Public Disclosure Synopsis
Protocol A4061022 – 28 August 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.: A4061022
PROTOCOL TITLE: A Phase 1 Study of AG-013736 in Patients in Japan With Advanced
Solid Tumors
Study Center: The study was performed at 1 center in Japan.
Study Initiation and Final Completion Dates: 06 February 2007 to 27 August 2009
Phase of Development: Phase 1090177e185aef1ef\Approved\Approved On: 17-Sep-2014 17:08

Study Objectives:
Primary Objective:

To evaluate the clinically recommended dose of axitinib (AG-013736) in Japanese
subjects by reviewing the safety of axitinib following single and multiple twice a day(BID) dosing.

Secondary Objectives:
To evaluate the plasma pharmacokinetics (PK) of axitinib in Japanese subjects following
single and multiple dosing.



To investigate the changes of the plasma concentration profiles of the pharmacodynamics
indices soluble vascular endothelial growth factor receptor (s-VEGFR) 2, s-VEGFR3,
soluble stem cell factor receptor (s-KIT), and vascular endothelial growth factor (VEGF).



To investigate the anti-tumor activity of axitinib.

To investigate the effect on the PK of axitinib by uridine
diphosphate-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) andcytochrome P450 (CYP) 3A4 and 5 genotyping. Genes suspected to affect the PK of
axitinib were also evaluated.

METHODS
Study Design: This was an open-label, non-randomized study in subjects with advanced
solid tumors to evaluate the safety, PK, pharmacodynamics and anti-tumor activity of

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Protocol A4061022 – 28 August 2014 – Finalaxitinib, and genomic effects on axitinib metabolism. This study consisted of single dosing
followed by multiple dosing cycles. A cycle length was 28 days and the study treatment
could be continued until the subject experienced intolerable toxicity or progressive disease(PD).

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Six subjects were initially enrolled and each of them received a single dose of 5 mg axitinib.
After monitoring the safety of a single 5 mg dose for at least 48 hours, 5 mg BID multiple
dosing was initiated. This study was to be expanded to add 6 new subjects to receive
multiple dosing in Cycle 1 depending on the number of subjects experiencing dose limiting
toxicities (DLTs) among the first 6 subjects. If no more than 1 of the 6 subjects experienced
DLT following a single 5 mg dose and 5 mg BID multiple dosing in Cycle 1, then the study
was to be expanded to include 6 additional subjects and multiple dosing was to be initiated(from Cycle 1 onwards); if 2 out of 6 subjects experienced DLT, an independent safety data
monitoring committee (DMC) meeting was to be held. The DMC was to suggest thenecessity of adding additional subjects to evaluate the safety of 5 mg BID multiple dosing; if
3 or more of 6 subjects experienced DLT, the maximum tolerated dose (MTD) was to be
assumed to have been exceeded, and the study would not be expanded. The schedule ofactivities is presented in Table 1 (Cycle 1) and Table 2 (Cycle 2 onwards).
For the single dosing PK assessment, approximately 5 mL blood samples were to becollected from the first 6 subjects before dosing and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours
after axitinib dosing.
For the multiple dosing PK assessment, approximately 5 mL blood samples were to becollected from all subjects at the following times:

Cycle 1: Predose on the morning of Days 1 and 15, and 0.5, 1, 2, 4, 8 and 12 hours
postdose (before the next dose).



Cycle 2: Prior to dosing on the morning of Day 1 (immediately before the morning dosetaken at the clinic).

When the dose was increased or decreased in Cycle 2 onwards: 4-hour serial PK samples
were to be collected at the visit which was performed 5 or more days after dose
increase/decrease (the day prior to next dose increase/decrease). Samples were to becollected immediately before the morning dose and 1, 2, 3, and 4 hours postdose.

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Table 1.

Schedule of Tests and Procedures (Up to Cycle 1*)090177e185aef1ef\Approved\Approved On: 17-Sep-2014 17:08

Observation

Screening
Within 14 Days
Within 4 Days
PredosePredoseSingle Dosing †(Days ± Acceptable Range)
Day 1
Day 2
PredoseAt Least 24
Hours
Postdose-4 Days-

Up to Cycle 1
Day 1
Predose-4 Days ‡Cycle 1
(Days ± Acceptable Range)
Day 8
Day 15

Day 22±4 Days±4 Days±4 Days
Informed consent
X
Subject backgrounda
X
Weightb, body temperature,
X
X
X
X
X
X
X
pulse rate
Blood pressurec
X
Xd
Xe
X
Xe
X
Home blood pressure
X (except the period of hospitalization)
monitoringf
ECOG performance status
X
X
X
X
X
X
X
Hematologyg
X
Xh
X
Xh
X
X
X
Coagulation testi
X
Xh
X
Xh
X
X
X
Blood chemistryj
X
Xh
X
Xh
X
X
X
Urinalysisk
Xl
Xh
X
Xh
X
X
12-lead ECGm
X
Xn
Blood samples for UGT1A1 and
X
Xo
CYP3A4/5 test
Blood samples for PK
Xp
Xq
Xq
s
Blood samples for
X
X
pharmacodynamic markersr
Pregnancy test
X
Tumor measurementst
X
Drug compliance
X
Concomitant
medications/therapies
AEs
SAEs* Follow-up observations were to be made to confirm dose limiting toxicity (DLT) up through Cycle 2, as necessary, depending on the timing of onset of DLT.
† Tests and procedures for single dosing were not necessary for subjects who started from multiple dosing.
‡ For subjects who started from single dosing and had the tests and procedures on single dosing Day 2 within 4 days before Cycle 1 Day 1, the tests and procedures on Cycle 1

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Protocol A4061022 – 28 August 2014 – Final

Table 1.

