Public Disclosure Synopsis
Protocol A4061046 – 29 September 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.: A4061046
PROTOCOL TITLE: Randomized, Double-Blind Phase 2 Study of Axitinib (AG 013736)
With or Without Dose Titration in Patients With Metastatic Renal Cell Carcinoma

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Study Center: A total of 52 centers took part in the study and enrolled subjects; 19 in the
United States, 15 in Japan, 6 in the Russian Federation, 5 in Germany, 4 in the Czech
Republic, and 3 in Spain.
Study Initiation, Primary Completion, and Final Completion Dates:
Study Initiation Date: 11 September 2009
Primary Completion Date (PCD): 12 October 2012
Final Completion Date: This study is still ongoing.
Phase of Development: Phase 2
Study Objectives:
Primary Objective: To compare the objective response rate (ORR) in subjects receiving
axitinib with or without dose titration (Arms A and B, respectively).
Secondary Objective: To assess the safety profile, other efficacy parameters,
pharmacokinetics (PK), biomarker and/or gene expression profiling correlations with clinicaloutcome and/or blood pressure (BP) measurements in subjects receiving axitinib with orwithout dose titration (Arms A and B, respectively). Although the main study comparison is
between Arms A and B, additional information such as those related to safety andbiomarker/gene expression profiling correlations with clinical outcome were also assessed in
the non-randomized group, Arm C. Subjects who discontinued the study during the lead-in
period, prior to the point of randomization decision, were analyzed in a separate arm(additional to Arms A, B, and C).
METHODS
Study Design: This was a randomized, double-blind (DB), placebo-controlled, Phase 2
study of axitinib with or without dose titration in subjects with metastatic renal cell
carcinoma (mRCC).
Eligible subjects were to be initially enrolled in a lead-in period (4 weeks) during which theyreceived a starting dose of axitinib 5 mg twice a day (BID) as Cycle 1 (Figure 1). After theTemplate version 1.1

Page 1

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

lead-in period, subjects who met the randomization criteria, were to be stratified by Eastern
Cooperative Oncology Group (ECOG) performance status (0 versus [vs] 1), and randomized(1:1 ratio) to dose titration with either axitinib (Arm A) or placebo (Arm B). Subjects who
did not meet randomization criteria were not to be randomized but were to continue on study
without dose titration (Arm C). Once assigned to a treatment arm, subjects were to remain in
the same treatment arm throughout the study; cross over to another treatment arm of thestudy was not permitted. Subjects were to receive treatment on an outpatient basis.
After the lead-in period (Cycle 1; Figure 1) and prior to randomization, the following
randomization criteria had to be met: systolic BP (sBP) 150 mm Hg and diastolic BP(dBP) 90 mm Hg, no Grade 3 or 4 axitinib-related toxicities, no dose reduction during
lead-in period, and no >2 concurrent antihypertensive medications. BP criteria were to be
met and documented by 2 BP readings taken 1 hour apart, just prior to randomization(1:1 ratio), on Cycle 2 Day 1. Randomization was using a Interactive Voice Response
System, and assigned to receive either axitinib + axitinib dose titration (Arm A) or
axitinib + placebo dose titration (Arm B), unless otherwise contraindicated per Investigator’s
judgment.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Figure 1.

Overview of the Study Design

BID = twice a day; BP = blood pressure.

The study duration for an individual subject included a 14-day screening period, a 4-weeks
lead-in period and subsequent treatment cycles with axitinib (with active titration or placebo
titration, Arm A or Arm B; or without dose titration, Arm C) until the end-of-study.
The detailed schedule of activities for the study is presented in Table 1.

Template version 1.1

Page 2

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 1.

Schedule of Activitiesa

Screening
Day -14 to
Day -1b

X

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Protocol Activityb

Informed consentgRandomization (if eligible)h
Assessment for dose titration
Medical and oncologic history
ECOG performance status
12-lead ECGi
Physical examinationjVital signskHome BP monitoring
Collect home BP diarylAssess/record BP interventionm
HematologynBlood chemistryo
Thyroid function testingp
Urine proteinqPregnancy test
rst
PK (serial 6-hr or sparse) , ,24 hour ABPM andutelemedicine
Brain MRI or CT scanv

Tumor assessmentsw

AE assessment
Concomitant medications
x
Biomarkers

yGenotypingzSurvival

Template version 1.1

Prior toLead-in
Period(Cycle 1)c
Day -1

Lead-indPeriod(Cycle 1)eDay 1

Lead-in
Period(Cycle 1)
Day 4

Lead-in
Period(Cycle 1)
Day 15

Cycle 2
Day 1

Cycle 2
Day 15

Cycle 3 &Subsequent
Odd Cycles
Day 1

Cycle 4 &Subsequent
Even
Cycles
Day 1

End
of
Study

Follow-Up
28 DaysAfter Last
f
Dose

X

(X)

(X)

X

X

X

X

X
X
X
X
X
X
X
X
X
X
X
--------------------Twice daily throughout the study period------------------------------X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X
X

X

X
X
X
X
X
X

X

X

X
X
X
X
X

X

r

X

X

Day -28 toDay -1Day -28 toDay -1
X
X

X
X

X

s

X

(X)

X
X
X
X

(X)

X

t

Q8 weeks X3, then Q12
weeks
Throughout the study period
Throughout the study period
X
XX

X (soluble
proteins,
Cycle 3
Day 1 only)

X (soluble
proteins,
Cycle 4
Day1 only)

X
X
X

X

X
X,
Q3 months

Page 3

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 1.

Schedule of Activities

ABPM = ambulatory blood pressure monitoring; AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase;
BID = twice a day; BP = blood pressure; CEC = circulating endothelial cell; CEP = circulating endothelial cell progenitor; CR = complete response; CRF = case report form;
dBP = diastolic blood pressure; EC = Ethics Committee; Hgb = hemoglobin; IRB = Institutional Review Bord; LDH = lactate dehydrogenase; PK = pharmacokinetic; PR = partial
response; sBP = systolic blood pressure; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; UGT1A1 = uridine diphosphate glucuronosyltransferase 1A1;
UPC = urine protein : creatinine (ratio); WBC = white blood cell.
a. Schedule could have varied 4 days (except where noted) to allow flexibility. Schedule of activities represents the minimum required procedures. Additional/more frequentassessments could be performed as clinically indicated and per standard medical practice.
b. Screening & baseline assessments: informed consent had been obtained prior to any procedures performed solely for study purposes.
c. Prior to lead-in period, Day -1 ABPM could be performed between Day -7 to Day -1, after enrollment eligibility had been confirmed.
d. Lead-in period was Cycle 1. Each cycle length was 4 weeks.
e. Day 1: was not to repeat Cycle 1 Day 1 assessments if they were performed and acceptable within previous 7 days.
f. Follow-up: performed 28 days after the last dose of study drug or at initiation of a new anticancer treatment, whichever occurred first.
g. Randomization criteria had to be met for randomization. After completing the lead-in period, subjects who met all of the following randomization criteria for 2 consecutive
weeks during the lead-in period (Cycle 1) were to be randomized, unless otherwise contraindicated per Investigator’s judgment: sBP 150 mm/Hg; and dBP 90 mm/Hg; andno Grade 3 or 4 axitinib-related toxicities; and no dose reduction during lead-in period; and no >2 concurrent antihypertensive medications. BP criteria were to be met anddocumented by 2 BP readings taken 1 hour apart. Subjects who did not meet randomization criteria were not to be randomized but were to continue on study without dose
titration in Arm C. Once a treatment arm had been assigned, crossover to another arm was not permitted.
h. Arms A and B only. Prior to dose titration, subjects had to meet the dose titration criteria for each step of dose titration. The maximum dose level was 10 mg BID. After at
least 2 consecutive weeks on the current dose, subjects satisfying the following dose titration criteria were to have their dose level increased by 1 additional dose level, unlessotherwise contraindicated per the Investigator’s clinical judgment: sBP 150 mm Hg; and dBP 90 mm Hg; and no Grade 3 or 4 axitinib-related toxicities; and no>2 concurrent antihypertensive medications.
i. Physical examination: included height/weight on initial examination. Subsequent targeted examinations based on signs and symptoms could be performed.
j. Vital signs included: BP taken with the subject in the seated position after the subject had been sitting quietly for 5 minutes, pulse, temperature, respiratory rate.
k. BP: BP was to be taken with the subject in the seated position after the subject had been sitting quietly for 5 minutes. All subjects were to receive home BP monitoring
devices. Subjects were to take BP at least twice daily prior to taking each dose of axitinib, and BP was to be recorded in a subject diary. Subjects were to be instructed tocontact their doctor immediately for guidance if their sBP rose above 150 mm Hg, dBP rose above 100 mm Hg, or if they developed symptoms perceived to be related toelevated BP (eg, headache, visual disturbance).
l. Assessed and recorded on CRF whether or not home BP measurement(s) resulted in any of the following clinical intervention(s) at any time point during the cycle: BP
medication added, BP medication dose adjusted, study drug temporarily held, study drug dose adjusted, study drug permanently discontinued, hospitalization, othermedical/pharmacological intervention (CRF). A CRF was to be completed each time home BP measurement(s) trigger(s) any of the above intervention(s), even if theintervention occurred outside of a clinic visit.
m. Hematology: Hgb, WBC, ANC, and platelets. All lab tests were to be performed at local labs.
n. Serum chemistry: sodium, potassium, chloride, LDH, AST, ALT, alkaline phosphatase, total bilirubin, total protein, albumin, BUN, creatinine, and glucose.
o. Serum or plasma thyroid function testing: TSH, total or free T3, and free T4.
p. Urine protein: if urine protein 2+ by semiquantitative method (eg, dipstick) then was to quantify by UPC ratio.
q. Pregnancy test (serum/urine): was to be performed within 72 hours of treatment only for women of childbearing potential. To be repeated during the study if clinicallyindicated or requested by the EC/IRB or required by local regulations.
r. Lead-in period Day 15 (Cycle 1 Day 15): serial 6-hour PK profiling was to be obtained from approximately 75 subjects at designated sites at the following time points:
predose, 0.5, 1, 2, 4, 6 hours postdose. A BP reading was to be obtained up to 5 minutes prior to each PK draw (BP reading could be obtained by manually prompting the
ABPM device and recording the time of manual prompting). Subjects were to be instructed to hold the morning axitinib dose on the day of PK sampling until the predose PK

Template version 1.1

Page 4

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 1.

Schedule of Activities

had been drawn. If subjects had inadvertently taken their morning axitinib dose prior to the serial PK draw, the serial 6-hour PK collections and the ABPM were to be deferred
to another day prior to Cycle 2 Day 1. Note that the Cycle 1 Day 15 ABPM was to be initiated on the same day as the Cycle 1 Day 15 serial 6-hour PK and ABPM was to be
initiated prior to the first PK collection of that day. Sparse PK samples were to be collected from the remaining subjects (who were not getting serial 6-hour PKs) at thefollowing 2 time points: predose and 1-2 hours postdose. Subjects were to be instructed to hold the morning axitinib dose on the day of PK sampling until the predose PK had
been drawn. If subjects had inadvertently taken their morning axitinib dose before arriving at the clinic, then 2 PK blood samples separated by at least 2 hours were to becollected at the clinic, and the time of axitinib dosing was to be recorded.
s. Postrandomization Day 15 (Cycle 2 Day 15) Arms A and B only: serial 6-hour PK profiling was to be obtained from approximately 12 subjects enrolled in each of Arm A
and B at designated sites at the following time points: predose, 0.5, 1, 2, 4, and 6 hours postdose. Note that these 12 subjects in each of Arm A and B were among the same
75 subjects who had PK performed on Day 15 of the lead-in period (Cycle 1 Day 15). Subjects were to be instructed to hold the morning axitinib dose on the day of PK
sampling until the predose PK had been drawn. If subjects had inadvertently taken their morning axitinib dose prior to the serial PK draw, the serial 6-hour PK collections
were to be deferred to another day prior to Cycle 3 Day 1. Sparse PK samples were to be collected from the remaining subjects (who were not getting serial 6-hour PK) at thefollowing 2 time points: predose and 1-2 hours postdose. Subjects were to be instructed to hold the morning axitinib dose on the day of PK sampling until the predose PK had
been drawn. If subjects had inadvertently taken their morning axitinib dose before arriving at the clinic, then 2 PK blood samples separated by at least 2 hours were to becollected at the clinic and the time of axitinib dosing was to be recorded.
t. Postrandomization, posttitration to 10 mg (Arms A and B only): sparse PK sampling: If applicable, all subjects in Arms A and B who titrated up to 10 mg BID doses were tohave 2 PK blood samples collected at least 4 days after starting on 10 mg BID (ie, at the next scheduled visit; regardless of which cycle [odd/even] titration to 10 mg occurred)at the following 2 time points: at predose and 1-2 hours postdose. Subjects were to be instructed to hold the morning axitinib dose until the predose PK had been drawn. If
subjects had inadvertently taken their morning axitinib dose prior to the sparse PK draw, then 2 sparse PK blood samples separated by at least 2 hours were to be collected at
the clinic, and the time of axitinib dosing was to be recorded.
u. A baseline ABPM was to be performed on Day -1 of the lead-in period on approximately 75 subjects at designated sites; note that these 75 subjects were also the same
75 subjects from whom serial 6-hour PK was to be collected. To allow flexibility in scheduling, Day -1 ABPM could be performed between Day -7 and Day -1, after
enrollment eligibility had been confirmed. On Day 4 and Day 15 of the lead-in period (Cycle 1 Day 4, Cycle 1 Day 15), ABPM was to be performed on the same 75 subjects
who had a baseline ABPM. ABPM was to be performed throughout the day. Additionally, a BP reading was to be obtained up to 5 minutes prior to each PK draw on Cycle 1
Day 15 (BP reading could be obtained by manually prompting the ABPM device and recording the time of manual prompting). Note that the Cycle 1 Day 15 ABPM was to be
initiated on the same day as the Cycle 1 Day 15 serial 6-hour PK, and ABPM was to be initiated prior to the first PK collection of that day. To allow flexibility in scheduling,Day 4 ABPM could be performed between Day 3 and Day 7; Day 15 ABPM could be performed between Day 13 and Day 17, as long as the Cycle 1 Day 15 serial 6-hour PK
was also performed on the same day as ABPM.
v. Radiographic tumor assessments: CT scan of chest, abdomen, and pelvis performed at Baseline and repeated every 8 weeks x 3, then every 12 weeks. A PR or CR was to be
confirmed with a repeat scan at least 4 weeks, but no later than 6 weeks, after the PR/CR.
w. AE assessments: the reporting period for nonserious AEs terminated 28 days after the last dose of study treatment or upon initiation of a new anticancer treatment, whicheveroccurred first. Ongoing treatment-related AEs were to be followed up until resolution, return to baseline, chronicity, or initiation of subsequent anticancer treatment. The
serious AEs reporting period ended 28 days after the last study treatment dose, irrespectively of start of any new anticancer treatment.
x. Biomarkers were to include blood samples for each of the following: 1) gene expression profiling in whole blood (2.5 mL); 2) gene expression profiling in CECs isolated fromwhole blood (9 mL); 3) enumeration and functional status of CECs/CEPs (7.5 mL); and 4) soluble proteins (6 mL).
y. Genotyping for UGT1A1 and other genes/drug metabolizing enzymes/transporters. 1 blood sample (2 mL).
z. Survival status was to be collected and recorded every 3 months after the follow-up study visit, until at least 1 year after the last subject had been randomized.

