primary Objective:

To evaluate plasma pharmacokinetics (PK) of axitinib (AG-013736) following single
doses of 5 mg, 7 mg, and 10 mg.

Secondary Objective:

To evaluate the safety of axitinib following single and multiple twice daily (BID) dosing.

To evaluate plasma PK of axitinib following multiple dosing.



To investigate the changes of the plasma concentration profiles of the pharmacodynamics(PD) indices, soluble vascular endothelial growth factor receptors (s-VEGFR1),
s-VEGFR2, s-VEGFR3, stem cell factor receptor (s-KIT) and vascular endothelial
growth factor (VEGF).



To investigate the antitumor activity of axitinib.

To investigate the effect on PK of axitinib by uridine
diphosphate-glucuronosyltransferase (UGT)1A1 and cytochrome P450 (CYP) 3A4/5
gene polymorphisms. Other genes suspected to affect the PK of axitinib could also havebeen evaluated.

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METHODS
Study Design: This study was an open-label, single-arm study in Japanese subjects withadvanced solid tumors to evaluate the PK, safety, PD, and antitumor activity of axitinib. In
addition, the potential effect of gene polymorphisms on the PK of axitinib was investigated.

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Six subjects were to receive single dosing of axitinib, (5, 7, and 10 mg), and multiple dosingof 5 mg BID. One cycle length was 28 days. If the drug was well tolerated at 5 mg BID, thedose of axitinib was titrated from 7 mg BID up to a maximum of 10 mg BID. Subjects
continued the study treatment until they experienced intolerable toxicity or progressive
disease. The schedule activities are presented in Table 1 (for the single dosing regimen) andTable 2 (for the multiple dosing regimen).

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Table 1.

Schedule of Tests and Procedures: Single Dosing of 5 mg, 7 mg, and 10 mg Axitinib

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Observation

Screening
Within 14
Within 4
Days Predose Days Predose

5 mg(Acceptable Range)
Day 1
Day 2
Predoseat 24 Hours
Postdose or
Later(-4 Days)-

Informed consentaSubject background

X
X

Weight , body temperature, pulse
ratecBlood pressure
ECOG PS

X

X

X

X
X

b

e

Hematology

Coagulation test

g

X

h

X

Blood chemistryi

Urinalysis

X
X

j

X
X

k

12-lead electrocardiogram
Blood samples for UGT1A1 andCYP3A4/5 test
Blood samples for PK

Single Dosing
7 mg(Acceptable Range)
Day 1
Day 2
Predose*At 24 Hours
Postdose or
Later(-4 Days**)
-

X

X

X

10 mg
(Acceptable Range)
Day 1
Day 2
Predose*at 24 Hours
Postdose or
Later(-4 Days**)
-

X

X

X
X

X
X
X

X
X

X
X
X

X
X

X

f

X

X

X

X

X

f

X

X

X

X

X

X

f

X

X

X

X

X

X

d

d

f

X

d

X
l

m

l

X
X

X

l

X

Blood samples for PD markers
Pregnancy test
XnX
Tumor measurements
Drug compliance
X
X
X
Concomitant
medications/therapies
AEs
SAEs* Minimum of 48-hour observation after the previous single dosing was required before initiating the next single dose.
** If the tests and procedures scheduled on each single dosing on Day 2 had performed within 4 days before Day 1 of each next single dosing, these tests and procedures except
for blood pressure measurement and pharmacokinetics sampling were not repeated.
AEs = Adverse events; CYP = cytochrome P450; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = end of treatment;

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Table 1.

Schedule of Tests and Procedures: Single Dosing of 5 mg, 7 mg, and 10 mg Axitinib