Schedule of Tests and Procedures (Up to Cycle 1*)

Day 1 were not required.
AEs = adverse events; APTT = activated partial thromboplastin times; CYP = cytochrome P450; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;
PK = pharmacokinetics; PT = prothrombin time; SAEs = serious adverse events; s-KIT = stem cell factor receptor; s-VEGFR = soluble vascular endothelial growth factor
receptor; VEGF = vascular endothelial growth factor; UGT = uridine glucuronyl transferase.

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a.
b.
c.
d.
e.
f.

g.
h.
i.
j.
k.
l.
m.
n.
o.
p.
q.
r.
s.
t.

Subject background included the status of smoking.
Weight was measured on Day 1 of single dosing and Day 1 of each Cycle.
Blood pressure was to be measured twice, separated by at least 1 hour, at subject visit (including Screening visit). Blood pressure was to be measured
at least twice daily during hospitalization that included measurements before each axitinib dosing. Blood pressure measurements were to be madewith the subject in the sitting position after the subject being seated quietly for 5 minutes.
Blood pressure was to be measured at pre dosing, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdosing.
Blood pressure was to be measured at pre dosing, 1, 2, 4, 6, 8, 10, and 12 hours postdosing.
Subjects were to be issued blood pressure cuffs (provided by the Sponsor) for home monitoring. Blood pressure measurements were to be made atleast twice daily prior to each axitinib dosing on an outpatient basis and recorded in a subject diary. Subjects were to be 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, subject were to restart dosing when systolic bloodpressure fell below 140 mm Hg and diastolic blood pressure fell below 90 mm Hg, and all symptoms related to elevated blood pressure were resolved.
Red blood cell count, hemoglobin, hematocrit, white blood cell count and its differential, and platelet count were measured.
If the predose tests at the screening were conducted within 4 days before single dosing (or before multiple dosing for subjects who started frommultiple dosing), the test on Day 1 in the single dosing step (or the test on Cycle 1 Day 1 for subjects who started from multiple dosing) were notnecessary.
The PT and APTT were to be measured.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total protein,
albumin, sodium, potassium, chloride, total bilirubin, blood urea nitrogen (BUN), creatinine, glucose, amylase/lipase, and thyroid stimulating
hormone (TSH) were measured.
pH, urinary protein, urine sugar, urine occult blood (qualitative for all), and urinary sediment (only at Screening) were measured. If urinalysis(semiquantitative testing, eg, dipstick) revealed urinary protein ≥1+, a 24-hour urine collection was to be performed.
If urinalysis (semiquantitative testing, eg, dipstick) revealed urinary protein ≥1+, a 24-hour urine collection was to be performed; subjects with total
protein < 500 mg/24 hours, the subject could be enrolled.
Additional ECG was to be performed if required on the basis of clinical symptoms.
ECG was to be performed 1-3 hours after dosing.
Blood samples were to be collected on Cycle 1 Day 1 for subjects who started with multiple dosing.
Blood samples were to be collected at predose, and 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose.
Blood samples were to be collected at predose, and 0.5, 1, 2, 4, 8, and 12 hours postdose.
Plasma concentrations of s-VEGFR 2, s-VEGFR3, soluble s-KIT, and VEGF were to be measured.
Blood samples were to be collected Cycle 1 Day 1 for subjects who started with multiple dosing.
Any results of evaluation which were performed within 28 days before treatment initiation could be used.

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Table 2.

Schedule of Tests and Procedures (Cycle 2 Onwards, EOT/Discontinuation, and Follow-Up)

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Observation
Cycle 2
(Days ± Acceptable
Range)Day 1
Day 15±4 Days±4 DaysX
X

aCycle 2 or Later
Cycle 3(Days ± Acceptable Range)

Cycle 4 or Later(Days ± Acceptable Range)

Day 1±4 DaysX

Day 1±4 DaysX

Day 15±4 DaysX

Day 15±4 DaysX

At EOT/
Discontinuation(Days ± Acceptable
Range)

Follow-Up
28 Days After
Last Dose+4 DaysX

Weight , body temperature,pulse rate
Blood pressureb
X
X
X
X
X
X
X
Home blood pressure
X (except the period of hospitalization)
monitoringc
ECOG performance status
X
X
X
X
X
X
X
Hematologyd
X
X
X
X
X
X
X
Coagulation teste
X
X
X
X
X
X
X
Blood chemistryf
X
X
X
X
X
X
X
Urinalysisg
X
X
X
X
h
12-lead ECG
X
Abbreviated PK sampling if
Xi
When dose was titrated/reducedj
dose was titrated
Blood samples for
X
X
X
X
pharmacodynamics markersk
Tumor assessmentl
X
X
Drug compliance
Concomitant
medications/therapies
AEs
SAEs
AEs = adverse events; APTT = activated partial thromboplastin times; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PK = pharmacokinetics;
PT = Prothrombin time; RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; s-KIT = stem cell factor receptor; s-VEGFR = solublevascular endothelial growth factor receptor; VEGF = vascular endothelial growth factor.

a.
b.

Weight was to be measured on Day 1 of each Cycle.
Blood pressure was to be measured twice, separated by at least 1 hour, at subject visit. Blood pressure was to be measured at least twice daily during
the hospitalization, included measurements before each axitinib dosing. Blood pressure measurements were to be made with the subjects in the sitting

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Table 2.