Template version 1.1

Page 5

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Number of Subjects (Planned and Analyzed): A total of 200 subjects were planned forenrollment in order to obtain approximately 70 randomizable subjects (35 in each, Arm A
and Arm B). A total of 213 subjects were enrolled and treated during the study: 56 subjects
each in Arm A and Arm B, 91 subjects in the non-randomized group, and 10 subjects in the
discontinued prior to randomization group.
Diagnosis and Main Criteria for Inclusion: Males and females, 18 years and older, whowere diagnosed with mRCC with clear cell component, who received no prior systemic
therapy (including no prior adjuvant or neo-adjuvant). Subjects had to have ECOG
performance status 0-1 and BP 140/90 mm Hg. Subjects with brain/central nervous systemmetastasis and subjects who were using >2 BP medications were excluded from the study.
Study Treatment: Axitinib and matching placebo were supplied as 1-mg and 5-mg,
immediate-release, film-coated tablets for oral administration.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

During the lead-in period, all enrolled subjects received a starting dose of axitinib 5 mg BID
taken orally, and dose titration was not permitted; however, dose reduction was permitted.
Subjects who required a dose reduction during the lead-in period, or otherwise did not meetthe randomization criteria, were not randomized and continued the study without dose
titration in Arm C.
Arm A Treatment: Subjects received a total dose of 7 mg of axitinib taken as 3 tablets BID(ie, axitinib 5 mg BID + 2 DB axitinib 1 mg BID). After at least 2 consecutive weeks at the
7 mg BID dose, subjects who continued to satisfy the dose titration criteria were to have their
DB dose level increased by 1 additional dose level, to 10-mg axitinib taken as 2 tablets BID(ie, axitinib 5 mg BID + 1 DB axitinib 5 mg BID), which was the maximum total dose in
Arm A.
Arm B Treatment: Subjects received a total dose of 5 mg of axitinib taken as 3 tablets BID(ie, axitinib 5 mg BID + 2 DB placebo for axitinib 1 mg BID). After at least 2 consecutive
weeks at the 5 mg BID dose, subjects who continued to satisfy the dose titration criteria were
to have their DB dose level increased by 1 additional dose level, to 5 mg axitinib taken as
2 tablets BID (ie, axitinib 5 mg BID + 1 DB placebo 5 mg BID), which was the maximum
total dose in Arm B.
If a dose reduction was necessary, it was to begin by reducing the blinded treatment first, andthen by reducing the open-label axitinib, if necessary.
Arm C Treatment: Non-randomized subjects received axitinib 5 mg BID or a reduced dose,as per the dose modification guideline. Dose titration was not permitted in this treatment
arm.
The general dose modifications guidelines, based on the Common Terminology Criteria for
Adverse Events (CTCAEs), are outlined in Table 2. Specific dose modifications werecreated for the management of hypertension and proteinuria, and dose interruption
requirement for surgery or surgical procedures.

Template version 1.1

Page 6

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 2.

Dose Modification Criteria for Drug-Related Adverse Events Other Than
Hypertension or Proteinuria

Related Adverse Events
Grade 1
Grade 2
Grade 3aGrade 4babIntervention
Continued at same dose level
Continued at same dose level
Decreased dose to 1 lower dose level.
Interrupted dosing; re-started at 1 lower dose level as soon as improvement to CTCAE
Grade 2. If subject required dose reduction below 2 mg BID, was to contact Sponsor for
discussion.
Subjects who developed Grade 3 nonhematologic toxicities that were controlled (ie, with medication) or Grade 3
asymptomatic biochemistry laboratory abnormalities could continue at the same dose level at the discretion of theInvestigator.
Subjects who developed Grade 4 lymphopenia or Grade 4 asymptomatic biochemistry laboratory abnormalities could
continue study treatment without interruption at the discretion of the Investigator.

Permitted concomitant medications were: palliative and supportive care for disease-related
symptoms (bisphosphonates, radiation), low-dose or short course of corticosteroids, antacidtherapy and antihypertensive treatment.
Efficacy, Pharmacokinetic, Pharmacodynamic and Safety Endpoints:

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Primary Endpoint:ORR (Arm A vs Arm B)

Secondary Endpoints:


Progression free survival (PFS; Arms A and B)

Overall survival (OS; Arms A and B)

Overall safety profile (Arms A, B, C)Duration of response (DR; Arms A and B)BP measurements



Plasma PK (Arms A and B)

Biomarker and gene expression profiling correlations with response rate and/or
BP measurements (Arms A, B, C)

Safety Evaluations: Safety evaluations included monitoring of adverse events (AEs),serious AEs (SAEs), laboratory evaluations (hematology, clinical chemistry, thyroid function
test, and urinalysis), physical examination, 12-lead electrocardiogram (ECG),
BP assessments, and 24 hour ambulatory BP monitoring (ABPM) and telemedicine at
specified time points during the study (Table 1).

Template version 1.1

Page 7

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Statistical Methods:
Analysis Sets: The full analysis (FA) population included all subjects who were randomized,with study drug assignment designated according to initial randomization, regardless ofwhether subjects received study drug or received a different drug from that to which they
were randomized. This was the primary analysis set for evaluating all efficacy endpoints aswell as subject characteristics.
The safety analysis (SA) population included all subjects who received at least 1 dose of
study medication with treatment assignments designated according to actual study treatment
received. This analysis set was the primary 1 for evaluating treatment
administration/compliance and safety.
The PK concentration population included all subjects who were treated and had at least
1 concentration on at least 1 PK assessment day. The PK parameter analysis data set
included all subjects treated who had at least 1 estimated PK parameter of primary interest.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

The biomarker analysis set included subjects receiving at least 1 dose of treatment, with a
Cycle 1 Day 1 biomarker result for at least 1 biomarker.
Statistical Analysis: Descriptive statistics and analyses were provided for subjects overall.
Baseline was defined as the last evaluation prior to the first dose of study medication.
Efficacy:
Primary Efficacy Analysis: ORR for the 2 treatment arms was compared with a 1-sided
Pearson chi-square test for unstratified analyses and the Cochran-Mantel-Haenszel (CMH)
test for stratified analyses. For the unstratified analyses, point estimates of the rates for eachtreatment arm and difference of the rates between treatment arms were provided along withthe corresponding 2-sided 95% confidence intervals (CIs) using an exact method based on
the F-distribution and using a normal approximation for constructing a CI for differences,respectively. For the stratified analyses, the relative risk ratio estimator was used to contrast
the treatment effects on the endpoint. Both a point estimate and a 2-sided 95% CI were
calculated using a normal approximation.
Secondary Efficacy Analysis: PFS in each arm was assessed using the Kaplan-Meier (KM)
method in the FA population and compared with a 1-sided stratified log rank test. Estimatesof the PFS curves from the KM method were presented. This method was applied to derive
the median event time and a CI for the median for each treatment arm. The CI was 2-sided,
had a stated coverage probability of 95%, and was calculated using normal approximation
methods.
As additional sub analyses, an un-stratified log-rank test was calculated. Also, Cox
proportional hazard models were used to explore the potential influences of the baseline
stratification factor. Additionally, a time-dependent Cox model was fitted to the axitinib
active titration arm to look at the influence of dose titration on PFS. The time-dependent
covariate for dose titration was coded as less than treatment arm median weeks at a titrated

Template version 1.1

Page 8

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Finaldose above 5 mg BID vs greater than or equal to treatment arm median weeks at a titrated
dose above 5 mg BID.
The same analyses were done for OS as were done for PFS. Additionally, the survival
probability at 1 year was estimated for each treatment arm using the KM method, and the2-sided 95% CI for the log (-log[1-year survival probability]) was calculated using a normal
approximation and then back transformed to give the CI for the 1-year survival rate itself.
Estimates of the DR curves from the KM method were presented. This method was applied
to derive the median event time and a CI for the median for each treatment arm. The CI was
2-sided, had a stated coverage probability of 95%, and was calculated using normal
approximation methods.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Safety: AEs were summarized by Medical Dictionary for Regulatory Activities (MedDRA)
system organ class (SOC) and preferred term (PT). The number and percentage of subjects
who experienced any AE, SAE, treatment-related AE or SAE, and who discontinued becauseof an AE were presented. Deaths were summarized by time period (on treatment vs duringfollow up) and cause of death.
For hematology, biochemistry, descriptive statistics were provided for each test result and forchange from Baseline by visit. Hematology and biochemistry results were graded according
to the National Cancer Institute CTCAE version 3.0. For urine, descriptive statistics were
provided for urine protein results and for change from Baseline by visit. For vital signs and
ECOG performance status, data were summarized and listed. For ECGs, data were listed.
All concomitant medications were coded by the World Health Organization (WHO) medical
dictionary. Data for concomitant medications, nondrug treatments, follow-up systemic
therapy for primary diagnosis, were summarized and listed.
Pharmacokinetics: For the 6-hour PK profiles obtained in this study, standard axitinib PK
parameters (maximum plasma concentration [Cmax], time at which Cmax is observed [Tmax],
terminal plasma elimination half life [t½], terminal phase rate constant [kel], area under theplasma concentration time curve from time 0 to the time of the last quantifiable concentration[AUClast], area under the plasma concentration time curve from time 0 to 24 hours [AUC24],
apparent oral clearance [CL/F], and apparent oral volume of distribution during theelimination phase [Vz/F]) were estimated using non compartmental methods.
The axitinib PK were summarized for approximately 75 subjects on Cycle 1 Day 15. PK on
Cycle 1 Day 15 for subjects eligible for dose titration (Arms A and B) vs subjects not eligiblefor dose titration (Arm C) were also summarized and reported.
The study was not powered to detect differences in axitinib PK. As an exploratory analysis,
the PK parameter data for the axitinib on Cycle 2 Day 15 between Arm A and Arm B weresummarized and reported.
Plasma concentrations for axitinib were listed by cycle, treatment arm, nominal time, andactual time postdose. Axitinib plasma concentrations were summarized by cycle, treatment
arm, and nominal time using descriptive statistics (number [n], mean, standard
Template version 1.1

Page 9Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

deviation [SD], percent coefficient of variation [%CV], median, minimum, maximum).
Linear and semi log plots of median axitinib plasma concentrations vs nominal time wereprepared by cycle, and treatment arm. Similar individual subject’s plasma concentrations
plots (with data from all visits on the same plot) were generated. For comparisons between
Arms A and B and Arm C on Cycle 1 Day 15, and comparisons between Arms A and B on
Cycle 2 Day 15, linear and semi log plots of median plasma concentrations vs nominal time
for axitinib were generated.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