PD = pharmacodynamics; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; s-KIT = stem cell factor receptor;
T3 = triiodothyronine; T4 = tetraiodothyronine; s-VEGFR1 = soluble vascular endothelial growth factor receptor; VEGF = vascular endothelial growth factor receptor; UGT
1A1 = uridine diphosphate-glucuronosyltransferase.
a. Subject background included the status of smoking.
b. Weight was measured on 5 mg single-dosing Day 1.
c. BP was measured twice at least 1 hour apart at the subject visit (including the screening visit). BP was measured at least twice daily during hospitalization that included
measurements before each axitinib dosing. Blood pressure measurements were made with the subject in the sitting position after the subject rested for 5 minutes.
d. BP was measured at predose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose. This serial BP measurement was performed on the same day of PK sampling.
e. Red blood cell count, hemoglobin, hematocrit, white blood cell count and its differential (neutrophil, eosinophil, basophil, lymphocyte, monocyte), and platelet count were
measured.
f. If the predose tests (at Screening) were conducted within 4 days before single dosing of 5 mg, the test on Day 1 of 5 mg single dosing was not necessary.
g. Prothrombin time and activated partial thromboplastin times were measured.
h. Aspartate aminotransferase (AST), alanine aminotransferase , lactate dehydrogenase, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, total
bilirubin, blood urea nitrogen, creatinine, total cholesterol, glucose (fasted state), creatine phosphokinase, amylase/lipase, and thyroid stimulating hormone, free-T3, free-T4,
thyroglobulin, anti-thyroid peroxidase antibody (at screening only), anti-thyroglobulin antibody (at screening only) were measured. Hypothyroidism should be treatedaccording to the standard medical practice to maintain euthyroid state.
i. pH, urinary protein, urine sugar, urine occult blood (qualitative/semi-quantitative for all), urinary sediment (at screening only) were measured. If urinalysis(semiquantitative testing such as dipstick) revealed urinary protein ≥2+, a 24-hour urine collection was performed.
j. If urinalysis (semiquantitative testing such as dipstick) revealed urinary protein ≥1+, a 24-hour urine collection was performed. Patients with urinary protein <2 g/24 hours
were enrolled.
k. Three consecutive 12-lead electrocardiograms were performed approximately 2 minutes apart to determine the mean QTc interval. Additional ECGs were performed if
clinically indicated.
l. Blood samples for pharmacokinetics were collected at predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hours post-dose.
m. Plasma concentrations of pharmacodynamic markers (s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT, VEGF) were measured.
n. Any results of evaluation which was performed within 28 days before treatment initiation could be used.

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Table 2.

Schedule of Tests and Procedures: Multiple Dosing

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Observation

Multiple Dosing
Day 1
Predose**(-4 Days)***Cycle 1*
(Acceptable Range)
Day 8
Day 15(±4 Days)

Weight , bodytemperature, pulse rate

X

Blood pressure

X

a

b

Post-Treatment(Acceptable Range)

Day 22

Cycle 2*
(Acceptable Range)
Day 1
Day 15

Cycle 3 or Later*(Acceptable Range)
Day 1
Day 15(±4 Days)(±4 Days)(±4 Days)(±4 Days)(±4 Days)(±4 Days)

At EOT/
Discontinuation(+4 Days)

X

X

X

X

X

X

X

X

Follow-Up
28 DaysAfter Last
Dose****
-

X

X

X

X

X

X

X

X

-

d

c

X (except for the hospitalization period)

Home BP monitoring
ECOG PSe
Hematology

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

-

Coagulation test

f

X

X

X

X

X

X

X

X

X

-

g

Blood chemistry

X

X

X

X

X

X

X

X

X

-

Urinalysis

X

X

X

X

X

X

X

X

X

-

-

-

j

X

-

-

-

-

-

X

-

-

-

k

X

-

-

-

-

-

X

-

h

i

12-lead ECG
Blood samples for PKm

Blood samples for PK
Blood samples for PDnmarkers

l

X

-

l

X

Cycle 4 and6 only

-

-

-

-

-

-

When dose was titrated/reduced
-

X

-

X
Up to
Cycle 12oX
X
Tumor assessment
Drug compliance
Concomitant
medications/therapies
AEs
SAEs* One cycle length was 28 days.
** Minimum of 48-hour observation after 10 mg single dosing was required before the initiation of the multiple dosing.
*** If the tests and procedures scheduled on 10 mg single dosing Day 2 had been performed within 4 days before the initiation of multiple dosing, these tests and procedures
except for blood pressure measurements on Cycle 1 Day 1 were not repeated.
**** AEs was to be collected at the visit after 28 days from last dosing.
AEs = Adverse events; BP = blood pressure; BID = twice daily; CYP = cytochrome P450; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group

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Table 2.