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c.

d.
e.
f.
g.
h.
i.
j.

k.
l.

Schedule of Tests and Procedures (Cycle 2 Onwards, EOT/Discontinuation, and Follow-Up)

position after the subject seated quietly for 5 minutes.
Subjects were to be issued blood pressure cuffs (provided by the Sponsor) for home monitoring. Blood pressure measurements were to be made atleast twice daily prior to each axitinib dosing on an outpatient basis and recorded in a subject diary. Subjects were to be 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 were to restart dosing when systolic bloodpressure fell below 140 mm Hg and diastolic blood pressure fell below 90 mm Hg, and all symptoms related to elevated blood pressure were resolved.
Red blood cell count, hemoglobin, hematocrit, white blood cell count and its differential, and platelet count were measured.
The PT and APTT were to be measured.
Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, sodium, potassium,chloride, total bilirubin, blood urea nitrogen, creatinine, glucose, amylase/lipase, and thyroid stimulating hormone were to be measured.
pH, urinary protein, urine sugar, and urine occult blood (qualitative for all) were measured. If urinalysis (semiquantitative testing, eg, dipstick)revealed urinary protein ≥1+, a 24-hour urine collection was to be performed.
Additional ECG was to be performed if required on the basis of clinical symptoms.
Blood samples were to be collected at predose (prior to the morning dose taken at the clinic).
For the subjects underwent dose titration/reduction in Cycle 2 or later, 4-hour serial PK sampling was to be performed at the visit which was made5 or more days after dose increase/decrease (the day prior to next dose increase/decrease). The collection timepoints for the 4-hour serial PK
sampling were: predose (prior to the morning dose taken at the clinic) and 1, 2, 3 and 4 hours postdose. If 4-hour serial PK sampling was performed
once at a particular dose, it was not required to perform another 4-hour serial PK sampling when the subject received the same dose following dose
increase/decrease.
Plasma concentrations of s-VEGFR 2, s-VEGFR 3, s-KIT, and VEGF were to be measured. Blood samples were to be collected at Day 1 of eachcycle from Cycle 2 to Cycle 12 and at end of treatment (EOT)/discontinuation.
Tumor assessment was to be done every other cycle (acceptable range: ±7 days) by the same method of tumor assessment used at the Baseline.
Acceptable range for tumor assessment at EOT/discontinuation was +28 days. When treatment was completed/discontinued less than 8 weeks after
the previous tumor assessment, no additional assessments were required. For subject in whom the tumor was evaluated as response (complete
response / partial response) by RECIST required confirmation at least 28 days (+7 days) after the response was to be noted.

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Number of Subjects (Planned and Analyzed): A total of 12 subjects were planned toenroll in this study. The sample size for the single dosing and multiple dosing through theend of Cycle 1 was set at 6. A total of 12 subjects were assigned to and treated with thestudy treatment.
Diagnosis and Main Criteria for Inclusion: Subjects aged 20 to 75 years (inclusive) withhistologically or cytologically diagnosed with advanced malignant solid tumors for whom
standard therapies were not effective, and no suitable therapies were available. Subjects withcentral lung lesions involving major blood vessels and subjects who were treated with
bevacizumab or other VEGFR inhibitor(s) were excluded from the study.
Study Treatment: Axitinib was to be initially administered as a single 5 mg dose, followedby continuous 5 mg BID dosing for the first 6 subjects. Single dosing for the second andsubsequent subjects was to be initiated after the first subject was monitored for at least
48 hours post single dosing.

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An additional 6 subjects were to receive multiple axitinib doses of 5 mg BID depending on
the number of subjects who experienced a DLT among the first 6 subjects. Axitinib wasadministered orally in fed state, taken as close to 12 hours apart as possible and at
approximately the same time each day. One cycle length was 28 days.
The dose of axitinib could be titrated or reduced. If a subject had a dose reduction due totreatment-related toxicity, the dose normally would not be re-escalated. However, subjects
who tolerated the lower dose for 8 weeks or longer without toxicities exceeding Grade 1
were to be considered for dose re-escalation and the Investigator was to discuss such caseswith the Sponsor.
The axitinib tablets were film-coated immediate release tablets and contained 1 mg or 5 mg
axitinib. Tablets were packed in bottles and supplied by the Sponsor.
Efficacy, Pharmacokinetic, Pharmacodynamic, and Safety Endpoints:
Primary Endpoint:Type and grade (Common Terminology Criteria for Adverse Events Version 3.0), timingof onset, outcome, causality with the study drug of all adverse events (AEs) observed,
including abnormal laboratory values.

Secondary Endpoints:PK parameters of axitinib.

Plasma concentrations of s-VEGFR2, s-VEGFR3, s-KIT, and VEGF.



Anti-tumor response according to the Response Evaluation Criteria in Solid Tumors(RECIST) criteria.

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Protocol A4061022 – 28 August 2014 – Final

Correlation between UGT1A1 and CYP3A4/5 genotyping and PK of axitinib. Genes
suspected to affect to PK of axitinib may also be evaluated.