PK parameters for axitinib were listed and summarized by cycle, and treatment arm using
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, and geometric mean
and its associated 95% CI as well as %CV around geometric mean). PK parameters with
0 values were excluded from the calculation of geometric means (and associated 95% CIs).
Dose normalized PK parameters (Cmax, AUClast, and AUC24) on Cycle 2 Day 15 werecompared between Arm A vs Arm B.
The correlation of changes in BP and axitinib PK were assessed. Cycle 1 Day 15 PK
parameters (AUC24, AUClast, and Cmax) and plasma concentrations were correlated with mean
absolute BP measurements (both sBP and dBP) obtained with ABPM on Cycle 1 Day 4 andCycle 1 Day 15. This analysis was conducted in subjects who had matched serial PK and
ABPM data. Scatter plots of mean ABPM on Cycle 1 Day 4 and Cycle 1 Day 15 as well as
the change in mean ABPM (change from Baseline [Cycle 1 Day -1] on Cycle 1 Day 4 andCycle 1 Day 15) vs axitinib AUC24, AUClast, and Cmax were generated. Box plots of AUC24,
AUClast and Cmax on Cycle 1 Day 15 in subjects with dBP (ABPM data) 90 mm Hg vs<90 mm Hg were generated. Similar plots for PK parameters in subjects with a BP change
from Baseline of 15 mm Hg and <15 mm Hg (ABPM data) were also generated.
In addition, for the evaluation of the potential effect of antacids on axitinib PK, linear andsemi logarithmic plots of median axitinib plasma concentration, tables with PK parametersummaries and box plots for axitinib PK parameters on Cycle 1 Day 15 in the absence andpresence of antacids were also generated. Separate presentations for proton pump inhibitors(PPIs), H2 blockers and all antacids (including locally-acting antacids, H2 blockers, and PPIs)
were generated.
For subjects in whom sparse samples (predose and 1 to 2 hour postdose) were obtained,
population PK analysis was performed in accordance with the Food and Drug Administration(FDA) guidance on Population Pharmacokinetics (February 1999).
Pharmacodynamics: As the circulating endolitheal cell (CEC) biomarkers were continuously
distributed, summaries were to include n, mean, SD, %CV, 25th, median, and 75th quartile,
minimum and maximum.
The p-values for tests specified below were considered significant if <0.05. The Bonferroni
adjustment to the comparison of p-values to a significance level were made based on
10 comparisons for the 10 individual biomarkers; the adjusted significance level was<0.05/10=0.005; comparisons were declared significant if the p-value was <0.005. If a
different number of biomarkers was assayed, the adjusted significance level was changed toreflect that number.

Template version 1.1

Page 10

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Analysis of CEC Biomarker Levels: Comparison of Arm A to Arm B was analyzed using
the Wilcoxon Rank Sum test for biomarker levels at Cycle 1 Day 1. Comparison of Arm A
and Arm B for ratio to baseline across postbaseline time points was analyzed using a linear
mixed effects model with terms of treatment, time, and treatment by time interaction as fixed
effects, and subject as random effect in the model. If the p-value for treatment by timeinteraction was <0.10, the hypothesis of equal time slope was rejected. A random slope andrandom intercept model could be used to include treatment and time as fixed effects, andintercept and time slope as random effects. A compound symmetry variance-covariancestructure could be included in the repeated measures linear mixed effects model to accountfor correlation among measurements made on a subject at different time points. Models
incorporating other covariance structure (eg, unstructured) might have been also examined asa sensitivity analysis. If the normality assumption was not satisfied, a logarithmictransformation could have been applied.
Analysis of the Relationship Between CEC Biomarkers and Objective Response: Summaryof CEC Biomarkers for Arm A, Arm B, Arm A + B, and Arm C, at Cycle 1 Day 1 and of
Cycle X Day X : Cycle 1 Day 1 on each response category were provided. Fisher’s exact test
was used to test for association between biomarker category defined by median biomarker
level at Cycle 1 Day 1 and of Cycle X Day X : Cycle 1 Day 1 and objective tumor responseby treatment arm. Estimated odds ratios (OR) between the biomarker categories and its
2-sided 95% CIs were provided. Logistic regression models could be used to explore thepotential influences of the baseline stratification factors and baseline subject characteristics
such as age, race, and sex.
Analysis of Relationship Between CEC Biomarkers and Time to Event Endpoints: OS and
PFS were compared between Arms A and B, and summarized for Arm A, Arm B,
Arm A + B, and Arm C on each stratum defined biomarker at Cycle 1 Day 1 using theKM method; p-values were not displayed when N <10 in either treatment arm. The
estimated hazard ratio (HR) and its 2-sided 95% CI, and median event time and its
2-sided 95% CI were reported for comparison of Arm A vs Arm B. For KM analysis of
PFS and OS, comparison between 2 groups of the CEC biomarker categorized by medianbiomarker level at Cycle 1 Day 1 and of Cycle X Day X : Cycle 1 Day 1 were made in thesimilar manner as above within Arm A and Arm B. Cox proportional hazard models might
be used to explore the potential influences of the baseline stratification factors and baselinesubject characteristics such as age, race, and sex.
Comparison of Arm A + B combined vs Arm C were made using descriptive statistics only.
Summary statistics were provided for the 2 groups of the CEC biomarker categorized bymedian biomarker level at Cycle 1 Day 1 and of Cycle X Day X : Cycle 1 Day 1 within
Arm A + B and Arm C.
RESULTS: Note that the data reported here are based on the PCD; full data will be reported
after the last subject last visit.
Subject Disposition and Demography: A summary of subject disposition and subjects
analyzed is presented in Table 3.

Template version 1.1

Page 11

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 3.

Subject Disposition and Subjects Analyzed

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Number (%) of Subjects

ActiveTitration

Placebo
Titration

Non-Randomized

Discontinued
Prior toRandomization101010
2 (20.0)0002 (20.0)
3 (30.0)03 (30.0)

Total subjects enrolled
56
56
91
Treated
56
56
91
a
38
48
58
Discontinued from treatment
Adverse event
5 (8.9)4 (7.1)9 (9.9)Subject died000Protocol violation0
1 (1.8)0
Lost to follow-up
00
1 (1.1)Other
0
3 (5.4)3 (3.3)
Objective progression or relapse
32 (57.1)
35 (62.5)
39 (42.9)
Global deterioration of health status
1 (1.8)1 (1.8)4 (4.4)
Subject refused to continue treatment for reason0
4 (7.1)2 (2.2)other than adverse event
b
25
28
37
9
Discontinued from study
Adverse event
1 (1.8)00
1 (10.0)
Subject died21 (37.5)
20 (35.7)
31 (34.1)
4 (40.0)
Protocol violation
00
0
0
Lost to follow-up
2 (3.6)4 (7.1)2 (2.2)0
Other0
3 (5.4)4 (4.4)2 (20.0)
Objective progression or relapse
1 (1.8)1 (1.8)00
Global deterioration of health status0000
Subject refused to continue treatment for reason000
2 (20.0)
other than adverse event
Ongoing at date of cut-off
31
28
54
1
Analyzed for safety
Adverse events
56
56
91
10
Laboratory data
56
56
91
8
c
847.5
810.4
1429.4
7.4
Total months on treatment
Data cut-off date: 12 October 2012.
CRF = case report form.
a. Discontinued from treatment = CRF page completed when subject was no longer taking study drug.
b. Discontinued from study = CRF page completed when survival follow-up was complete, subject died or subject was lost
to follow-up.
c. Months on study included all subjects (defined for each subject as: [last dose date-first dose date +1]/30.44).

A summary of demographic characteristics is presented in Table 4.

Template version 1.1

Page 12

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 4.

Demographic Characteristics

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

ActiveTitration
N=56
n (%)

Placebo
Titration
N=56
n (%)

Non-Randomized
N=91
n (%)

Discontinued Prior to
Randomization
N=10
n (%)

Age (years)
n
56
56
91
10
Mean
59.7
59.6
62.9
62.9
SD
10.2
10.5
8.9
7.5
Median
60.00
62.00
63.00
61.50
Min, max
33, 8128, 7943, 8749, 77<65
38 (67.9)
38 (67.9)
54 (59.3)
6 (60.0)
18 (32.1)
18 (32.1)
37 (40.7)
4 (40.0)
65
Sex
Male
37 (66.1)
45 (80.4)
55 (60.4)
6 (60.0)
Female19 (33.9)
11 (19.6)
36 (39.6)
4 (40.0)
RaceWhite
49 (87.5)
49 (87.5)
55 (60.4)
9 (90.0)Black00
2 (2.2)0
Asian
6 (10.7)
6 (10.7)
33 (36.3)
1 (10.0)
Other
1 (1.8)1 (1.8)1 (1.1)0
Weight (kg)
n
56
56
91
10
Mean
76.2
79.9
77.7
87.7
SD
14.9
18.5
20.3
25.9
Median
73.0
79.9
77.3
81.8
Min, max
51.0, 120.6
40.9, 155,0
38.0, 145.4
62.0, 134.9
Smoking status
Never smoked
29
26
48
7
Smoker8
13
3
1
Ex-smoker
19
17
40
2
a
ECOG performance status0
37 (66.1)
36 (64.3)
1
19 (33.9)
20 (35.7)200bECOG performance status0
36 (64.3)
34 (60.7)
63 (69.2)
3 (30.0)1
20 (35.7)
22 (39.3)
27 (29.7)
7 (70.0)200
1 (1.1)0
Data cut-off date: 12 October 2012.
ECOG = Eastern Cooperative Oncology Group; Max = maximum; Min = minimum; N = number of subjects in each group;n = number of subjects meeting prespecified criteria; SD = standard deviation.
a. ECOG status was taken from IMPALA.
b. ECOG status was taken from the case report form and is the last measure taken prior to dosing.

Template version 1.1

Page 13

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Efficacy, Pharmacokinetic, and Pharmacodynamic Results:
Primary Endpoint Result: The ORR, stratified by the ECOG performance status, wasstatistically significantly higher in the active titration group (53.6%) compared with theplacebo titration group (33.9%) (p=0.0189; 1-sided stratified CMH test). Therefore, thestudy achieved its primary objective and demonstrated superiority of active dose titration
over placebo titration in terms of ORR. The risk ratio of active vs placebo titration, adjusted
for ECOG performance status, was 1.578 (95% CI: 1.017 to 2.448). Therefore, in relative
terms the estimated probability to achieve an objective response is 58% higher in the active
titration group than in the placebo titration group (Table 5). A similar superior effect ofactive vs placebo titration was observed in the unstratified analyses.
Table 5.

Summary of Best Overall Response by Treatment, Stratified Analysis (All Randomized and Non-Randomized Subjects)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Active Titration
N=56
56 (100)
56 (100)

Placebo Titration
N=56
56 (100)55 (98.2)

Non-Randomized
N=91
91 (100)
91 (100)

Subjects with baseline assessment (n [%])
Subjects with measurable disease at Baseline (n [%])
Best overall response
Complete response (CR)
1 (1.8)0 (0.0)0 (0.0)Partial response (PR)29 (51.8)
19 (33.9)
54 (59.3)
Stable disease
13 (23.2)
24 (42.9)
23 (25.3)
Progressive disease
13 (23.2)
11 (19.6)
11 (12.1)
Not assessed
0 (0.0)1 (1.8)2 (2.2)
Indeterminate
0 (0.0)0 (0.0)1 (1.1)
Overall confirmed objective response rate (CR + PR)
30 (53.6)
19 (33.9)
54 (59.3)a39.7%-67.0%
21.8%-47.8%
48.5%-69.5%
95% exact CI
Treatment comparison (active titration versus placebo titration)b
1.578
Risk ratio
95% CI of risk ratiob
1.017–2.448c0.0189p-Value
Data cut-off date: 12 October 2012.
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N = number of subjects in each group; n = numberof subjects meeting prespecified criteria.
a. Using exact method based on F-distribution.
b. Risk ratio and CI based on the Mantel-Haenszel estimator; risk ratio was adjusted for same stratification factors as
Cochran-Mantel-Haenszel test.
c. For the overall stratified analysis the p-value was from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG
performance status.

In all 213 treated subjects, the ORR was 48.4% (95% CI: 41.5% to 55.3%) (Table 6).

Template version 1.1

Page 14

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 6.