Schedule of Tests and Procedures: Multiple Dosing

performance status; EOT = end of treatment; PD = pharmacodynamics; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse
events; s-KIT = stem cell factor receptor; T3 = triiodothyronine; T4 = tetraiodothyronine; s-VEGFR1 = soluble vascular endothelial growth factor receptor; VEGF = vascularendothelial growth factor receptor; UGT 1A1 = uridine diphosphate-glucuronosyltransferase.
a. Weight was measured every Cycle (Day 1) and EOT/discontinuation.
b. Blood pressure was measured twice at least 1 hour apart at the subject visit. Blood pressure was to be measured at least twice daily during hospitalization that included
measurements before each axitinib dosing. Blood pressure measurements were made with the subject in the sitting position after the subject rested for 5 minutes.
c. Blood pressure was measured at predose, 1, 2, 4, 6, 8, 10, and 12 hours postdose (12 hours post dose measurement was made before the next dosing). These serial bloodpressure measurements were performed on the same day of PK samplingd. Subjects were issued blood pressure cuffs (provided by the Sponsor) for home monitoring. Blood pressure measurements were made at least twice daily prior to each axitinib
dosing on an outpatient basis and were recorded in a subject diary. Subjects were instructed by the study staff to hold doses temporarily and contact their Physician
immediately for guidance if their systolic blood pressure was elevated above 150 mm Hg, or diastolic blood pressure was elevated above 100 mm Hg, or if they developed
symptoms perceived to be related to elevated blood pressure (eg, headache, visual disturbance). If subjects were unable to contact their Physician for guidance, subjects wereto restart dosing when systolic blood pressure fell below 140 mm Hg, diastolic blood pressure fell below 90 mm Hg, and all symptoms related to elevated blood pressure
resolved.
e. Red blood cell count, hemoglobin, hematocrit, white blood cell count and differential (neutrophil, eosinophil, basophil, lymphocyte, monocyte), platelet count were measured.
f. Prothrombin time (PT) and activated partial thromboplastin times were measured.
g. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, total
bilirubin, blood urea nitrogen (BUN), creatinine, total cholesterol, glucose (fasted state), creatine phosphokinase, amylase/lipase, thyroid stimulating hormone, free-T3,
free-T4, thyroglobulin were measured. Hypothyroidism was treated per standard medical practice to maintain euthyroid state.
h. pH, urinary protein, urine sugar, urine occult blood (qualitative/semi-quantitative for all). If urinalysis (semiquantitative testing such as dipstick) revealed urinary protein≥2+, a 24-hour urine collection was performed.
i. Three consecutive 12-lead ECGs were performed approximately 2 minutes apart to determine the mean QTc interval. Additional ECGs was performed if clinically indicated.
j. 12-lead ECG was performed at 1-3 hours postdose on Day 15 of Cycle 1.
k. Blood samples for PK were collected at predose and 0.5, 1, 2, 4, 8, and 12 hours postdose (12 hour post dose sampling was conducted before next dosing). All PK samplings
was completed before the dose titration if dose was titrated to 7 mg BID on Day 15 of Cycle 1.
l. Blood samples for population pharmacokinetic analysis were collected at the clinic, prior to the morning dose and 2 hours after the dose on Day 1 of Cycle 2, Cycle 4, andCycle 6.
m. Blood samples for PK were collected for the subjects who underwent dose titration/reduction on Day 15 of Cycle 1 or later. A 4-hour serial PK sampling was performed at
subject visit, 5 days or more after dose increase/decrease (prior to the next dose increase/decrease). The collection time points for the 4-hour serial PK sampling were predose(prior to the morning dose), 1, 2, 3, and 4 hours postdose. It was not necessary to repeat 4-hour serial PK sampling when subject increased/decreased to the dose which had
been previously received and 4-hour serial PK sampling had been performed.
n. Blood samples for plasma concentrations of pharmacodynamic markers (s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT, VEGF) were collected on Day 1 of Cycle 2 to Cycle 12,
and at EOT/discontinuation.
o. Tumor assessment was performed on Day 1 of every other cycle (acceptable range: ±7 days). The tumor was evaluated by the same method used at the Baseline. Acceptable
range of tumor assessment at EOT/discontinuation was + 28 days. If treatment was completed/discontinued less than 8 weeks after the previous tumor assessment, anotherassessment was not necessary. For subjects in whom the tumor was evaluated as response by RECIST (complete response /partial response), confirmation was required atleast 28 days after the response was noted.

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Number of Subjects (Planned and Analyzed): Six subjects were planned for enrollment toassess the PK of axitinib by single administration of 5 mg, followed by 7, and subsequently
10 mg dose. Enrollment of additional subjects was planned in case any subject discontinued
the study and did not complete the PK evaluation. A total of 6 subjects were enrolled andassigned to study treatment and all enrolled subjects were treated with axitinib.

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Diagnosis and Main Criteria for Inclusion: Subjects were male or female aged 20 years
and older with histologically or cytologically diagnosed advanced solid tumors with Eastern
Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2, with nouncontrolled hypertension, and for whom standard therapies were not effective or there were
no appropriate therapies. Subjects who had central lung lesions involving major bloodvessels, required anticoagulant therapy, had active epilepsy symptoms, brain metastases
requiring treatment, spinal cord compression or carcinomatous meningitis were excluded
from the study.
Study Treatment: Subjects received a single 5-mg dose of axitinib, followed by single
7- and 10-mg doses. After administration of each of these single doses, subjects weremonitored for at least 48 hours when no additional axitinib was administered. When themonitoring period was completed following the 10 mg single dose, subjects received
multiple dosages of axitinib at 5 mg BID. Axitinib was administered orally to subjects in the
fed state. Doses were to be taken as close to 12 hours apart as possible and at approximately
the same time each day.
Subjects who tolerated axitinib without any treatment-related adverse events (AEs) above theCommon Terminology Criteria for AEs (CTCAE [version 3.0,]) Grade 2 for consecutive
2-week periods from Day 1 of Cycle 1 had their dose titrated to 7 mg BID and then to a
maximum of 10 mg BID, unless the subject had systolic blood BP >150 mm Hg or diastolic
BP >90 mm Hg, or were receiving antihypertensive medication. Subjects were monitored forminimum of 2 weeks before every dose titration. Subjects who experienced hypertension,
hemoptysis, proteinuria, other treatment-related nonhematological or AEs >Grade 3 (up to
and including treatment-related Grade 4 hematological AEs) were considered for dosage
reduction or a temporary discontinuation of axitinib treatment.
In this study, subjects continued study treatment until they experienced intolerable toxicity or
progressive disease.
Efficacy, Pharmacokinetic, Pharmacodynamic, and Safety Endpoints:
Primary Endpoint:

Plasma PK of axitinib following single dosing

Secondary Endpoints:


AEs



Plasma PK of axitinib following multiple dosing

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Protocol A4061044 – 27 June 2014 – Final

Plasma concentrations of s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT and VEGF



Anti-tumor effect; evaluate tumor response according to Response Evaluation Criteria in
Solid Tumors (RECIST) by tumor type for subjects in whom the tumor was evaluated by
RECIST

Pharmacogenomics (PG); correlation between UGT1A1 and CYP3A4/5 genotype and
PK of axitinib. Other genes suspected to affect to PK of axitinib was also evaluatedSafety Evaluations: Safety was assessed by monitoring adverse events, and laboratory test
results, vital signs measurements, and electrocardiograms (ECGs).

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Statistical Methods: Efficacy: The number of subjects assessed as complete response,
partial response, stable disease and progressive disease according to the RECIST wassummarized by tumor type.
Pharmacokinetic Analysis: Each PK parameter was summarized by cycle/day and included
the set of summary statistics. For subjects who underwent dose modification, maximum
plasma concentration (Cmax), area under the plasma concentration-time curve from Time 0
until 4 hours postdose (AUC4h), time to first occurrence of Cmax (Tmax) and minimum plasma
concentration (Cmin) were calculated for each modified dose per subject.
Pharmacodynamics Analysis: Time profiles of individual PD parameters (plasma
concentrations of s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT, and VEGF) were summarized
in graphs and tables, and descriptive statistics were calculated for measured values.
Pharmacogenomics (Genotyping): The correlation between UGT1A1 and CYP3A4/5
genotype and the PK of axitinib were investigated. Other genes suspected to affect the PK of
axitinib could also have been evaluated.
RESULTS
Subject Disposition and Demography: A total of 6 subjects were assigned to study
treatment and all were treated with axitinib. This study was continued until all subjects
discontinued; the reason for discontinuation was lack of efficacy in all subjects (Table 3).
Table 3.

Subject Disposition

Subject Category (Number of Subjects)

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Axitinib(N=6)

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Protocol A4061044 – 27 June 2014 – Final
TreatedCompleted
Discontinued
Reason for Discontinuation
Related to Study Drug
Lack of Efficacy

6
0
6
6a

N = total number of enrolled subjects; PD = progressive disease.

a.

All were assessed as having PD.

All 6 subjects were included in the each analysis set for PK, PD, PG, efficacy, and safety(Table 4).
Table 4.

Data Sets Analyzed

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Category (Number of Subjects)
Assigned to Study Treatment
Analyzed for PK
Analyzed for PD
Analyzed for PG
Analyzed for Efficacy
Anti-Tumor Response
Analyzed for Safety
Adverse events
Laboratory data
N = total number of enrolled subjects; PD = pharmacodynamics; PG = pharmacogenomics;
PK = pharmacokinetics.

Axitinib
(N=6)
6
6
6
6
6
6
6

Demography and baseline characteristics are summarized in Table 5. All (6) enrolled
subjects were Japanese. Three subjects were male, 3 were female, and all were aged between
25 and 66 years, inclusive (mean age =53.8 years). No enrolled subjects were current
smokers or had any kind of allergy. The baseline ECOG PS was 0 in 1 subject and 1 in 5
subjects.

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Table 5.

Subjects Demographics

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Characteristic

Axitinib
N=6Gender, n3
Male3
FemaleAge (years) , n
0
<18
1
18-44
3
45-64
2
65
53.8
Mean
15.8
SD
25–66
Range
Race, n6
Asian (Japanese)
Height (cm)
161.9
Mean
6.8
SD
151.6-70.6
Range
Weight (kg)
52.1
Mean
11.8
SD
37.3-65.9
Range
Smoking habit, n
0
Yes
a
No
6
Allergy, n
0
Yes
6
No
ECOG Performance Status, n1051ECOG PS = Eastern Cooperative Oncology Group Performance Status; N = total number of subjects;n = number of subjects in specified category; SD = standard deviation.
a. Three ex-smokers included.