Safety Evaluations: Safety was to be assessed by monitoring AEs, and through laboratory
test results, vital signs measurements, physical examination, and electrocardiograms (ECGs).
DLTs were to be assessed in the first 6 subjects following a single dose or multiple dosing in
Cycle 1 to investigate the recommended clinical dose of axitinib for Japanese subjects. DLT
criteria defined in this study were Grade 4 neutropenia >7 days, Grade 4 thrombocytopenia,
Grade ≥3 non-hematological toxicities, hemoptysis >½ teaspoon (2.5 mL)/day unless it
resolves to baseline within 7 days, and proteinuria ≥2 g/24 hours.
Statistical Methods:

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No confirmatory inferential analyses were planned due to the exploratory nature of thisstudy.


Full Analysis Set (FAS): Subjects who received the study drug at least once. All theanalyses in this study were conducted in the FAS, unless otherwise specified. This
analysis set was also used as the safety analysis set.



DLT evaluation set: Subjects who received a single dose and multiple doses and in whom
DLT had been observed before the end of Cycle 1 or who had completed the Cycle 1
observations. Subjects had to have a compliance rate ≥75% in order to be included in the
DLT evaluation set.

PK, pharmacodynamics, and pharmacogenomics (PG) analysis set: Among the FAS, thesubjects who completed PK, pharmacodynamics, and PG blood sampling for at least
1 day.



Anti-tumor response analysis set: Subjects with at least 1 target lesion according to
RECIST and who received at least 1 dose of study drug.

Efficacy Analysis: The number of subjects assessed as complete response (CR), partial
response (PR), stable disease (SD) and PD according to the RECIST were summarized bytumor type.
PK Analysis: The axitinib PK parameter values were to be calculated for each subject, basedon concentration-time data using non-compartmental analysis by WinNonlin software(Table 3).

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Table 3.

Pharmacokinetic Evaluation

Single dosing:Cmax, AUClast, AUCinf, AUC12h, Tmax, t1/2, and kel, CL/F, and Vz/F
Multiple dosing:
Cycle 1 Day 1
Cmax, AUCtau *, Tmax, t1/2, kel, and Cmin
Cycle 1 Day 15
Cmax, AUCtau *, AUC4h, Tmax, t1/2, kel, Cmin, CL/F, Rac (AUC) and Rac (Cmax)
Cycle 2 Day 1
Cminτ = 12 hours postdose.
AUC = area under curve; AUClast = area under the plasma concentration-time curve from zero time until thelast measurable concentration; AUCinf = area under the plasma concentration-time curve from time zero totime infinity; AUC12h =area under the plasma concentration-time curve from zero time until 12 hours
postdose; AUCtau = area under the plasma concentration-time curve over dosing interval τ; AUC4h = area
under the plasma concentration-time curve from zero time until 4 hours postdose; Cmax = maximum plasma
concentration; Cmin = minimum plasma concentration; Tmax = time to first occurrence of Cmax;
CL/F = apparent oral clearance; kel = terminal phase elimination rate constant; t1/2 = terminal phase plasma
half-life; Vz/F = apparent volume of distribution during the elimination phase; Rac = accumulation ratio.

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Single dosing and multiple dosing was to be analyzed using descriptive statistics. The
terminal half-life in multiple dose periods was not evaluated because the terminal elimination
phase was not adequately characterized following multiple dosing for all subjects.
Pharmacodynamic Analysis: The time profiles of individual plasma concentrations of sVEGFR2, s-VEGFR3, s-KIT, and VEGF were to be summarized in figures and tables, anddescriptive statistics were to be calculated for measured values.
Pharmacogenomics (Genotyping): The potential correlation between UGT1A1 andCYP 3A4/5 genotype and the PK of axitinib were to be investigated.
RESULTS
Subject Disposition and Demography: A total of 12 Japanese subjects were assigned to thestudy treatment and all were treated with axitinib. This study was continued until all subjects
discontinued due to intolerable toxicity or PD. The reason for discontinuation was lack ofefficacy in all except 1 subject who discontinued due to a treatment-related adverse event(Table 4). The first 6 subjects had treatment compliance 75% and, therefore, were includedin the assessment for DLT, according to the protocol.

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Table 4.

Subject Disposition and Subject Analyzed

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Subject Category
Number of Subjects (%)
Enrolled
TreatedCompleted
Discontinued
Reason for Discontinuation
Related to Study Drug
Adverse Event
Lack of Efficacy
Subject Analyzed
Full Analysis Set
Analyzed for PK
Analyzed for Pharmacodynamics
Analyzed for Pharmacogenomics
Analyzed for Safety
Dose limiting toxicity
Adverse events
Laboratory data
PD = progressive disease; PK = pharmacokinetics.
a.
All were assessed as having PD.

Axitinib
1212 (100)0
12 (100)
1 (8.3)11a (91.7)
12 (100)
12 (100)
12 (100)
12 (100)
6 (100)12 (100)
12 (100)

Demography and baseline characteristics are summarized in Table 5.

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Table 5.

Subject Demography and Baseline Characteristics

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Characteristic

Axitinib
N=12Gender, n (%)
Male
7 (58.3)
Female5 (41.7)
Age (years), n (%)
<18
0
18-44
2 (16.7)
45-64
6 (50.0)
4 (33.3)
65
Mean
60.2
SD
13.1
Range
32-75
Race, n (%)
Asian (Japanese)
12 (100)
Height (cm)
Mean
162.7
SD
9.8
Range
148.7-180.2
Weight (kg)
Mean
59.7
SD
13.4
Range
43.6-83.2
Smoking habit, n (%)
Yes
1 (8.3)aNo
11 (91.7)
Allergy, n (%)
Yes
4 (33.3)No
8 (66.7)
ECOG-PS, n (%)
0
6 (50.0)1
5 (41.7)
2
1 (8.3)ECOG-PS = Eastern Cooperative Oncology Group Performance status; N = total number of subjects,n = number of subjects in specified category, SD = standard deviationa.
This included 9 ex-smokers.