Summary of Best Overall Response by Treatment, Derived Investigator’s
Assessment (All Subjects)

All Subjects(N=213)Stratification
Stratification
OverallCategory:
Category:
ECOG = 0
ECOG = 1
N
139
74
213
Subjects with baseline assessment (n [%])
139 (100)
74 (100)
213 (100)
Subjects with measurable disease at Baseline (n [%])
138 (99.3)
74 (100)
212 (99.5)
Complete response (CR)
1 (0.7)0
1 (0.5)
Partial response (PR)72 (51.8)30 (40.5)102 (47.9)
Stable disease43 (30.9)
17 (23.0)
60 (28.2)
Progressive disease18 (12.9)
20 (27.0)
38 (17.8)
Not assessed
2 (1.4)7 (9.5)9 (4.2)
Indeterminate
2 (1.4)0
2 (0.9)Overall confirmed objective response rate (CR+PR)
73 (52.5)
30 (40.5)103 (48.4)
95% exact CIa
43.9%-61%
29.3 %-52.6 %41.5 %-55.3 %One subject did not have any target lesions at Baseline, and therefore did not have measurable disease at Baseline.
ECOG values for randomized subjects were from IMPALA.
ECOG values for subjects who were non-randomized or discontinued prior to randomization were from CRF and was thelast measure taken prior to dosing.
One subject having ECOG = 2 was included in ECOG = 1 page for analysis.
% = (n/N) × 100.
Data cutoff date: 12 October 2012.
CI = confidence interval; CRF = case report form; ECOG = Eastern Cooperative Oncology Group; N = number of subjects
in each group; n = number of subjects with specified criteria.
a. Using exact method based on binomial distribution.

Secondary Endpoint Results:
Progression Free Survival: A summary of PFS is provided in Table 7. The HR (active vsplacebo titration) for PFS stratified by ECOG performance status was
0.849 (95% CI: 0.535 to 1.348) in favor of active titration with a p-value of
0.2444 (1-sided stratified log-rank test). The unstratified analysis of PFS gave similar
results.

Template version 1.1

Page 15

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 7.

Selected Summary of Progression-Free Survival From First Dose by
Treatment, Overall Stratified Analysis (All Randomized and
Non-Randomized Subjects)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Active Titration
N=56
35 (62.5)

Placebo Titration
N=56
38 (67.9)

Non-Randomized
N=91
54 (59.3)

Subjects observed to have progressed or died due to any
cause while on study (n [%])a
Type of event (n [%])
Objective progression
34 (97.1)
38 (100.0)
52 (96.3)
Increase in existing lesion (target or non target)
12 (35.3)
16 (42.1)
14 (26.9)
New lesion
9 (26.5)
16 (42.1)
25 (48.1)
Increase and a new lesion
13 (38.2)
6 (15.8)
13 (25.0)
Other
0 (0.0)0 (0.0)0 (0.0)Death without objective progression
1 (2.9)0 (0.0)2 (3.7)
Subject did not progress or die due to any cause while on
21 (37.5)
18 (32.1)
37 (40.7)
study (n [%])a
No baseline or on-study assessments
0 (0.0)1 (5.6)2 (5.4)
Alive, on study and progression free at the time of
17 (81.0)
7 (38.9)
26 (70.3)
analysis
At least 1 on study assessment and discontinue
4 (19.0)9 (50.0)
9 (24.3)
treatment prior to documented PD on study
PD occurred after given new anti-tumor treatment
0 (0.0)1 (5.6)0 (0.0)Kaplan-Meier estimates of time-to-event (months)
Quartiles (95% CI)b25%
2.9 (1.8, 9.2)
5.4 (3.6, 8.3)
5.7 (4.6, 8.6)
50%
14.5 (9.2, 24.5)
15.7 (8.3, 19.4)
16.6 (11.2, 22.5)
75%-(24.5,-)24.8 (19.1,-)
28.5 (25.1,-)
Treatment comparison (active titration versus placebo
titration)c
0.849
Hazard ratio
95% CI of hazard ratio
0.535–1.348
p-Valued
0.2444
Data cut-off date: 12 October 2012.
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N = number of subjects; n = number of subjects
meeting pre-specified criteria; PD = progressive disease.
a. On study included treatment plus 28-day follow-up period.
b. Based on Brookmeyer and Crowley method.
c. Assuming proportional hazards, a hazard ratio <1 indicates a reduction in hazard rate in favor for active titration; ahazard ratio >1 indicates a reduction in favor of placebo titration.
d. For the overall stratified analysis the p-value is from a 1-sided log-rank test stratified by ECOG performance status.
ECOG values are from IMPALA.

For all 213 treated subjects combined, 130 (61.0%) PFS events were recorded during thestudy and PFS was 14.6 months (95% CI: 11.5 to 17.5 months) (Table 8).

Template version 1.1

Page 16

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 8.

Summary of Progression-Free Survival From First Dose - Derived
Investigator’s Assessment (All Subjects)

N
Subject observed to have progressed or died due to any cause while on
study (n [%])a
Type of event (n [%])
Objective progression
Increase in existing lesion (target or non target)
New lesion
Increase and a new lesion
Other
Death without objective progression
Subject did not progress or die due to any cause while on study (n [%])a
Reason for censorship (n [%])
No baseline or on-study assessments
Alive, on study and progression free at the time of the analysis
At least 1 on study disease assessment and discontinue
treatment prior to documented PD on study
PD or death occurs after 2 consecutive, missed assessments
PD occurs after given new anti-tumor treatment
Withdrew consent for follow-up
Lost to follow-up
Subject taking new anti-tumor therapy
Other
Kaplan-Meier estimates of time to event (months)
Quartiles (95% CI)b
25%
50%

Stratification
Category:
ECOG = 0139
83 (59.7)

All Subjects(N=213)Stratification
Category:
ECOG = 1
74
47 (63.5)213
130 (61.0)

81 (97.6)
32 (39.5)
31 (38.3)
18 (22.2)
0
2 ( 2.4)
56 (40.3)

46 (97.9)
13 (28.3)
19 (41.3)
14 (30.4)
01 (2.1)27 (36.5)

127 (97.7)
45 (35.4)
50 (39.4)
32 (25.2)0
3 (2.3)83 (39.0)

2 ( 3.6)
35 (62.5)
18 (32.1)

7 (25.9)
15 (55.6)
5 (18.5)

9 (10.8)
50 (60.2)
23 (27.7)

0
1 (1.8)
0
0
0
0

0
0
0
0
0
0

0
1 (1.2)
0
0
0
0

8.2
(5.6, 10.1)
16.6(13.0, 22.9)
28.5 (25.1, -)

2.3(1.8, 4.6)
10.3
(4.7, 16.6)- (17.4, -)

5.3(3.6, 7.4)
14.6
(11.5, 17.5)
28.5 (25.1, -)Overall75%
ECOG values for randomized subjects are from IMPALA.
ECOG values for subjects who were non-randomized or discontinued prior to randomization are from CRF and is the lastmeasure taken prior to dosing.
One subject having ECOG = 2 was included in ECOG = 1 page for analysis.
% = (n/N) × 100.
Data cutoff date: 12 October 2012.
CI = confidence interval; CRF = case report form; ECOG = Eastern Cooperative Oncology Group; N = number of subjects
in each group; n = number of subjects with specified criteria; PD = progression of disease.
a. On study includes treatment plus 28-day follow-up period.
b. Based on the Brookmeyer and Crowley Method.

In total, 35 (62.5%) subjects in the active titration group and 38 (67.9%) subjects in theplacebo titration group had disease progression or died. To explore the potential influence ofthe baseline ECOG stratification factor on PFS, Cox proportional hazard models were used.
The HR for the effect of baseline ECOG status (ECOG = 1 vs ECOG = 0) on PFS from firstdose was 1.127 (95% CI: 0.697 to 1.823) with a p-value of 0.627. Therefore, no significant
influence of baseline ECOG status was shown.
Overall Survival: A summary of OS (cut-off date: 12 October 2012) is presented in Table 9.
There were 22 (39.3%) deaths (from first dose) in the active titration group,21 (37.5%) deaths in the placebo titration group, and 31 (34.1%) deaths in the
Template version 1.1

Page 17

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

non-randomized group, ie, at the time of analysis of the primary endpoint, most subjects werealive and the survival data were immature. The estimated HR (risk of death in the active
versus placebo titration group) was 1.213 (95% CI: 0.661 to 2.229) for OS data recorded
from first dose and stratified by ECOG performance status, representing an increase of
21.3% in hazard for active titration over placebo titration. Similar results were obtained foranalyses of OS recorded from randomization with stratified and unstratified data. OS data
was not mature at the time of data cut-off date.
Table 9.

Summary of Overall Survival From First Dose by Treatment, Overall
Stratified Analysis (All Randomized and Non-Randomized Subjects)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Active Titration
N=56
22 (39.3)

Placebo Titration
N=56
21 (37.5)

Non-Randomized
N=91
31 (34.1)

Dead (n [%])
Cause of death (n [%])
Disease under study
21 (95.5)
18 (85.7)
26 (83.9)
Study treatment toxicity
0 (0.0)0 (0.0)0 (0.0)Unknown
1(4.5)
1 (4.8)2 (6.5)Other
0
2 (9.5)3 (9.7)
Alive (n [%])a34 (60.7)
35 (62.5)
60 (65.9)
Alive
31 (91.2)
30 (85.7)
57 (95.0)
Subject no longer willing to participate
0 (0.0)1 (2.9)1 (1.7)
Lost to follow-up
3 (8.8)4 (11.4)
2 (3.3)
Survival probability at Month 12 (95% CI)b74.6 (61.0, 84.0)
81.6 (68.7, 89.6)
80.0 (70.2, 86.9)
Kaplan-Meier estimates of time-to-event (months)
Quartiles (95% CI)c25%
11.9 (6.1, 24.7)
19.2 (10.6, 24.6)
15.6 (10.8, 29.9)50%- (24.7,-)
35.2 (23.7, - )32.3 (29.9, -)75%
NA- (35.2, -)Treatment comparison (active vs placebo titration)
Hazard ratiod
1.213
95% CI of hazard ratio
0.661–2.229
p-Valuee0.7319
Data cut-off date: 12 October 2012.
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N = number of subjects, n = number of subjects
meeting prespecified criteria; NA = not applicable; vs = versus.
a. Subjects who were not known to be dead at the time the database was closed for analysis were censored on the date they
were last known to be alive.
b. Calculated from the log (-log[12-month survival probability]) using a normal approximation and back transformation.
c. Based on the Brookmeyer and Crowley Method.
d. Assuming proportional hazards model, a hazard ratio <1 indicates a reduction in hazard rate in favor of active titration; ahazard ratio >1 indicates a reduction in favor of placebo titration.
e. For the overall stratified analysis, the p-value is based on a 1-sided log-rank test stratified by ECOG performance status.

For analysis of OS from first dose in all 213 subjects, the median OS was
35.2 months (95% CI: 32.3, -) (Table 10).

Template version 1.1

Page 18

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 10. Summary of Overall Survival From First Dose - Stratified Analysis (All
Subjects)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Stratification
Category: ECOG = 0
41 (29.5)

All Subjects(N=213)Stratification
Category: ECOG = 1
37 (50.0)

Overall

Dead (n [%])
78 (36.6)
Cause of death (n [%])
Disease under study
37 (90.2)
32 (86.5)
69 (88.5)
Study treatment toxicity000Unknown
2 (4.9)2 (5.4)4 (5.1)Other
2 (4.9)3 ( 8.1)
5 (6.4)
Alive (n [%])a98 (70.5)
37 (50.0)
135 (63.4)
Reason for censorship (n [%])Alive
88 (89.8)
33 (89.2)
121 (89.6)
Subject no longer willing to participate
3 (3.1)2 (5.4)5 (3.7)
Lost to follow-up
7 (7.1)2 (5.4)9 (6.7)
Survival probability at Month 12 (95% CIb)
86.0 (78.9, 90.8)
60.9 (48.5, 71.2)
77.5 (71.2, 82.7)
Kaplan-Meier estimates of time to event (months)
Quartiles (95% CI)c25%
23.5 (15.6, 35.2)
7.0 (4.0, 11.4)
14.7 (10.9, 21.2)
50%
35.2 (32.3, -)21.2 (11.7, -)35.2 (29.9, -)75%- (35.2, -)- (35.2, -)Data cutoff date: 12 October 2012.
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N = number of subjects; n = number of subjects
with specified criteria.
a. Subjects who are not known to be dead at the time the database was closed for analysis are censored on the date they
were last known to be alive.
b. Calculated from the log (-log [12-month survival probability]) using a normal approximation and back transformation.
c. Based on the Brookmeyer and Crowley Method.

Duration of Response: A summary of duration of tumor response among responders isprovided in Table 11.