Efficacy, Pharmacokinetic, and Pharmacodynamic Results:
Pharmacokinetic Results: A summary of the plasma PK parameters after administration of
single oral doses of axitinib (5, 7, and 10 mg [in the fed state]) is provided in Table 6.
Geometric mean (coefficient of variation [CV, %]) for Cmax after administration of a single
oral dose of axitinib 5, 7 and 10 mg were 17.01 ng/mL (69.9%), 23.30 ng/mL (88.2%) and
34.91 ng/mL (114.7%), respectively. Geometric mean (CV%) for AUCinf afteradministration of a single oral dose of axitinib 5, 7 and 10 mg were 142.0 ngh/mL (85.9%),
180.6 ngh/mL (80.2%) and 287.7 ngh/mL (91.1%), respectively. Tmax and t1/2 were similar
after administration of each of the 3 dose levels.

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Table 6.

Axitinib Plasma Pharmacokinetic Parameters After 5, 7, and 10 mg
Single-Dose

Dose
(mg)

Variable57
10

Geometric mean
CV (%)
Geometric Mean
CV (%)
Geometric Mean
CV (%)

Cmax(ng/mL)
17.01
69.9
23.30
88.2
34.91
114.7

AUCinf(ngh/mL)
142.0
85.9
180.6
80.2
287.7
91.1

Tmax
(h)
4.100a(3.95, 6.02)c
4.000a(0.983, 9.88) c
4.015a(2.05, 6.00) c

t1/2
(h)
4.778b
58.9
5.088b50.9
5.880b
58.8

CL/F
(L/h)
35.25
56.9
38.79
61.8
34.74
73.3

Vz/F
(L)
206.4
87.2
254.3
82.8
246.3
126.0

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AUCinf = area under the plasma concentration-time curve from time zero to time infinity; CV = coefficient ofvariation; Cmax = maximum plasma concentration; CL/F = apparent oral clearance; Tmax = time to firstoccurrence of Cmax; t1/2 = terminal phase plasma half life; Vz/F = apparent volume of distribution.
a. Medianb. Arithmetic meanc. (minimum, maximum)

A summary of plasma PK parameters of axitinib after multiple oral dosing (5 mg BID in fed
state) on Cycle 1 Day 15 is provided in Table 7. Geometric mean (CV%) for Cmax and AUCτon Cycle 1 Day 15 were 21.40 ng/mL (83.7%) and 137.6 ngh/mL (77.9%), respectively.
Median (min, max) for Tmax on Cycle 1 Day 15 was 4.04 (3.93, 7.70) hours. The geometricmean (90% CI) of observed accumulation ratio (Rac) for Cmax and AUC were 1.257(0.8728-1.811) and 1.372 (1.082-1.738), respectively. The observed Rac was consistent withthe value predicted from the mean half-life.
Table 7.

Pharmacokinetic Parameters (5 mg BID at Cycle 1, Day 15)

Variable
Geometric Mean
CV (%)
90% CI

Cmax(ng/mL)
21.40
83.7
NC

AUC
(ngh/mL)
137.6
77.9
NC

Tmax
(h)
a
4.040
b
(3.93, 7.70)
NC

Rac
Cmax
1.257
39.4
0.8728-1.811

AUC
1.372
27.9
1.082-1.738

N=6.
AUC = area under the plasma concentration-time curve over dosing interval ; CV = coefficient of variation;
CI = confidence interval; Cmax = maximum plasma concentration; N = total number of subjects; NC = Not
calculated; Rac = accumulation ratio; Tmax = time to first occurrence of Cmax; Vz/F = apparent volume of
distribution.
a. Medianb. (minimum, maximum)

Plasma concentrations of soluble proteins are summarized in Table 8.

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Table 8.

Soluble Protein Plasma Concentrations

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Soluble Protein

Visit/DayN

Axitinib
Median (Minimum,
MeanSD
Maximum)s-VEGFR1

Baseline (pg/mL)
Cycle 2 Day 1 (pg/mL)
Percent change from Baseline (%)

a

6
4
4

90.9522.03
66.9517.68–28.742.99

96.20 (60.9, 119.0)
72.00 (41.8, 82.0)–29.15 (–31.4, –25.3)

s-VEGFR2

Baseline (pg/mL)
Cycle 2 Day 1 (pg/mL)
Percent change from Baseline (%)

a

6
4
4

8106.71060.3
5460.01504.3–37.7214.21

8250.0 (6480, 9450)
6035.0 (3290, 6480)–33.16 (–58.4, –26.2)

s-VEGFR3

Baseline (pg/mL)
Cycle 2 Day 1 (pg/mL)
Percent change from Baseline (%)

a

6
4
4

31616.710028.0
15627.57266.4–55.2710.1027000.0 (24600, 50400)
15550.0 (8310, 23100)–56.38 (–66.2, –42.1)

s-KIT

Baseline (pg/mL)
Cycle 2 Day 1 (pg/mL)
Percent change from Baseline (%)

a

6
4
4

51666.710748.9
44400.011869.3–14.537.57

48250.0 (40900, 69500)
43300.0 (31200, 59800)–14.59 (–23.7, –5.2)