Efficacy, Pharmacokinetic, and Pharmacodynamic Results: Primary endpoint in the
study was safety.
Secondary Efficacy Endpoint: Ten (83.3%) out of 12 subjects had a best RECIST defined
response of SD. The target lesion size was decreased from Baseline in 9 subjects (5/6 withcolorectal cancer [CRC], 1/2 with renal cell carcinoma [RCC], 1/1 with ovarian cancer,
1/1 with non-small cell lung cancer [NSCLC], and 1/1 with thymoma malignant) (Table 6).

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Table 6.

Individual Tumor Response (Investigator-Assessed)

Serial Number

Primary Diagnosis(MedDRA)Best Overall
Response (RECIST)

Maximum % Changeain Target Lesion Size
From Baseline

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1
Colorectal cancer
SD
–12.9
2
Rectosigmoid cancer
SD
–5.7
3
Ovarian cancer
SD
–9.2
4
Liposarcoma
PD
46.8
5
Non-small cell lung cancer
SD
–27.9
6
Rectal cancer
SD
–2.5
7
Thymoma malignant
SD
–24.5
8
Rectal cancer
SD
0.5
9Rectal cancer
SD
–30.3
10
Renal cell carcinoma
SD
–1.9
11
Renal cell carcinoma
PD
46.6
12
Colon cancer
SD–35.9
MedDRA version 12.1 was used.
MedDRA = Medical Dictionary for Regulatory Activities; PD = progressive disease; SD = stable disease;
RECIST = Response Evaluation Criteria in Solid Tumors.
a.
When the sum of the longest diameter of target lesions was the lowest during the study.

PK Parameter of Axitinib: A summary of plasma PK parameters after administration of asingle oral 5-mg dose of axitinib (fed state) is provided in Table 7 and the mean plasma
concentration profile is presented in Figure 1.
Table 7.

Axitinib Plasma Pharmacokinetic Parameters (Single Dose)

Cmax
AUCinf
Tmax
t½
CL/F
Vz/F
(ng/mL)(ng•h/mL)
(h)
(h)
(L/h)
(L)
N=6
N=6
N=6
N=6
N=6
N=6
Geometric Mean
28.59
181.3
4.0a
4.8b
27.57
186.56
c
CV %
33.25
69.7
(2, 6)
23.9
42.66
49.97
AUCinf = area under the plasma concentration-time curve from time zero to time infinity; Cmax = maximum
plasma concentration; CV = coefficient of variation; CL/F = apparent oral clearance; Tmax = time to firstoccurrence of Cmax; t1/2 = terminal phase plasma half-life; Vz/F = apparent volume of distribution during theelimination phase.
a.
Median.
b.
Arithmetic mean.
c.
Minimum, maximum.

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Figure 1. Mean Axitinib Plasma Concentration (Single Dose) Linear Plot

A summary of plasma PK parameters of axitinib after multiple oral dosing (5 mg BID in the
fed state) on Cycle 1 Day 15 (5 mg BID in the fed state) is provided in Table 8.
Table 8.

Axitinib Plasma Pharmacokinetic Parameters (Cycle 1, Day 15)

Cmax (ng/mL)
AUCtau (ng•h/mL)
AUC4h (ng•h/mL)
Tmax(h)
N=11a
N=11a
N=11a
N=11a
Geometric Mean
27.01
149.8
59.4
4.0b
CV (%)
56.13
66.7
55.3
(1, 4)c
AUCtau = area under the plasma concentration-time curve over dosing interval τ; AUC4h = area under theplasma concentration-time curve from zero time until 4 hours postdose; Cmax = maximum plasma
concentration; CV = coefficient of variation; N = number of subjects assessed.
a.
One subject was excluded from summary statistics because the Day 14 morning axitinib dose was
not administered.
b.
Median.
c.
Minimum, maximum.

Mean axitinib plasma concentration profiles for Cycle 1 Day 1 and Day 15 are presented in
Figure 2 and Figure 3, respectively.

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Figure 2. Mean Axitinib Plasma Concentration (Cycle 1 Day 1) Linear Plot

Figure 3. Mean Axitinib Plasma Concentration (Cycle 1 Day 15) Linear Plot

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Summary for accumulation ratio (Rac) for Cmax and area under the plasma concentration-time
curve over dosing interval τ (AUCtau) of axitinib following 5 mg BID dosing are provided inTable 9.
Table 9.

Accumulation Ratio (Rac) for Axitinib following 5 mg BID dosing

Rac Cmax
Rac AUCtau
a
a
N=11
N=11
Geometric Mean
1.389
1.481
CV (%)
32.53431.768
90% CI
1.180-1.634
1.266-1.731
AUCtau = area under the plasma concentration-time curve over dosing interval τ; Cmax = maximum plasma concentration;
CV = coefficient of variation; N = number of subjects assessed; Rac = accumulation ratio; CI = confidence intervala.
One subject was excluded from summary statistics at Cycle 1 Day 15 because the Day 14 axitinib morning dose
was not administered090177e185aef1ef\Approved\Approved On: 17-Sep-2014 17:08