Template version 1.1

Page 19

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 11. Selected Summary of Duration of Tumor Response Among Responders by
Treatment – (All Randomized and Non-Randomized Subjects)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Active Titration
N=30
13 (43.3)

Placebo Titration
N=19
10 (52.6)

Non-Randomized
N=54
26 (48.1)

Subjects observed to have progressed or died due to anyacause while on study (n [%])
Type of event (n [%])
Objective progression
13 (100.0)
10 (100.0)
25 (96.2)
Increase in existing lesion (target or non target)
5 (38.5)
4 (40.0)
10 (40.0)
New lesion
5 (38.5)
4 (40.0)
9 (36.0)
Increase and a new lesion
3 (23.1)
2 (20.0)
6 (24.0)
Other
0 (0.0)0 (0.0)0 (0.0)Death without objective progression
0 (0.0)0 (0.0)1 (3.8)
Subject did not progress or die due to any cause while on
17 (56.7)
9 (47.4)
28 (51.9)
study (n [%])a
No baseline or on-study assessments
0 (0.0)0 (0.0)0 (0.0)
Alive, on study and progression free at the time of
17 (100.0)
8 (88.9)28 (100.0)
analysis
At least 1 on study assessment and discontinued
0 (0.0)0 (0.0)0 (0.0)treatment prior to documented PD on study
PD occurred after given new anti-tumor treatment
0 (0.0)1 (11.1)
0 (0.0)Kaplan-Meier estimates of time-to-event (months)b
Quartiles (95% CI)
25%
9.4 (6.5, 20.6)
11.1 (6.4, 21.2)
12.0 (7.0, 16.8)
50%- (10.8, - )21.2 (11.1, 25.8)
23.3 (15.7, 28.6)
75%
NA25.8 (21.2, 25.8)
28.6 (23.3,- )Data cut-off date: 12 October 2012.
CI = confidence interval; N = number of subjects; n = number of subjects meeting prespecified criteria; NA = notapplicable; PD = progressive disease.
a. On study included treatment plus 28-day follow-up period.
b. Based on Brookmeyer and Crowley method.

Pharmacokinetic Results: The axitinib plasma PK parameter values at steady state on
Cycle 1 Day 15 are summarized in Table 12.

Template version 1.1

Page 20

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 12. Summary of Axitinib Steady-State Pharmacokinetic Parameters Following
Administration of Multiple Doses of Axitinib (5 mg BID) in Subjects With
Advanced Renal Cell Carcinomaa
AUClasta
AUC24a
CL/F
Vz/F
t½
Cmax
(ng•hr/mL)(ng•hr/mL)(L/hr)(L)(hr)(ng/mL)
Axitinib (N=73)
30.9
107
268
37.3
146
3.98
(25.9, 36.8)(89.1, 129)
(213, 338)
(29.6, 47.0)(115, 186)
(129)
Values reported are geometric mean with 95% CI for Cmax; AUClast; AUC24; CL/F; and Vz/F; arithmetic mean with %CV fort½ .
One subject was excluded from summary statistics for all PK parameters because all the sample concentrations were BLQ.
Five subjects were excluded from summary statistics for all PK parameters because of errors in sample collection. AUC24,
CL/F, Vz/F could not be reported for N=20 subjects due to non-estimable half-life.
AUC24 = area under the plasma concentration versus time curve from 0 to 24 hrs; AUClast = area under the plasma
concentration versus time curve from 0 to time of the last quantifiable concentration; BLQ = below limit of quantification;
CI = confidence interval; Cmax = maximal plasma concentration; CL/F = apparent oral clearance; CV = coefficient ofvariation; N = number of subjects; PK = pharmacokinetics; t½ = plasma terminal elimination half-life; Vz/F = apparent
volume of distribution during the elimination phase.
a. Dose normalized to 5 mg dose.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Treatment

Arms A and B included subjects who were eligible for dose titration above the 5 mg BID
starting dose on Cycle 2 Day 1; Arm C included subjects not eligible for dose titration on
Cycle 2 Day 1. The axitinib steady-state plasma concentrations following multiple oral 5 mg
BID dosing on Cycle 1 Day 15 are compared in subjects eligible for dose titration(Arms A and B) vs those that were not (Arm C) (Table 13).
Table 13. Comparison of Axitinib Steady-State Pharmacokinetic Parameters on
Cycle 1 Day 15 Following Administration of Multiple Doses of Axitinib(5 mg BID) in Subjects Eligible or Not Eligible for Dose Titration
Treatment ArmaCmax(ng/mL)

AUClasta(ng•hr/mL)

AUC24a(ng•hr/mL)

CL/F(L/hr)

Vz/F
(L)

t1/2
(hr)

Eligible for
25.3
78.4
181
55.3
158
2.42
dose-titration(20.1, 31.9)(62.2, 98.7)(138, 237)
(42.2, 72.4)(113, 219)
(94)
(Arms A + B; N=39)
Not eligible for
38.7
154
432
23.1
133
5.87
dose-titration(30.2, 49.6)(120, 197)
(321, 581)
(17.2, 31.2)(92.8, 192)
(116)
(Arm C; N=34)
Values reported are geometric mean with 95% CI for Cmax, AUClast, AUC24, CL/F, and Vz/F, arithmetic mean with %CV fort½ .
One subject was excluded from summary statistics for all PK parameters because all the sample concentrations were BLQ.
Five subjects were excluded from summary statistics for all PK parameters because of sample collection error. AUC24,
CL/F, Vz/F and t½ could not be reported for N=20 subjects due to non-estimable plasma half-life.
AUC24 = area under the plasma concentration versus time curve from 0 to 24 hrs; AUClast = area under the plasma
concentration versus time curve from 0 to time of the last quantifiable concentration; BLQ = below limit of quantification;
CI = confidence interval; Cmax = maximal plasma concentration; CL/F = apparent oral clearance; CV = coefficient ofvariation; N = number of subjects; PK = pharmacokinetics; t½ = plasma terminal elimination half-life; Vz/F = apparent
volume of distribution during the elimination phase.
a. Dose normalized to 5 mg dose.

In Cycle 2, subjects in Arms A and B had their dose increased with either axitinib (Arm A)
or placebo (Arm B). Therefore, PK data on Cycle 2 Day 15 represents steady-state PK for
axitinib at the up-titrated dose. The corresponding axitinib steady-state plasma PK parametervalues in these 2 arms are summarized in Table 14.

Template version 1.1

Page 21

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 14. Comparison of Axitinib Steady-State Pharmacokinetic Parameters inArms A and B on Cycle 2 Day 15 Following Multiple Oral Doses of Axitiniba
AUClasta
AUC24a
CL/F
Vz/F
t½
Cmax
(ng•hr/mL)(ng•hr/mL)(L/hr)(L)(hr)(ng/mL)
Axitinib dose titration
31.7
105
259
54.2
158
2.48
(Arm A; N=16)(21.6, 46.6)(70.2, 158)
(150, 445)
(31.5, 93.1)(98.4, 254)
(77)
Placebo dose titration
23.1
78.4
161
61.9
217
2.81
(Arm B; N=20)(16.4, 32.5)(54.5, 113)
(102, 255)
(39.2, 97.9)(145, 324)
(60)
Values reported are geometric mean with 95% CI for Cmax, AUClast, AUC24, CL/F, and Vz/F, arithmetic mean with %CV fort½ .
Five subjects were excluded from summary statistics for all PK parameters because of sample collection error. AUC24,
CL/F, Vz/F and t½ could not be reported for N=12 subjects due to non-estimable half-life.
AUC24 = area under the plasma concentration versus time curve from 0 to 24 hrs; AUClast = area under the plasma
concentration versus time curve from 0 to time of the last quantifiable concentration; BID = twice a day; BLQ = below limitof quantification; CI = confidence interval; Cmax = maximal plasma concentration; CL/F = apparent oral clearance;
CV = coefficient of variation; N = number of subjects; PK = pharmacokinetics; t½ = plasma terminal elimination half-life;
Vz/F = apparent volume of distribution during the elimination phase.
a. Dose normalized to 7 mg dose for subjects in Arm A and to 5 mg for subjects in Arm B.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Treatment Arm

Correlation Between Ambulatory Blood Pressure and Axitinib Pharmacokinetics: The meandBP represented the average of 24 hour diastolic ABPM on Cycle 1 Day 15. In addition, themean change in dBP was estimated as the difference between the mean dBP at Baseline andat Cycle 1 Day 15. The geometric mean Cmax and AUC24 are higher in subjects with mean
diastolic ABPM 90 mm Hg than those in subjects with mean diastolic ABPM <90 mm Hg.
A similar outcome was observed when using mean change in dBP (from Baseline) instead ofabsolute dBP values. The geometric mean Cmax and AUC24 were higher in subjects withmean change from Baseline of diastolic ABPM 15 mm Hg than those subjects with meanchange of baseline of diastolic ABPM <15 mm Hg. A weak correlation was observed
between axitinib plasma steady-state exposure and mean absolute diastolic ABPM on
Cycle 1 Day 15 (R2=0.126). A similar observation was seen with the use of mean change ofdiastolic ABPM on Cycle 1 Day 15 from Baseline (R2=0.225).
Pharmacodynamic Results:
Plasma Levels of Circulating Endolitheal Cells: There were no statistically significant
findings.
Correlation Between Circulating Endolitheal Cells and Response According to Response
Evaluation Criteria in Solid Tumors Criteria: The comparison of CEC values at Baseline andratios to Baseline at each time point, between subjects having a response and those without a
response, there were no statistically significant findings. For cluster of differentiation(CD)146 +/CD105 + vascular endothelial growth factor receptor (pVEGFR) + expressing
cells at Baseline, the ORR was higher in 62.5% of subjects with <median values (OR = 4.44,
95% CI = 1.1 to 17.7, p=0.047) compared to 27.3% of subjects with greater than or equal tomedian values for the combined active titration and placebo titration groups. No otherfindings were statistically significant.
Analysis of PFS by Median CEC Values at Baseline and by Median Ratios to Baseline:
There were no statistically significant findings.

Template version 1.1

Page 22

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Analysis of OS by Median CEC Values at Baseline and by Median Ratios to Baseline: There
were 3 significant observations for the combined active + placebo titration groups: atBaseline, subjects with less than median CD31+/146+ platelet-derived growth factor
receptor  (pPDGFR) expressing cells had a longer OS than subjects with greater than orequal to median values; at Baseline, subjects with less than median CD31 +/146 + pVEGFR
expressing cells had a longer OS than subjects with greater than or equal to median values;
for the Cycle 2 Day 15/Cycle 1 Day 1 ratio, subjects with less than median CD31 +/CD146 +pVEGFR expressing cells had a shorter OS than subjects with greater than or equal tomedian values.
Kaplan-Meier OS Curves Comparing Less Than Median CEC Values Versus Greater Thanor Equal to Median Values at Baseline Amongst Treatment Arms: There were no
statistically significant findings.
Pharmacogenomics Results:

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Baseline Characteristics: The baseline characteristics were similar between active titrationand placebo titration groups.
Analysis of PFS by Vascular Endothelial Growth Factor (VEGF)-A or VEGFR3 Genotype:
When all subjects were grouped together, median PFS was longer for the referenceG/G genotype (22.17 weeks) vs G/A genotype (11.50 weeks) or A/A genotype (8.57 weeks).
For the VEGFR3 rs448012 polymorphism, when all subjects were grouped together, median
PFS was longer for subjects with the reference G/G genotype (19.42 weeks) compared tosubjects with the G/C genotype (10.28 weeks). However, PFS for the C/C genotype was not
significantly different (17.51 weeks). There were no other consistent trends of genotype
effect on PFS.
Analysis of OS by VEGF-A or VEGFR3 Genotype: When all subjects were grouped
together, there were no significant associations of genotype vs OS. There were no otherconsistent trends of genotype effect on OS.
Analysis of ORR by VEGF-A or VEGFR3 Genotype: When all subjects were grouped
together, there were no significant associations of genotype vs ORR. For the
VEGFR3 polymorphism rs448012, in the combined active + placebo titration group, subjects
with the reference G/G genotype had an increased ORR (67.7%) compared to subjects with
the G/C genotype (31.8%). However, ORR was not different for these genotypes in the
non-randomized group. There were no other consistent trends of genotype effect on ORR.
Analysis of Postbaseline dBP <90 mmHg According to VEGF-A or VEGFR3 Genotype:For active titration, placebo titration, combined active titration + placebo titration, andnon-randomized groups, no significant observations of association of genotype vspostbaseline dBP <90 mmHg were reported, other than 1 significant observation for a
genotype where N=1.
Analysis of Post-Baseline dBP Increase of >15 mmHg According to VEGF-A or VEGFR3
Genotype: For active titration, placebo titration, combined active titration + placebo titration,

Template version 1.1

Page 23

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

and non-randomized groups, for the VEGF-A rs699947 polymorphism, in the
non-randomized group only, there was a higher chance of an observed 15 mm Hg increase
in dBP for subjects with the A/C genotype (OR = 5.40; p=0.022) and C/C genotype(OR = 8.25; p=0.034) compared to the reference A/A genotype. There were no othersignificant observations of association of genotype vs postbaseline dBP increase of
15 mm Hg.
Analysis of Grade 3 Hypertension by VEGF-A or VEGFR3 Genotype: For active titration,
placebo titration, non-randomized, and combined active titration + placebo titration, for the
VEGFR3 rs307821 polymorphism, in the non-randomized group only, subjects with the
G/T genotype had a lower chance of a Grade 3 hypertension event (OR = 0.19; p=0.043)
than subjects with the reference G/G genotype. There were no other consistent trends ofgenotype effect with Grade 3 hypertension.
Safety Results: An overall summary of treatment-emergent AEs (TEAEs) is provided inTable 15.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 15. Overall Summary of All-Causality and Treatment-Related
Treatment-Emergent Adverse Events According to Study Arm
ActiveTitration