VEGF

Baseline (pg/mL)
Cycle 2 Day 1 (pg/mL)
Percent change from Baseline (%)

a

6
4
4

126.80144.52
246.73142.84
460.15660.56

67.80 (21.3, 414.0)
249.00 (88.9, 400.0)
179.52 (37.0, 1444.6)

N = number of subjects with the given soluble protein at each visit; S.D. = standard deviation; s-KIT = soluble
stem cell factor receptor; s-VEGFR = soluble vascular endothelial growth factor receptor; VEGF = vascularendthelial growth factor.
a. Plasma concentration value at Single dose Day 1 was used as the baseline value.

No subjects were identified as having heterozygous or homozygous variants for
CYP3A4*1B, CYP3A4*2, CYP3A5*1B, CYP3A5*1C, CYP3A5*6, CYP3A5*7,
UGT1A1*27 and UGT1A1*6. There were also no homozygous variants detected for
UGT1A1*60, UGT1A1*93, or the UGT1A1 TA repeat. The relationship between PK
parameters and genotype was not readily evident. For CYP3A5*3, the relationship between
PK and genotype was unclear due to the limited number of subjects with this particulargenotype.

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Table 9.

Predicted Genotype

Gene

Variant Genotyped

Axitinib

N=6
Predicted Genotype
Homozygous Wild Type
Heterozygous
Homozygous Variant
Number of Subjects
Number of Subjects
Number of Subjects
n (%)
n (%)
n (%)
CYP3A41B
6 (100%)2
6 (100%)
CYP3A51B
6 (100%)1C
6 (100%)3
1 (16.7%)
5 (58.3%)
6
6 (100%)7
6 (100%)UGT1A127
6 (100%)*6
6 (100%)*60
2 (33.3%)
4 (66.7%)*93
5 (83.3%)
1 (16.7%)*36
5 (83.3%)
1 (16.7%)
CYP = cytochrome P450; n = number of subjects with the given genomic marker; N = total number of enrolled subjects;
UGT1A1 = uridine diphosphate-glucuronosyltransferase.

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Efficacy Results: Individual tumor response assessed by the Investigator is listed inTable 10.
Three (3)/6 subjects (50.0%) had a best RECIST defined response of stable disease. No
subject showed RECIST defined CR or PR in this study. The target lesion size wasdecreased from baseline in 2 subjects (1 subject each with esophageal carcinoma andpancreatic carcinoma), with a maximum percentage decrease of 11.5% in 1 subject withpancreatic carcinoma.
Table 10. Individual Tumor Response (Investigator-Assessed)
Serial Number

1
2
3
4
5
6

Primary Diagnosis(MedDRA)Best Overall
Response (RECIST)

Synovial sarcoma
Oesophageal carcinoma
Hypopharyngeal cancer
Gastric cancer
Pancreatic carcinoma
Liposarcoma

SD
SD
PD
PD
SD
PD

a

Maximum % Change
in Target Lesion Size
From Baseline
b
NA
–6.1
30.5
27.2
–11.5
25.5

MedDRA version 13.0 coding dictionary applied.
NA = not applicable; PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors;
SD = stable disease.
a. When the sum of the longest diameter of target lesions was the smallest during the study.
b. No measurable lesion at Baseline.

Safety Results: Commonly reported all-causality nonserious AEs were fatigue,
hypertension, blood TSH increased, proteinuria, palmar-plantar erythrodysasthesia syndrome(Table 11).

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Table 11. Treatment-Emergent Nonserious Adverse Events by System Organ Classand Preferred Term (All Causalities)
System Organ Class and MedDRA
Preferred Term
Number of subjects: evaluable for AEs n (%)
Number of subjects: with AEs n (%)
Endocrine disorders
Thyroiditis chronic
Eye disorders
Eye irritation
Gastrointestinal disorders
Abdominal pain upper
Ascites
Cheilitis
Constipation
Diarrhoea
NauseaStomatitis
General disorders and administration site conditions
Chest pain
Fatigue
Mucosal inflammation
OedemaHepatobiliary disorders
Jaundice cholestatic
Infections and infestations
Nasopharyngitis
Paronychia
Injury, poisoning and procedural complications
Contusion
Fracture
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood amylase increased
Blood cholesterol increased
Blood lactate dehydrogenase increased
Blood potassium increased
Blood thyroid stimulating hormone decreased
Blood thyroid stimulating hormone increased
Blood urine present
Lipase increased
Neutrophil count decreased
Platelet count decreased
Thyroglobulin increased
Thyroxine free decreased
Thyroxine free increased
Tri-iodothyronine free decreased
Weight decreased
White blood cell count decreased
Metabolism and nutrition disorders
Decreased appetite
Musculoskeletal and connective tissue disorders