Plasma Concentrations of s-VEGFR2, s-VEGFR3, s-KIT, and VEGF: All subjects had adecrease in s-VEGFR2 plasma concentration at Cycle 2 Day 1; the mean  standard
deviation (SD; median, range) percent change from Baseline was –34.7614.99% (-41.73%,-53.2% to –10.1%). Individual changes at Cycle 3 and in later cycles were gradual in most of
subjects; the mean  SD (median, range) percent change from Baseline at study
discontinuation was -34.8514.12% (–40.57%, –53.0% to –8.4%).
All subjects were noted to have a decrease of s-VEGFR3 plasma concentration at Cycle 2
Day 1 and the mean  SD (median, range) percent change from Baseline was –45.5522.20% (–52.50%, –93.7% to –15.6%). Changes at Cycle 3 showed a slight increase
compared to Cycle 2 Day 1 in all subjects and thereafter varied from individual to individual
until study discontinuation. The mean  SD (median, range) percent change from Baseline atstudy discontinuation was –44.3637.14% (–65.48%, –81.2% to 39.4%).
There were no consistent changes in s-KIT plasma concentrations between subjects. In
general, there was little change in mean s-KIT plasma concentration with the mean  SD
(median, range) percent change from Baseline being -0.6015.62% (-0.26%, –23.8% to33.5%) at Cycle 2 Day 1 and –4.59  16.08% (4.66%, –31.2% to 12.9%) at study
discontinuation.
All subjects had an increase of VEGF plasma concentration at Cycle 2 Day 1 and themean  SD (median, range) percent change from Baseline was 288.06287.28% (266.92%,
14.9% to 1030.4%). VEGF plasma concentration fluctuated and individually varied; themaximum mean  SD (median, range) change was 398.14423.40% (292.06%, –43.9% to1113.9%) at Cycle 4 Day 1, and the mean  SD (median, range) percent at thediscontinuation 123.00167.50% (43.48%, –15.5% to 423.1%)
Pharmacogenomics: For CYP3A4*1B, CYP3A4*2, CYP3A5*1B, CYP3A5*1C,
CYP3A5*6, CYP3A5*7, UGT1A1*27, UGT1A1*36, and *37, none of the 12 subjects were
heterozygous or homozygous variants (wt/v, v/v). For UGT1A1*28, *6, *60 and *93, noneof the 12 subjects were homozygous variants (Table 10).

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No correlation between pharmacokinetic parameters and genotype was observed. However,this may have been due to the limited number of subjects in this study.
Table 10. Predicted Genotype
Gene

Variant
Genotyped

N

Axitinib
Predicted Genotype

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Homozygous Wild
Homozygous
Type,
Heterozygous,
Variant,
Number of Subjects
Number of Subjects (%)
Number of Subjects(%)(%)
CYP3A4*1B
1212 (100)*2
12
12 (100)
CYP3A5*1B
12
12 (100)*1C
12
12 (100)*3
12
1 (8.3)4 (33.3)
7 (58.3)*6
12
12 (100)*7
12
12 (100)
UGT1A1*27
12
12 (100)*28
12
7 (58.3)
5 (41.7)*6
12
6 (50.0)
6 (50.0)*60
12
7 (58.3)
5 (41.7)*93
12
7 (58.3)
5 (41.7)
CYP = cytochrome P450; N = number of subjects with the given genomic marker; UGT1A1 = uridine
diphosphate-glucuronosyltransferase 1 family, polypeptide A1.

Safety Results: All-causality treatment-emergent AEs are summarized in Table 11. Overall,commonly reported AEs in all cycles were decreased appetite, fatigue, diarrhea, stomatitis,
and increased blood thyroid stimulating hormone.

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Table 11. Treatment-Emergent Non Serious Adverse Events by System Organ Classand Preferred Term (All Causalities)
System Organ Class and MedDRA
Preferred Term
Number (%) of subjects: evaluable for AEs
Number (%) of subjects: with AEs
Blood and lymphatic system disorders
Lymphopenia
Neutropenia
Cardiac disorders
Palpitations
Ear and labyrinth disorders
Ear discomfort
Endocrine disorders
Hyperthyroidism
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain
Constipation
Diarrhoea
Dyspepsia
NauseaProctalgia
Stomatitis
Toothache
General disorders and administration site conditions
Face oedema
Fatigue
Generalised oedema
Pyrexia
ThirstInfections and infestations
Herpes zoster
Nasopharyngitis
Onychomycosis
Tinea infection
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood albumin decreased
Blood alkaline phosphatase increased
Blood amylase increased
Blood bilirubin increased
Blood creatinine increased
Blood glucose increased
Blood thyroid stimulating hormone decreased
Blood thyroid stimulating hormone increased
Blood urea increased
Blood urine present
Haemoglobin decreased
Lipase increased
Platelet count decreased
Thyroxine free decreased
Thyroxine free increased

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Axitinibn (%)
12
12 (100.0)
1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)12 (100.0)
1 (8.3)5 (41.7)
6 (50.0)
10 (83.3)
2 (16.7)
4 (33.3)
1 (8.3)9 (75.0)
2 (16.7)
11 (91.7)
1 (8.3)10 (83.3)
1 (8.3)1 (8.3)1 (8.3)5 (41.7)
1 (8.3)3 (25.0)
1 (8.3)1 (8.3)12 (100.0)
3 (25.0)
6 (50.0)
1 (8.3)6 (50.0)
1 (8.3)3 (25.0)
1 (8.3)5 (41.7)
4 (33.3)
9 (75.0)
1 (8.3)7 (58.3)
1 (8.3)5 (41.7)
5 (41.7)
1 (8.3)3 (25.0)