Placebo
Titration

Non-Randomized

N=56
All Grades
n
%

N=56
All Grades
n
%

N=91
All Gradesn%Discontinued
Prior toRandomization
N=10
All Gradesn%All-Causality TEAEs
Number of AEs
713
689
1578
64
Subjects with AEs
55
98.2
51
91.1
91
100.0
9
90.0
Subjects with SAEs
15
26.8
13
23.2
35
38.5
2
20.0
Subjects with Grade 3 or Grade 4 events
34
60.7
26
46.4
73
80.2
7
70.0
Subjects with Grade 5 events
2
3.6
0
8
8.8
0
Subjects discontinued treatment due to AEs
7
12.5
6
10.7
11
12.1
2
20.0
Subjects with dose reduced due to AEs
15
26.8
8
14.3
16
17.6
1
10.0
Subjects with temporary discontinuation
28
50.0
25
44.6
71
78.0
4
40.0
due to AEs
Treatment-Related TEAEs
Number of AEs
512
481
1176
49
Subjects with AEs
53
94.6
48
85.7
90
98.9
8
80.0
Subjects with SAEs
10
17.9
4
7.1
15
16.5
1
10.0
Subjects with Grade 3 or Grade 4 events
30
53.6
16
28.6
63
69.2
6
60.0
Subjects with Grade 5 events
0
0
1
1.1
0
Subjects discontinued treatment due to AEs
4
7.1
2
3.6
6
6.6
1
10.0
Subjects with dose reduced due to AEs
15
26.8
6
10.7
15
16.5
1
10.0
Subjects with temporary discontinuation
25
44.6
18
32.1
64
70.3
4
40.0
due to AEs
Includes data up to 28 days after last dose of study drug.
Except for the number of AEs, subjects were counted only once per treatment in each row.
Data cut-off date: 12 October 2012.
AE = adverse event; N = number of subjects; n = number of subjects meeting prespecified criteria; SAE = serious adverse
event; TEAE = treatment-emergent adverse event.

All-Causality Treatment-Emergent Adverse Events: A summary of nonserious all-causality
TEAEs reported in 5% of subjects in any treatment group is presented in Table 16.

Template version 1.1

Page 24

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 16. Treatment-Emergent Nonserious Adverse Events Reported in 5% of
Subjects in any Treatment Group (All-Causalities)
Number (%) of Subjects With Adverse Events by:
System Organ Class
Preferred Term
Number (%) of subjects evaluable for adverse events
Number (%) of subjects with adverse events
Being queried
Transient ischemic attack
Blood and lymphatic system disorders
Anaemia
Lymphopenia
Thrombocytopenia
Cardiac disorders
Sinus tachycardia
Ear and labyrinth disorders
Tinnitus
Endocrine disorders
Hypothyroidism
Gastrointestinal disorders
Abdominal discomfort
Abdominal distension
Abdominal pain
Abdominal pain upper
Cheilitis
Constipation
Diarrhoea
Dry mouth
Dyspepsia
Dysphagia
Flatulence
Gastritis
Gastrooesophageal reflux disease
Haemorrhoids
NauseaProctalgia
Stomatitis
Vomiting
General disorders and administration site conditions
Asthenia
Chest pain
ChillsFatigue
General physical health deterioration
Mucosal inflammation
Oedema peripheral
Pain
Pyrexia
Infections and infestations
Nasopharyngitis
Rhinitis
Sinusitis
Upper respiratory tract infection
Urinary tract infection

ActiveTitrationn (%)
56
55 (98.2)
00
7 (12.5)
4 (7.1)0
4 (7.1)0000
18 (32.1)
18 (32.1)
41 (73.2)
1 (1.8)1 (1.8)9 (16.1)
4 (7.1)1 (1.8)10 (17.9)
34 (60.7)
6 (10.7)
6 (10.7)0
7 (12.5)
2 (3.6)
1 (1.8)1 (1.8)21 (37.5)
2 (3.6)9 (16.1)
17 (30.4)
34 (60.7)
6 (10.7)4 (7.1)2 (3.6)25 (44.6)
0
11 (19.6)
4 (7.1)3 (5.4)4 (7.1)14 (25.0)
4 (7.1)3 (5.4)4 (7.1)4 (7.1)2 (3.6)

Template version 1.1

Page 25

Placebo
Titrationn (%)
56
50 (89.3)
00
6 (10.7)
3 (5.4)0
3 (5.4)
1 (1.8)1 (1.8)3 (5.4)3 (5.4)13 (23.2)
13 (23.2)
41 (73.2)0
3 (5.4)7 (12.5)
2 (3.6)2 (3.6)8 (14.3)
35 (62.5)
1 (1.8)5 (8.9)2 (3.6)3 (5.4)2 (3.6)3 (5.4)
1 (1.8)19 (33.9)
04 (7.1)
11 (19.6)
32 (57.1)
5 (8.9)2 (3.6)
1 (1.8)26 (46.4)
0
7 (12.5)
4 (7.1)3 (5.4)3 (5.4)12 (21.4)
3 (5.4)6 (10.7)
2 (3.6)3 (5.4)
1 (1.8)

NonRandomizedn (%)
91
91 (100.0)00
20 (22.0)
8 (8.8)2 (2.2)14 (15.4)
00
3 (3.3)3 (3.3)41 (45.1)
41 (45.1)
78 (85.7)
6 (6.6)3 (3.3)
11 (12.1)
10 (11.0)
5 (5.5)27 (29.7)
57 (62.6)
7 (7.7)18 (19.8)
2 (2.2)3 (3.3)8 (8.8)4 (4.4)3 (3.3)31 (34.1)
5 (5.5)17 (18.7)
23 (25.3)
58 (63.7)
6 (6.6)6 (6.6)5 (5.5)49 (53.8)
1 (1.1)13 (14.3)
14 (15.4)
4 (4.4)4 (4.4)28 (30.8)
15 (16.5)
4 (4.4)2 (2.2)5 (5.5)10 (11.0)

Discontinued Prior
to Randomizationn (%)
10
9 (90.0)
1 (10.0)
1 (10.0)
2 (20.0)
1 (10.0)
1 (10.0)02 (20.0)
2 (20.0)00
2 (20.0)
2 (20.0)
5 (50.0)00
1 (10.0)00
3 (30.0)
1 (10.0)00
1 (10.0)000
1 (10.0)
2 (20.0)00
2 (20.0)
5 (50.0)000
4 (40.0)
1 (10.0)00001 (10.0)00001 (10.0)

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 16. Treatment-Emergent Nonserious Adverse Events Reported in 5% of
Subjects in any Treatment Group (All-Causalities)
Number (%) of Subjects With Adverse Events by:
System Organ Class
Preferred Term
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood creatinine increased
Blood glucose decreased
Blood glucose increased
Blood potassium increased
Blood thyroid stimulating hormone increased
Blood triglycerides increased
Fibrin d dimer increased
Haemoglobin decreased
Weight decreased
Metabolism and nutrition disorders
Decreased appetite
Dehydration
Hyperglycaemia
Hyperkalaemia
Hyperlipidaemia
Hyperuricaemia
Hypoalbuminaemia
Hypoglycaemia
Hyponatraemia
Hypophosphataemia
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain
Bone pain
Flank pain
Groin pain
Muscle spasms
Muscular weakness
Musculoskeletal chest pain
Musculoskeletal pain
Musculoskeletal stiffness
Myalgia
Neck pain
Pain in extremity
Nervous system disorders
Dizziness
Dysgeusia
Dyskinesia
HeadacheHypoaesthesia
Paraesthesia
Peripheral sensory neuropathy
Psychiatric disorders
AnxietyConfusional state
Delirium
Depression
Insomnia

ActiveTitrationn (%)
26 (46.4)
4 (7.1)4 (7.1)3 (5.4)
1 (1.8)3 (5.4)4 (7.1)3 (5.4)8 (14.3)2 (3.6)0
1 (1.8)15 (26.8)
28 (50.0)
21 (37.5)
3 (5.4)5 (8.9)5 (8.9)0
1 (1.8)3 (5.4)0
4 (7.1)1 (1.8)27 (48.2)
11 (19.6)
13 (23.2)
3 (5.4)
1 (1.8)02 (3.6)3 (5.4)3 (5.4)7 (12.5)
1 (1.8)4 (7.1)4 (7.1)7 (12.5)
24 (42.9)
8 (14.3)
9 (16.1)
08 (14.3)2 (3.6)5 (8.9)4 (7.1)9 (16.1)
3 (5.4)
1 (1.8)0
3 (5.4)2 (3.6)

Template version 1.1

Page 26

Placebo
Titrationn (%)
22 (39.3)
9 (16.1)
10 (17.9)
4 (7.1)6 (10.7)4 (7.1)7 (12.5)
3 (5.4)7 (12.5)
2 (3.6)
1 (1.8)1 (1.8)12 (21.4)
24 (42.9)
16 (28.6)
4 (7.1)3 (5.4)
1 (1.8)00
1 (1.8)3 (5.4)
1 (1.8)2 (3.6)23 (41.1)
9 (16.1)
8 (14.3)2 (3.6)3 (5.4)0
2 (3.6)2 (3.6)3 (5.4)4 (7.1)3 (5.4)3 (5.4)4 (7.1)5 (8.9)21 (37.5)
10 (17.9)
5 (8.9)0
12 (21.4)
0
3 (5.4)
1 (1.8)10 (17.9)
3 (5.4)
1 (1.8)04 (7.1)4 (7.1)

NonRandomizedn (%)
53 (58.2)
12 (13.2)
11 (12.1)
6 (6.6)14 (15.4)
1 (1.1)10 (11.0)
4 (4.4)9 (9.9)5 (5.5)0
5 (5.5)25 (27.5)
49 (53.8)
35 (38.5)
5 (5.5)5 (5.5)4 (4.4)6 (6.6)9 (9.9)2 (2.2)2 (2.2)4 (4.4)4 (4.4)56 (61.5)
16 (17.6)
15 (16.5)
4 (4.4)2 (2.2)
1 (1.1)5 (5.5)2 (2.2)2 (2.2)15 (16.5)
3 (3.3)8 (8.8)5 (5.5)23 (25.3)
42 (46.2)
12 (13.2)
20 (22.0)026 (28.6)
3 (3.3)3 (3.3)3 (3.3)19 (20.9)
7 (7.7)00
6 (6.6)7 (7.7)

Discontinued Prior
to Randomizationn (%)
2 (20.0)00
2 (20.0)
1 (10.0)02 (20.0)000
1 (10.0)0
1 (10.0)
3 (30.0)
3 (30.0)
0
0
0
0
0
0
0
1 (10.0)
1 (10.0)
2 (20.0)00001 (10.0)
0
0
0
0
0
0
0
2 (20.0)
2 (20.0)
1 (10.0)
1 (10.0)
1 (10.0)0
1 (10.0)
1 (10.0)03 (30.0)02 (20.0)
1 (10.0)0
1 (10.0)

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 16. Treatment-Emergent Nonserious Adverse Events Reported in 5% of
Subjects in any Treatment Group (All-Causalities)
Number (%) of Subjects With Adverse Events by:
ActivePlacebo
NonDiscontinued Prior
System Organ Class
Titration
Titration
Randomized
to Randomization
Preferred Term
n (%)
n (%)
n (%)
n (%)
Renal and urinary disorders
12 (21.4)
11 (19.6)
39 (42.9)
2 (20.0)
Haemoglobinuria
2 (3.6)3 (5.4)5 (5.5)
1 (10.0)
Proteinuria
11 (19.6)
11 (19.6)
39 (42.9)
2 (20.0)
Respiratory, thoracic and mediastinal disorders
22 (39.3)
26 (46.4)
63 (69.2)
4 (40.0)
Cough
7 (12.5)
8 (14.3)
17 (18.7)0Dysphonia
18 (32.1)
20 (35.7)
44 (48.4)
3 (30.0)
Dyspnoea
6 (10.7)
7 (12.5)
26 (28.6)
1 (10.0)
Epistaxis
4 (7.1)3 (5.4)11 (12.1)
0Oropharyngeal pain
3 (5.4)2 (3.6)7 (7.7)0
Skin and subcutaneous tissue disorders
24 (42.9)
21 (37.5)
55 (60.4)
0Alopecia
2 (3.6)3 (5.4)14 (15.4)
0
Dry skin
7 (12.5)
3 (5.4)7 (7.7)0
Erythema0
2 (3.6)6 (6.6)0Hyperkeratosis
2 (3.6)4 (7.1)5 (5.5)0Palmar-plantar erythrodysaesthesia syndrome
18 (32.1)
10 (17.9)
40 (44.0)0Pruritus
2 (3.6)6 (10.7)
12 (13.2)0Rash
4 (7.1)8 (14.3)
19 (20.9)
0Vascular disorders
34 (60.7)
26 (46.4)
77 (84.6)
5 (50.0)
Hypertension
34 (60.7)
24 (42.9)
75 (82.4)
5 (50.0)
Hypotension0
8 (14.3)
9 (9.9)0Subjects were only counted once per treatment for each row.
Includes data up to 28 days after last dose of study drug.
MedDRA (v15.0) coding dictionary applied.
Data cutoff date: 12 October 2012.
MedDRA (v15.0) = Medical Dictionary for Regulatory Activities (version 15.0); n = number of subjects with adverse
events.