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Axitinib
N=66
6 (100.0)
1 (16.7)
1 (16.7)
1 (16.7)
1 (16.7)
4 (66.7)
1 (16.7)
1 (16.7)
1 (16.7)
2 (33.3)
3 (50.0)
2 (33.3)
2 (33.3)
5 (83.3)
1 (16.7)
5 (83.3)
1 (16.7)
2 (33.3)
1 (16.7)
1 (16.7)
2 (33.3)
2 (33.3)
1 (16.7)
2 (33.3)
1 (16.7)
1 (16.7)
6 (100.0)
1 (16.7)
2 (33.3)
3 (50.0)
3 (50.0)
2 (33.3)
3 (50.0)
1 (16.7)
2 (33.3)
4 (66.7)
1 (16.7)
1 (16.7)
2 (33.3)
1 (16.7)
1 (16.7)
2 (33.3)
1 (16.7)
2 (33.3)
1 (16.7)
2 (33.3)
3 (50.0)
3 (50.0)
3 (50.0)

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Table 11. Treatment-Emergent Nonserious Adverse Events by System Organ Classand Preferred Term (All Causalities)
System Organ Class and MedDRA
Axitinib
Preferred Term
N=6
Back pain
1 (16.7)
Myalgia
2 (33.3)
Neck pain
1 (16.7)
Neoplasms benign, malignant and unspecified (inclusive cysts and2 (33.3)
polyps)Cancer pain
2 (33.3)
Nervous system disorders
4 (66.7)
Dizziness
1 (16.7)
Headache2 (33.3)
Neuropathy peripheral
3 (50.0)
Somnolence
1 (16.7)
Renal and urinary disorders
4 (66.7)
Proteinuria
4 (66.7)
Reproductive system and breast disorders
1 (16.7)
Menstruation irregular
1 (16.7)
Respiratory, thoracic and mediastinal disorders
3 (50.0)Cough
1 (16.7)
Dysphonia
2 (33.3)
Epistaxis
2 (33.3)
Skin and subcutaneous tissue disorders
5 (83.3)
Dermatitis
1 (16.7)
Dermatitis acneiform
1 (16.7)
Haemorrhage subcutaneous
1 (16.7)
Palmar-plantar erythrodyasthesia syndrome
4 (66.7)
Pruritus
1 (16.7)Rash
3 (50.0)
Telangiectasia
1 (16.7)
Urticaria
1 (16.7)
Vascular disorders
5 (83.3)
Hypertension
5 (83.3)
Hypotension
2 (33.3)
Subjects were only counted once per treatment for each row.
Includes data up to 28 days after last dose of study drug.
MedDRA (version 13.0) coding dictionary applied.
AE = adverse events; n = number of subjects with AEs; N = total number of enrolled subjects.

Treatment-related AEs are summarized in Table 12.

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Table 12. Summary of Treatment-Emergent Adverse Events (Treatment Related, All
Cycles)

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System Organ Class
Preferred Term

Axitinib
(N=6)
n (%)
6 (100.0)
1 (16.7)
1 (16.7)
1 (16.7)
1 (16.7)
4 (66.7)
1 (16.7)
1 (16.7)
2 (33.3)
3 (50.0)
1 (16.7)
2 (33.3)
5 (83.3)
5 (83.3)
1 (16.7)
2 (33.3)
1 (16.7)
1 (16.7)
5 (83.3)
2 (33.3)
2 (33.3)
1 (16.7)
4 (66.7)
1 (16.7)
2 (33.3)
1 (16.7)
1 (16.7)
2 (33.3)
2 (33.3)
1 (16.7)
2 (33.3)
2 (33.3)
2 (33.3)
2 (33.3)
2 (33.3)
2 (33.3)
2 (33.3)
1 (16.7)
1 (16.7)
4 (66.7)
4 (66.7)
1 (16.7)
1 (16.7)
3 (50.0)
2 (33.3)
2 (33.3)
5 (83.3)
1 (16.7)
1 (16.7)

Any AEs
Endocrine disorders
Thyroiditis chronic
Eye disorders
Eye irritation
Gastrointestinal disorders
Ascites
Cheilitis
Constipation
Diarrhoea
NauseaStomatitis
General disorders and administration site conditions
Fatigue
Mucosal inflammation
OedemaInfections and infestations
Paronychia
Investigations
Blood amylase increased
Blood cholesterol increased
Blood potassium increased
Blood thyroid stimulating hormone increased
Lipase increased
Neutrophil count decreased
Platelet count decreased
Thyroglobulin increased
Thyroxine free decreased
Tri-iodothyronine free decreased
Weight decreased
White Blood cell count decreased
Metabolism and nutrition disorders
Decreased appetite
Musculoskeletal and connective tissue disorders
Myalgia
Nervous system disorders
Headache
Neuropathy peripheral
Somnolence
Renal and urinary disorders
Proteinuria
Reproductive system and breast disorders
Menstruation irregular
Respiratory, thoracic and mediastinal disorders
Dysphonia
Epistaxis
Skin and subcutaneous tissue disorders
Dermatitis
Dermatitis acneiform