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Table 11. Treatment-Emergent Non Serious Adverse Events by System Organ Classand Preferred Term (All Causalities)
System Organ Class and MedDRA
Axitinib
Preferred Termn (%)
Tri-iodothyronine free increased
3 (25.0)
Urine bilirubin increased
2 (16.7)
Weight decreased
4 (33.3)
White blood cell count decreased
3 (25.0)
Metabolism and nutrition disorders
11 (91.7)
Decreased appetite
11 (91.7)
Hypoalbuminaemia
1 (8.3)
Musculoskeletal and connective tissue disorders
5 (41.7)
Arthralgia
1 (8.3)
Back pain
3 (25.0)
Musculoskeletal pain
2 (16.7)
Musculoskeletal stiffness
1 (8.3)
Myalgia
1 (8.3)
Neoplasms benign, malignant and unspecified (inclusive
3 (25.0)
cysts and polyps)
Tumour associated fever
1 (8.3)Tumour pain
2 (16.7)
Nervous system disorders
6 (50.0)
Dysgeusia
1 (8.3)
Headache3 (25.0)
Lacunar infarction
1 (8.3)
Post herpetic neuralgia
1 (8.3)
Somnolence
2 (16.7)
Psychiatric disorders
2 (16.7)
Insomnia
2 (16.7)
Renal and urinary disorders
6 (50.0)
Proteinuria
6 (50.0)
Respiratory, thoracic and mediastinal disorders
11 (91.7)
Cough
4 (33.3)
Dysphonia
7 (58.3)
Dyspnoea
2 (16.7)
Dyspnoea exertional
1 (8.3)
Epistaxis
3 (25.0)
Haemoptysis
1 (8.3)
Nasal mucosal disorder
1 (8.3)Skin and subcutaneous tissue disorders
10 (83.3)
Alopecia
1 (8.3)
Erythema
1 (8.3)
Palmar-plantar erythrodysaesthesia syndrome
8 (66.7)Rash
3 (25.0)
Vascular disorders
6 (50.0)
Hypertension
6 (50.0)
Subjects were only counted once per treatment for each row.
Included data up to 28 days after last dose of study drug.
MedDRA (version 12.1) coding dictionary applied.
AEs = adverse events, MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects
with AEs.

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A total of 222 all-causality AEs and 167 treatment-related AEs were reported for the
12 subjects enrolled in the study. Seven subjects reported all-causality CTCAE Grade 3 or 4
AEs and these 7 subjects had at least 1 treatment-related Grade 3 or 4 AEs (Table 12).
Table 12. Overall Incidence of Treatment-Emergent Adverse Events(Treatment-Related)
Number of Subjects (%)
All Cycles
N=12Treatment-Related
12 (100)167
0
7 (58.3)
01 (8.3)9 (75.0)

Axitinib
Single dose
Cycle 1
N=6
N=12Treatment-Related Treatment-Related
2 (33.3)
12 (100)
378
0
0
0
2 (16.7)000004 (33.3)

Subjects with at least 1 AE
Number of AEs
Subjects with at least 1 SAE
Subjects with grade 3 or 4 AEs
Subjects with grade 5 AEs
Discontinuation due to AEs
Temporarydiscontinuation/dose reduction
due to AEs
AE = adverse event; N = number of subjects assessed; SAE = serious adverse event.

Cycle 1-3
N=12Treatment-Related
12 (100)132
0
5 (41.7)
00
6 (50.0)090177e185aef1ef\Approved\Approved On: 17-Sep-2014 17:08

Serious AEs (SAEs) are summarized in Table 13.
Table 13. Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All Causalities)
System Organ Class and MedDRA
Axitinib
Preferred Termn (%)
Number (%) of subjects: evaluable for AEs
12
Number (%) of subjects: with AEs
5 (41.7)
Cardiac disorders
1 (8.3)
Cardiac tamponade
1 (8.3)
Gastrointestinal disorders
2 (16.7)
Intestinal obstruction
2 (16.7)
General disorders and administration site conditions
2 (16.7)
Pyrexia
2 (16.7)
Infections and infestations
1 (8.3)
Liver abscess
1 (8.3)
Subjects were only counted once per treatment for each row.
AEs = adverse events; MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects with SAEs.

All SAEs (Table 14) were considered not related to the study drug.

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Table 14. Serious Adverse Events
SerialNumber

Daily
Dose

AE
(MeDRA Preferred
Term)Intestinal obstruction

CTCAEGrade

Onseta
Cycle/Day

Causality

1

5 mg

3

Cycle 4/13

2

NA

NA

6 mg

PseudomembranouscolitisCardiac tamponade

3
4

6 mg

5

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6

b

c

Drug
ActionOutcomeNot related

No action

Still present

Post therapy

Not related

No action

Resolved

4

Cycle 5/20

Not related

Resolved

Intestinal obstruction

3

Cycle 4/25

Not related

5 mg

Pyrexia2

Cycle 1/3

Not related

5 mg

Liver abscess3

Cycle 1/3

Not related

14 mg

Pyrexia2

Cycle 2/15

Not related

Stoppedtemporarily
Stoppedtemporarily
Stoppedtemporarily
Stoppedtemporarily
Stoppedtemporarily

d

e

f

Still presentgResolved
Resolved
Resolved

CTCAE Version 3.0 was adopted.
AE = adverse events; CTCAE = Common Terminology Criteria for Adverse Events; MedDRA = Medical Dictionary forRegulatory Activities; NA = not applicable.
a.
Day relative to the date of first dose in multiple dosing.
b.
Investigator causality.
c.
Outcome recorded in the study database.
d.
This event occurred while the subject was pending dose for fatigue.
e.
This event was reported as resolved in the safety database at the follow-up observation.
f.
The outcome was entered in the study database as “resolved” after the pericardial fluid removal: however, it wasentered as “resolving” in the safety database as the subject was still being hospitalized.
g.
The event was reported as resolving in the safety database at the follow-up observation.