Treatment-Emergent Treatment-Related Adverse Events: A summary of alltreatment-related TEAEs reported in 5% of subjects in any treatment group is provided inTable 17.

Template version 1.1

Page 27

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 17. Treatment-Emergent Treatment-Related Adverse Events Reported in 5%of Subjects in any Treatment Group
Number (%) of Subjects With Adverse Events by:
System Organ Class
Preferred Term
Number (%) of subjects evaluable for adverse events
Number (%) of subjects with adverse events
Being queried
Transient ischemic attack
Blood and lymphatic system disorders
Anaemia
Lymphopenia
Thrombocytopenia
Cardiac disorders
Sinus tachycardia
Endocrine disorders
Hypothyroidism
Gastrointestinal disorders
Abdominal distension
Abdominal pain
Abdominal pain upper
Cheilitis
Constipation
Diarrhoea
Dry mouth
Dyspepsia
Flatulence
Gastritis
Gastrooesophageal reflux disease
Haemorrhoids
NauseaStomatitis
Vomiting
General disorders and administration site conditions
Asthenia
Fatigue
Mucosal inflammation
Oedema peripheral
Pain
Infections and infestations
Rhinitis
Upper respiratory tract infection
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood creatinine increased
Blood glucose decreased
Blood glucose increased
Blood potassium increased
Blood thyroid stimulating hormone increased
Fibrin D dimer increased
Weight decreased

ActiveTitrationn (%)
56
53 (94.6)
00
7 (12.5)
4 (7.1)0
4 (7.1)00
18 (32.1)
18 (32.1)
38 (67.9)
1 (1.8)8 (14.3)
4 (7.1)1 (1.8)5 (8.9)32 (57.1)
5 (8.9)3 (5.4)6 (10.7)
2 (3.6)0
1 (1.8)18 (32.1)
9 (16.1)
14 (25.0)
32 (57.1)
5 (8.9)23 (41.1)
11 (19.6)
2 (3.6)2 (3.6)2 (3.6)2 (3.6)022 (39.3)
4 (7.1)3 (5.4)0
1 (1.8)3 (5.4)4 (7.1)3 (5.4)8 (14.3)
014 (25.0)

Template version 1.1

Page 28

Placebo
Titrationn (%)
56
47 (83.9)
00
5 (8.9)2 (3.6)0
3 (5.4)
1 (1.8)1 (1.8)13 (23.2)
13 (23.2)
37 (66.1)
3 (5.4)3 (5.4)
1 (1.8)1 (1.8)7 (12.5)
32 (57.1)
1 (1.8)2 (3.6)2 (3.6)2 (3.6)3 (5.4)0
15 (26.8)
3 (5.4)10 (17.9)
29 (51.8)
4 (7.1)24 (42.9)
7 (12.5)
3 (5.4)3 (5.4)7 (12.5)
6 (10.7)
3 (5.4)20 (35.7)
9 (16.1)
9 (16.1)
4 (7.1)3 (5.4)4 (7.1)7 (12.5)
3 (5.4)7 (12.5)
1 (1.8)10 (17.9)

NonRandomizedn (%)
91
89 (97.8)
00
16 (17.6)
4 (4.4)2 (2.2)
12 (13.2)
00
41 (45.1)
41 (45.1)
70 (76.9)
1 (1.1)7 (7.7)5 (5.5)5 (5.5)18 (19.8)
56 (61.5)
6 (6.6)14 (15.4)
3 (3.3)6 (6.6)4 (4.4)3 (3.3)28 (30.8)
17 (18.7)
19 (20.9)
48 (52.7)
4 (4.4)42 (46.2)
13 (14.3)
10 (11.0)0
3 (3.3)3 (3.3)047 (51.6)
12 (13.2)
11 (12.1)
6 (6.6)10 (11.0)
1 (1.1)7 (7.7)4 (4.4)9 (9.9)025 (27.5)

Discontinued Prior
to Randomizationn (%)
10
8 (80.0)
1 (10.0)
1 (10.0)
1 (10.0)0
1 (10.0)02 (20.0)
2 (20.0)
2 (20.0)
2 (20.0)
4 (40.0)0
1 (10.0)00
1 (10.0)
1 (10.0)000001 (10.0)
2 (20.0)02 (20.0)
4 (40.0)04 (40.0)
0
0
0
0
0
0
2 (20.0)00
2 (20.0)
1 (10.0)0
1 (10.0)00
1 (10.0)
1 (10.0)

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Table 17. Treatment-Emergent Treatment-Related Adverse Events Reported in 5%of Subjects in any Treatment Group
Number (%) of Subjects With Adverse Events by:
ActivePlacebo
NonDiscontinued Prior
System Organ Class
Titration
Titration
Randomized
to Randomization
Preferred Term
n (%)
n (%)
n (%)
n (%)
Metabolism and nutrition disorders
21 (37.5)
16 (28.6)
44 (48.4)
3 (30.0)
Decreased appetite
17 (30.4)
13 (23.2)
34 (37.4)
3 (30.0)
Hyperkalaemia
3 (5.4)
1 (1.8)3 (3.3)0Hyperlipidaemia
00
5 (5.5)0Hyperuricaemia
00
8 (8.8)0
Hypoalbuminaemia
3 (5.4)
1 (1.8)1 (1.1)0
Hyponatraemia
1 (1.8)0
2 (2.2)
1 (10.0)
Hypophosphataemia
1 (1.8)2 (3.6)4 (4.4)
1 (10.0)
Musculoskeletal and connective tissue disorders
18 (32.1)
14 (25.0)
32 (35.2)
2 (20.0)
Arthralgia
9 (16.1)
5 (8.9)11 (12.1)
0Back pain
6 (10.7)4 (7.1)5 (5.5)0Bone pain
3 (5.4)2 (3.6)
1 (1.1)0Groin pain000
1 (10.0)
Muscular weakness
3 (5.4)0
1 (1.1)0
Musculoskeletal pain
2 (3.6)3 (5.4)6 (6.6)0Musculoskeletal stiffness0
3 (5.4)2 (2.2)0
Myalgia
4 (7.1)1 (1.8)5 (5.5)0
Neck pain
2 (3.6)3 (5.4)2 (2.2)0
Pain in extremity
3 (5.4)2 (3.6)13 (14.3)
2 (20.0)
Nervous system disorders
18 (32.1)
13 (23.2)
37 (40.7)
1 (10.0)
Dizziness
5 (8.9)5 (8.9)6 (6.6)
1 (10.0)
Dysgeusia
9 (16.1)
5 (8.9)20 (22.0)
1 (10.0)
Headache
7 (12.5)
6 (10.7)
22 (24.2)
0
Hypoaesthesia
1 (1.8)0
2 (2.2)
1 (10.0)
Paraesthesia
3 (5.4)
1 (1.8)3 (3.3)
1 (10.0)
Psychiatric disorders
2 (3.6)4 (7.1)8 (8.8)2 (20.0)
Confusional state0
1 (1.8)0
1 (10.0)
Depression
1 (1.8)3 (5.4)3 (3.3)0Insomnia
1 (1.8)1 (1.8)6 (6.6)
1 (10.0)
Renal and urinary disorders
11 (19.6)
10 (17.9)
38 (41.8)
1 (10.0)
Haemoglobinuria
2 (3.6)3 (5.4)4 (4.4)0
Proteinuria
10 (17.9)
10 (17.9)
37 (40.7)
1 (10.0)
Respiratory, thoracic and mediastinal disorders
20 (35.7)
23 (41.1)
55 (60.4)
4 (40.0)
Cough
4 (7.1)4 (7.1)7 (7.7)0Dysphonia
18 (32.1)
18 (32.1)
44 (48.4)
3 (30.0)
Dyspnoea
4 (7.1)5 (8.9)17 (18.7)
1 (10.0)
Epistaxis
4 (7.1)3 (5.4)11 (12.1)
0Oropharyngeal pain
3 (5.4)
1 (1.8)7 (7.7)0
Skin and subcutaneous tissue disorders
24 (42.9)
19 (33.9)
53 (58.2)0
Alopecia
2 (3.6)2 (3.6)13 (14.3)
0
Dry skin
7 (12.5)
3 (5.4)6 (6.6)0Palmar-plantar erythrodysaesthesia syndrome
18 (32.1)
10 (17.9)
40 (44.0)0Pruritus
2 (3.6)6 (10.7)
11 (12.1)0Rash
3 (5.4)7 (12.5)
17 (18.7)
0
Vascular disorders
34 (60.7)
24 (42.9)
75 (82.4)
5 (50.0)
Hypertension
34 (60.7)
24 (42.9)
75 (82.4)
5 (50.0)
Subjects were only counted once per treatment for each row.
Includes data up to 28 days after last dose of study drug.
MedDRA (v15.0) coding dictionary applied.
Data cutoff date: 12 October 2012.
MedDRA (v15.0) = Medical Dictionary for Regulatory Activities (version 15.0); n = number of subjects with adverse
events.

Template version 1.1

Page 29

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

All-Causality Serious Adverse Events: A summary of all-causality SAEs reported during thestudy is presented in Table 18.
Table 18. Treatment-Emergent Serious Adverse Events (All-Causalities)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

System Organ Class
Preferred Term
Number of subjects with at least 1 SAE
Being queried
Transient ischemic attack
Blood and lymphatic system disorders
Neutropenia
Anaemia
Cardiac disorders
Myocardial ischaemia
Acute myocardial infarction
Angina pectoris
Coronary artery stenosis
Diastolic dysfunction
Myocardial infarction
Ear and labyrinth disorders
Tinnitus
Endocrine disorders
Hypothyroidism
Eye disorders
Cataract
Gastrointestinal disorders
Diarrhoea
NauseaVomiting
Diverticulum intestinal haemorrhagic
Abdominal distension
Abdominal pain
Abdominal pain upper
AscitesCrohn’s disease
Enterocolitis
Gastrointestinal hypomotility
Gingivitis
Ileus
Intestinal obstruction
Pancreatitis
General disorders and administration site conditions
Disease progression
General physical health deterioration
Chest pain
FatiguePyrexia
Hepatobiliary disorders
Cholecystitis chronic
Biliary colic
Cholelithiasis
Infections and infestations
Cystitis
Lung abscess
Pneumonia
Appendicitis
Infection
Lung infection

Template version 1.1

ActiveTitration
N=56
n (%)
15 (26.8)
00
1 (1.8)1 (1.8)0
1 (1.8)1 (1.8)
0
0
0
0
0
0
0
0
0
0
0
5 (8.9)2 (3.6)2 (3.6)2 (3.6)
1 (1.8)
0
0
0
0
0
0
0
0
0
0
0
2 (3.6)
1 (1.8)1 (1.8)000
1 (1.8)1 (1.8)00
2 (3.6)
1 (1.8)1 (1.8)1 (1.8)0
0
0Page 30

Placebo
Titration
N=56
n (%)
13 (23.2)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5 (8.9)1 (1.8)0
1 (1.8)0
1 (1.8)1 (1.8)02 (3.6)0
1 (1.8)000
1 (1.8)04 (7.1)1 (1.8)1 (1.8)00
2 (3.6)00
00
4 (7.1)1 (1.8)02 (3.6)
1 (1.8)00NonRandomized
N=91
n (%)
35 (38.5)
1 (1.1)1 (1.1)1 (1.1)0
1 (1.1)6 (6.6)0
1 (1.1)2 (2.2)
1 (1.1)1 (1.1)2 (2.2)
1 (1.1)1 (1.1)1 (1.1)1 (1.1)1 (1.1)1 (1.1)7 (7.7)
1 (1.1)0
1 (1.1)00
1 (1.1)1 (1.1)0
1 (1.1)1 (1.1)1 (1.1)1 (1.1)1 (1.1)0
1 (1.1)8 (8.8)6 (6.6)0
1 (1.1)1 (1.1)1 (1.1)2 (2.2)0
1 (1.1)1 (1.1)5 (5.5)00
1 (1.1)0
1 (1.1)1 (1.1)

Discontinued Prior
to Randomization
N=10
n (%)
2 (20.0)
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
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

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 18. Treatment-Emergent Serious Adverse Events (All-Causalities)