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Table 12. Summary of Treatment-Emergent Adverse Events (Treatment Related, All
Cycles)System Organ Class
Preferred Term

Axitinib
(N=6)
n (%)
1 (16.7)
4 (66.7)
1 (16.7)
3 (50.0)
1 (16.7)
1 (16.7)
5 (83.3)
5 (83.3)

Haemorrhage subcutaneous
Palmar-plantar erythrodysaesthesia syndrome
Pruritus
Rash
Telangiectasia
Urticaria
Vascular disorders
Hypertension
MedDRA (version 13.0) coding dictionary applied.
SAEs and AEs are not separated out in this table.
AEs = adverse events; MedDRA = Medical Dictionary for Regulatory Activities; N = total number ofsubjects; n = number of subjects with AEs; SAE = serious adverse events.

No SAEs was reported other than 1 disease progression (gastric cancer) resulted in death.

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Table 13. Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All Causalities)
System Organ Class and MedDRA
Axitinib
Preferred Term
N=6
Number of subjects: evaluable for AEs n (%)
6
Number of subjects: with AEs n (%)
1 (16.7)
General disorders and administration site conditions
1 (16.7)
Disease progression
1 (16.7)
Subjects were only counted once per treatment for each row.
Included data up to 28 days after last dose of study drug.
MedDRA (version 13.0) coding dictionary applied.
AE = adverse events; MedDRA = medical Dictionary for Regulatory Activities, n = number of subjects with
AEs; N = total number of enrolled subjects.

Discontinuations: No subject discontinued the study due to an AE. Four (4) of the 6 total
subjects temporarily discontinued the study drug due to AEs and 2 of them also had dose
reductions. Frequently observed AEs which caused temporary discontinuations were
hypertension (4 subjects), proteinuria (1 subject), dysphonia (1 subject), and palmar-plantar
erythrodyasthesia syndrome (1 subject). The reasons for dose reductions were proteinuria
and palmar-plantar erythrodyasthesia syndrome (1 subject each).
Deaths: There was 1 death reported in this study, a 57-year-old female subject died on the
study on Day 72 due to disease progression (gastric cancer, not-related to the study drug).
Electrocardiogram, Clinical Laboratory and Vital Sign Results: The mean changes (±SD) of
ECG QTc interval from the baseline were 0.4±11.1 msec at Cycle 1 Day 15 and -13.1±9.2
msec at the end of treatment /discontinuation. No subject had a clinically significant
abnormal ECG value throughout the study.

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All 6 subjects had at least 1 post baseline laboratory test value abnormal regardless of thebaseline abnormality. Decreased lymphocytes (%) was observed in all 6 subjects. Thyroid
stimulating hormone (TSH) abnormal was the most commonly reported laboratory test
abnormality; Increased TSH was reported in 5/6 subjects and decreased TSH was reported in
3/6 subjects. Other common abnormalities reported in >50% of subjects were decreased
hemoglobin (4 subjects) and increased basophils (%; 4 subjects).
Elevations in mean BP were observed with the peak at 8 to 10 hours postdose. Five subjects
reported hypertension as an AE, and 3/6 experienced at least 1 Grade 3 event. However,these events were controllable with antihypertensive agents.

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CONCLUSIONS:Cmax and AUC were increased dose-proportionally for axitinib single 5, 7, and 10 mg
doses in subjects with solid tumors.

Axitinib was absorbed with peak plasma axitinib concentrations observed at 4 hours after
dosing in fed state and had an elimination half-life of 4.778-5.880 hours. The Rac forCmax and AUC was consistent with the value predicted from mean half-life of the drug.

Common treatment-related AEs (>50%) were fatigue, hypertension, blood TSH
increased, proteinuria, and palmar-plantar erythrodysaesthesia syndrome. Common
Grade 3 treatment-related AEs were hypertension. No SAEs was reported other than
1 disease progression resulted in death (gastric cancer, not-related to the study drug). No
subject discontinued the study due to a AEs. Overall, axitinib was well tolerated in thisstudy.



Axitinib increased VEGF and decreased plasma s-VEGFR1, s-VEGFR2, s-VEGFR3, ands-KIT concentrations. The changes in s-KIT were less pronounced relative tos-VEGFR1, 2, and 3.

Correlations between PK and CYP3A4/5 and UGT genotypes were not readily evident;
however, this may have been due to the limited number of subjects.



The best tumor response according to RECIST was stable disease in 3 of 6 subjects.
Three subjects entered ≥12 cycles of study treatment (with a maximum of 17 cycles)
before progressive disease was noted.

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