Discontinuations and Deaths: One subject permanently discontinued the study due to an AE.
Proteinuria initially occurred in this subject in Cycle 1 Day 6 as a Grade 2 event. Due to
Grade 3 proteinuria (6.4 g/day and 9.2 g/day respectively) the subject temporarily
discontinued study twice, and permanently discontinued the study in Cycle 4 when a third
Grade 3 proteinuria (7.8 g/day) was experienced. At the follow-up observation, proteinuria
still persisted, but was alleviated to Grade 2. The event, coded as a Grade 3 proteinuria, wasconsidered to be treatment-related.
A total of 10/12 subjects temporarily discontinued the study drug due to an AE and 5/12
subjects also had dose reductions. Frequently observed AEs which caused temporary
discontinuations were fatigue (6 subjects) followed by diarrhea and pyrexia (3 subjects each).
No deaths occurred during the study.
All 12 subjects had at least 1 post-baseline abnormal laboratory test value regardless of thebaseline abnormality. Abnormal TSH was the most commonly reported laboratory test
abnormality; increased TSH was reported in 11/12 subjects and decreased TSH was reported
in 6/12 subjects. Other common abnormalities reported in ≥50% of subjects were increased
glucose level (9 subjects), positive urine blood (7 subjects), decreased lymphocytes(%; 6 subjects), and increased neutrophils (%; 6 subjects). CTCAE Grade 3
hypoalbuminemia, alkaline phosphatase, hyperglycemia, and lipase results were recorded in
1 subject each at the planned laboratory tests. No other test results were recorded as CTCAE
Grade 3 or higher after the treatment.

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All subjects had baseline hematology test results (hemoglobin, platelets, white blood cells,
neutrophils, lymphocytes, and prothrombin time)  CTCAE Grade 2. No subjects reported
events related to coagulation factors.
A total of 7/12 subjects reported urine protein (qualitative) at the planned laboratory tests;
3/12 subjects had CTCAE Grade 1, 4/12 subjects had CTCAE Grade 2. Although no subject
reported urine protein  CTCAE Grade 3 by qualitative test, 1 subject was re-graded as
CTCAE Grade 3 after urinary protein > 3.5 g/ 24 hours was confirmed at a 24 hour urine
collection.

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Elevation of blood pressure was observed with the peak at 8 to 12 hours postdose. Maximum
mean ± SD increases from the baseline in systolic blood pressure (SBP) and diastolic bloodpressure (DBP) were 16.2±18.3 mm Hg and 7.2±9.1 mm Hg with absolute values of
137.8±24.7 mm Hg and 81.0±9.7 mm Hg, respectively at 12 hours after administration of asingle dose; 12.8±16.5 mm Hg and 9.3±8.1 mm Hg with absolute values of 133.8±21.9 mm
Hg and 82.3±12.8 mm Hg, respectively at 8 hours postdose on Cycle 1 Day 1. The change
from Baseline was smaller at 8 hours postdose on Cycle 1 Day 15 (SBP: 6.7±12.6 mm Hg
and DBP: 2.2±8.8 mm Hg) with absolute values of 128.8±16.1 mm Hg and 81.2±7.7 mm Hg,
respectively. Blood pressure subsequently remained relatively stable following adequate
anti-hypertensive treatment.
The mean changes (±SD) of ECG QTc interval from the baseline were –26.3±20.1 msec at
Cycle 1 Day 15 and 1.3±15.9 msec at study discontinuation. No subject had a QTc interval
480 msec or had QTc interval increased 30 msec.
CONCLUSIONS:Only 1 subject experienced a DLT (Grade 3 proteinuria and Grade 3 fatigue) in thisstudy. Common treatment-related AEs occurring in ≥50% subjects were decreased
appetite, fatigue, diarrhea, blood TSH increased, stomatitis, palmar-plantar
erythrodysaesthesia syndrome, blood urine present, dysphonia, and hypertension.
Common Grade 3 treatment-related AEs were fatigue and hypertension. There were notreatment-related SAEs or deaths reported in this study. One subject discontinued thestudy due to an AE (treatment-related proteinuria). Overall, axitinib was well tolerated inthis study.

The peak plasma axitinib concentration was reached at a median of 4 hours postdose in
the fed state and axitinib was eliminated from plasma with a mean half-life of 4.8 hours.
The mean (90% CI) for axitinib Rac for AUCtau was 1.481 (1.266 - 1.731); the observed
Rac was consistent with the value predicted from the mean half-life of the drug.



Axitinib treatment increased VEGF and decreased plasma s-VEGFR2 and s-VEGFR3
concentrations; in contrast, axitinib had little effect on s-KIT plasma concentrations.



No correlations between PK and CYP3A4/5 and UGT genotypes were observed;
however, this may have been due to the limited number of subjects.

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The best tumor response (RECIST) was “stable disease” in 10/12 subjects. Four subjects
entered ≥9 cycles of study treatment (with a maximum of 29 cycles) before PD wasnoted.

The clinically recommended starting dose for Japanese subjects was determined to be
5 mg BID.

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

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