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

System Organ Class
Preferred Term
Osteomyelitis
Peritonitis bacterial
Postoperative wound infection
Injury, poisoning and procedural complications
Lumbar vertebral fracture
Overdose
Postoperative hernia
Postoperative wound complication
Road traffic accident
Investigations
Blood creatinine increased
Blood sodium decreased
Metabolism and nutrition disorders
Dehydration
Decreased appetite
Hypercalcaemia
Hypokalaemia
Hyponatraemia
Musculoskeletal and connective tissue disorders
Back pain
Haemarthrosis
Neoplasms benign, malignant and unspecified(including cysts and polyps)
Metastases to central nervous system
Nervous system disorders
Cerebrovascular insufficiency
SyncopeEncephalopathy
HeadachePresyncope
Somnolence
Psychiatric disorders
Delirium
Renal and urinary disorders
Renal colic
Postrenal failure
Renal failure
Renal failure acute
Urinary retention
Reproductive system and breast disorders
Pelvic prolapse
Respiratory, thoracic and mediastinal disorders
Atelectasis
Dyspnoea
Cough
Pleural effusion
Pulmonary hypertension
Pulmonary oedema
Skin and subcutaneous tissue disorders
Dermatitis
Surgical and medical procedures
Incisional hernia repair
Vascular disorders
Circulatory collapse
Hypertension
Hypertensive crisis

Template version 1.1

ActiveTitration
N=56
n (%)
0
0
0
0
0
0
0
0
0
0
0
0
4 (7.1)4 (7.1)1 (1.8)000
1 (1.8)1 (1.8)0
0Placebo
Titration
N=56
n (%)
0
0
0
1 (1.8)1 (1.8)000
1 (1.8)2 (3.6)2 (3.6)
1 (1.8)1 (1.8)0
1 (1.8)000
1 (1.8)0
1 (1.8)1 (1.8)

NonRandomized
N=91
n (%)
1 (1.1)1 (1.1)1 (1.1)2 (2.2)0
1 (1.1)1 (1.1)1 (1.1)00
00
7 (7.7)3 (3.3)2 (2.2)0
1 (1.1)1 (1.1)1 (1.1)1 (1.1)00Discontinued Prior
to Randomization
N=10
n (%)
0
0
0
0
0
0
0
0
0
0
0
0
1 (10.0)
1 (10.0)0
1 (10.0)
0
0
0
0
0
0

0
2 (3.6)
1 (1.8)1 (1.8)00
0
0
00
1 (1.8)1 (1.8)000
000
2 (3.6)
1 (1.8)1 (1.8)0000
1 (1.8)1 (1.8)
0
0
0
0
0
0

1 (1.8)2 (3.6)00
1 (1.8)1 (1.8)00
1 (1.8)1 (1.8)
0
0
0
0
0
0
0
0
2 (3.6)0
1 (1.8)1 (1.8)
0
0
0
0
0
0
0
1 (1.8)0
1 (1.8)00
3 (3.3)000
1 (1.1)1 (1.1)1 (1.1)00
3 (3.3)0
1 (1.1)0
1 (1.1)2 (2.2)
1 (1.1)1 (1.1)2 (2.2)000
1 (1.1)1 (1.1)1 (1.1)00
1 (1.1)1 (1.1)4 (4.4)
1 (1.1)1 (1.1)
0

0
0
0
0
0
0
0
0
0
0
1 (10.0)00
1 (10.0)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (10.0)00
1 (10.0)

Page 31

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 18. Treatment-Emergent Serious Adverse Events (All-Causalities)
System Organ Class
Preferred Term

ActiveTitration
N=56
n (%)
0
0

Placebo
Titration
N=56
n (%)
0
0

NonRandomized
N=91
n (%)
1 (1.1)1 (1.1)

Discontinued Prior
to Randomization
N=10
n (%)
0
0

Hypotension
Orthostatic hypotension
MedDRA (v15.0) coding dictionary applied.
Subjects were only counted once per treatment for each row.
Data source is from CRF page.
Data cutoff date: 12 October 2012.
CRF = case report form; MedDRA (v15.0) = Medical Dictionary for Regulatory Activities (version 15.0); N = number ofsubjects in each group; n = number of subjects with adverse events; SAE = serious adverse event.

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

Treatment-Related Serious Adverse Events: A summary of treatment-related SAEs reported
during the study is presented in Table 19.

Template version 1.1

Page 32

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 19. Treatment-Emergent Treatment-Related Serious Adverse Events

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

System Organ Class
Preferred Term

ActivePlacebo
NonDiscontinued Prior
Titration
Titration
Randomized
to Randomization
N=56
N=56
N=91
N=10
n (%)
n (%)
n (%)
n (%)
Number of subjects with at least 1 SAE
10 (17.9)
4 (7.1)15 (16.5)
1 (10.0)
Being queried00
1 (1.1)
0
Transient ischemic attack00
1 (1.1)0
Cardiac disorders
1 (1.8)0
2 (2.2)0
Myocardial ischaemia
1 (1.8)00
0
Angina pectoris
00
1 (1.1)0
Diastolic dysfunction
00
1 (1.1)0
Ear and labyrinth disorders00
1 (1.1)0
Tinnitus00
1 (1.1)0
Endocrine disorders00
1 (1.1)0
Hypothyroidism
00
1 (1.1)0
Gastrointestinal disorders
5 (8.9)2 (3.6)4 (4.4)0
Diarrhoea
2 (3.6)
1 (1.8)1 (1.1)0
Nausea2 (3.6)000Vomiting
2 (3.6)
1 (1.8)0
0Diverticulum intestinal haemorrhagic
1 (1.8)000Abdominal distension0
1 (1.8)00Abdominal pain upper00
1 (1.1)0Enterocolitis
01 (1.8)00Gingivitis
00
1 (1.1)0
Pancreatitis
00
1 (1.1)0
General disorders and administration site conditions
0
1 (1.8)2 (2.2)0
Chest pain00
1 (1.1)0
Pyrexia0
1 (1.8)1 (1.1)0
Infections and infestations
1 (1.8)1 (1.8)2 (2.2)0Lung abscess
1 (1.8)000Pneumonia
1 (1.8)000
Appendicitis01 (1.8)00Osteomyelitis
00
1 (1.1)0
Postoperative wound infection
00
1 (1.1)0Metabolism and nutrition disorders
2 (3.6)
1 (1.8)4 (4.4)0Dehydration
2 (3.6)0
1 (1.1)0
Decreased appetite01 (1.8)2 (2.2)0
Hypokalaemia
00
1 (1.1)0
Musculoskeletal and connective tissue disorders0
1 (1.8)0
0
Haemarthrosis0
1 (1.8)00
Nervous system disorders
1 (1.8)0
1 (1.1)0
Cerebrovascular insufficiency
1 (1.8)000Presyncope
00
1 (1.1)0
Respiratory, thoracic and mediastinal disorders
2 (3.6)0
1 (1.1)0
Atelectasis
1 (1.8)0
0
0
Dyspnoea
1 (1.8)00
0Pulmonary hypertension00
1 (1.1)0
Skin and subcutaneous tissue disorders
1 (1.8)000Dermatitis
1 (1.8)000
Vascular disorders0
1 (1.8)2 (2.2)
1 (10.0)
Circulatory collapse00
1 (1.1)0Hypertension0
1 (1.8)1 (1.1)0Hypertensive crisis
00
0
1 (10.0)
MedDRA (v15.0) coding dictionary applied. Subjects were only counted once per treatment for each row. Data source isfrom CRF page. Data cutoff date: 12 October 2012.
CRF = case report form; MedDRA (v15.0) = Medical Dictionary for Regulatory Activities (version 15.0); N = number ofsubjects in each group; n = number of subjects with adverse events; SAE = serious adverse event.

Template version 1.1

Page 33

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Permanent Discontinuations due to Adverse Events: A summary of AEs that led to treatment
discontinuation in 2% of subjects in any treatment group is presented in Table 20.
Table 20. Summary of Adverse Events That led to Treatment Discontinuation in 2%of Subjects in any Treatment Group

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

System Organ Class
Preferred Term

Active Titration

Placebo Titration

NonRandomized

N=56
n (%)
No. of Subjects(%)
7 (12.5)
1 (1.8)N=56n (%)
No. of Subjects(%)
6 (10.7)
2 (3.6)N=91n (%)
No. of Subjects(%)
11 (12.1)
3 (3.3)

Discontinued
Prior toRandomization
N=10
n (%)
No. of Subjects(%)
2 (20.0)
1 (10.0)

Any AEs
General disorders and administrationsite conditions
General physical health
1 (1.8)1 (1.8)1 (1.1)1 (10.0)
deterioration
Disease progression
0 (0.0)1 (1.8)2 (2.2)0 (0.0)
Vascular disorders
0 (0.0)0 (0.0)2 (2.2)
1 (10.0)
Hypertension
0 (0.0)0 (0.0)1 (1.1)1 (10.0)% = (n/N) × 100.
MedDRA (v15.0) coding dictionary applied.
Data cutoff date: 12 October 2012.
AE = adverse event; MedDRA (v15.0) = Medical Dictionary for Regulatory Activities (version 15.0); N = number ofsubjects in each group; n = number of subjects with adverse events; No. = number.

Deaths: Similar percentages of subjects died across treatment groups. The most common
cause of death was disease under study. No subject died due to study treatment toxicity.
A summary of causes of death is presented in Table 21.

Template version 1.1

Page 34

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

Table 21. Causes of Death

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

ActiveTitration
N=56
n
%
22
39.3
2
3.6
2
3.6
0
0
0
0
0
0
0

Placebo
Titration
N=56
n
%
21
37.5
1
1.8
0
0
0
1
1.8
0
0
1
1.8
0

Non-Randomized
N=91
n
31
8
5
0
0
3
1
1
0
1

Discontinued Prior
to Randomization
N=10
n
%
4
40.0
0
0
0
0
0
0
0
0
0

%
Subjects who died
34.1
Subjects who died on-studya
8.8
Disease under study
5.5Study treatment toxicity
Unknown
Other
3.3
Acute circulatory failure
1.1
Pneumonia
1.1
Fatal disease progression
General physical health
1.1
deterioration
Subjects who died during follow-upb
20
35.7
20
35.7
23
25.3
4
40.0
Disease under study
19
33.9
18
32.1
21
23.1
4
40.0
Study treatment toxicity
0000Unknown
1
1.8
1
1.8
2
2.2
0
Other
0
1
1.8
0
0
Upper GI bleed
0
1
1.8
0
0
Data cut-off date: 12 October 2012.
GI = gastrointestinal; N = number of subjects; n = number of subjects meeting prespecified criteria.
a. On-study deaths are those that occurred after the first dose of study drug and within 28 days of the last dose of study
drug.
b. Follow-up deaths are those that occurred >28 days after the last dose of study drug.

Vital Signs, Laboratory Findings, and Other Observations Related to Safety: In general,
there were no clinically relevant observations regarding results of vital sign assessments inthis study.
There were no clinically-significant hematological and biochemistry abnormalities reported.
In the active titration group, the proportion of subjects whose TSH values shifted to
postbaseline TSHs 10 IU/mL was higher than in the placebo group (41.8% and 19.6%,
respectively). In the non-randomized group, the TSH values of 51.6% of subjects shifted to
TSH values 10 IU/mL.
Urine protein values for 2 (3.6%) subjects in the active titration group shifted from Grade 0
to Grade 3 and for 1 (1.8%) subject from Grade 0 to Grade 4; values for 1(1.8%) subject
shifted from Grade 1 to Grade 3. In the placebo titration group, urine protein values for3 (5.5%) subjects shifted from Grade 0 to Grade 3. In the non-randomized group, urine
protein values for 10 (11.1%) subjects shifted from Grade 0 to Grade 3 and for
1 (1.1%) subject from Grade 0 to Grade 4.
Discontinuations from study due to an abnormal laboratory test were reported for 1 subject in
the placebo titration group (increased blood creatinine, SAE, unrelated to study drug), and for
1 subject in the non-randomized group (proteinuria, AE, related to study drug).

Template version 1.1

Page 35

Public Disclosure Synopsis
Protocol A4061046 – 29 September 2014 – Final

090177e185c6cb31\Approved\Approved On: 06-Oct-2014 16:00

CONCLUSIONS:The primary objective of the study was achieved and the ORR was significantly higher in
the active titration arm compared to the placebo titration arm. There were no statisticallysignificant differences in secondary efficacy endpoints, PFS or OS, between the
2 randomized arms. The overall median PFS was 14.6 months.

The most common all-causality, all grade AEs in the randomized arms were diarrhea,
hypertension, and fatigue. More hypertension was reported in active titration arm than in
the placebo titration arms; rates of diarrhea and fatigue were similar in both arms. In
general, the non-randomized arm had more all-causality, all grade AEs. Overall, the AEs
observed in treatment-naïve subjects with advanced RCC in this study were consistent
with the risk/benefit profile observed in completed studies in previously-treated subjects
with advanced RCC; there were no new or unexpected AEs in this study.

The axitinib PK in treatment- naïve subjects with advanced RCC is consistent with thatobserved in previously-treated subjects with advanced RCC subjects receiving a starting
dose of 5 mg BID.



There were no significant associations of genotype vs ORR (primary objective) or
OS (secondary objective). For some polymorphisms it was shown that median PFS for
the G/G genotype was longer than for other genotypes. No significant observations ofassociation of genotype vs postbaseline DBP <90 mm Hg were reported.

Template version 1.1

Page 36