Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – 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.: A4061058
PROTOCOL TITLE: A multicentre, global, randomized, double-blind study of axitinib
plus best supportive care versus placebo plus best supportive care in patients with advanced
hepatocellular carcinoma following failure of one prior antiangiogenic therapy.
Study Centers: 70 centers in 13 countries worldwide: Belgium (2 centers),
China (7 centers), France (11 centers), Germany (3 centers), United Kingdom (5 centers),
Hong Kong (2 centers), Hungary (2 centers), Italy (7 centers), Japan (9 centers),
Korea (3 centers), Slovakia (3 centers), Taiwan (7 centers), and United States ofAmerica (9 centers).
Study Initiation Date and Primary Completion or Final Completion Dates: Study
Initiation Date: 06 December 2010
Primary completion date: 03 March 2014
Final Completion Date: This study is still ongoing.
Phase of Development: Phase 2
Study Objectives: This study is being conducted in two parts (randomized and nonrandomized) and had the following objectives.
Non-randomized Portion (Selected Sites Only)••

To evaluate the plasma pharmacokinetics (PK) of axitinib in subjects with advanced
hepatocellular carcinoma (HCC) following failure of one prior antiangiogenic therapy
andTo determine the tolerability and recommended starting dose of axitinib in subjects
with advanced HCC with Child-Pugh Class B disease (score 7) following failure of
one prior antiangiogenic therapy.

Randomized Portion (All Sites)
Primary Objective:• To compare the overall survival (OS) of subjects with advanced HCC receiving
axitinib + Best Supportive Care (BSC) versus placebo + BSC following failure of one
prior antiangiogenic therapy.
Secondary Objectives:

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Protocol A4061058 – 27 January 2015 – Final

•
•
•
•
•
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•
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To compare progression-free survival (PFS) between both arms;
To compare time to progression (TTP) between both arms;
To compare overall response rate (ORR) between both arms;
To evaluate duration of response (DR) within each treatment arm;
To compare Clinical Benefit Rate (CBR) between both arms;
To evaluate the safety and tolerability of axitinib in this subject population;
To evaluate the PK of axitinib in this subject population;
To compare subjects’ health-related quality of life (HRQoL) and health status
between both arms;
To evaluate baseline blood vascular endothelial growth factor (VEGF) - C level as apotential predictive biomarker of axitinib efficacy; andTo evaluate blood soluble protein concentrations and ribonucleic acid (RNA)transcripts associated with angiogenesis or tumor growth.

METHODS
Study Design
Non-randomized portion (selected sites only)This was an open-label, non-randomized portion of this study at selected sites only. Subjects
were assigned to 2 cohorts according to Child-Pugh score. It was planned to have an equal
number of subjects (12) in each of the 2 cohorts.
Cohort 1: Subjects with advanced HCC and Child-Pugh Class A disease, score 5 or 6.
Cohort 2: Subjects with advanced HCC and Child-Pugh Class B disease, score 7 without
ascites or encephalopathy.
Subjects with Child-Pugh Class A disease (score 5 or 6) could have been enrolled into either
the non-randomized (Cohort 1) portion at selected sites to characterize the PK of axitinib orto the randomized portion of this study at a starting axitinib dose of 5 mg twice daily (BID).
Subjects with Child-Pugh Class B disease (score 7) were initially enrolled at selected sites
into the non-randomized portion of this study to determine the recommended starting dose of
axitinib for this population. Following determination of the recommended axitinib starting
dose based on tolerability and PK assessments, subjects with Child-Pugh Class B disease(score 7) were to begin enrollment into the randomized portion of the study.
Initially, 6 subjects with Child-Pugh Class B disease (score 7) at selected sites were enrolled
into Cohort 2 of the non-randomized portion at a 2 mg BID axitinib starting dose. The
maximum tolerated dose (MTD) was defined as the dose level in which 0/6 subjects or 1/6
subjects experience dose limiting toxicity (DLT) during Cycle 1 of treatment with the next
higher dose level having 2 or more subjects experiencing DLT within their first treatment
cycle.

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Protocol A4061058 – 27 January 2015 – Final•

If 0/6 or 1/6 subject experienced DLT during Cycle 1 (4 weeks) of treatment with 2
mg BID axitinib starting dose, then 5 mg BID axitinib starting dose was explored in 6
subjects. If 0/6 or 1/6 subject at 5 mg BID dose level experience DLT during Cycle 1,then 5 mg BID was the recommended starting dose for the randomized portion unlessthe PK data indicated a lower starting dose should be used. If 2/6 or more subjects at
5 mg BID dose level experienced DLT during Cycle 1, then the recommended
starting dose was 2 mg BID for the randomized portion for Child-Pugh Class B (score
7) subjects.

•

If 2/6 or more subjects experienced DLT during Cycle 1 of treatment with 2 mg BID
axitinib starting dose, then 6 additional subjects were enrolled at the next lower
starting dose level (1 mg BID). If 0/6 or 1/6 subject at 1 mg BID dose level
experienced DLT during Cycle 1, then 1 mg BID was the recommended starting dose
for the randomized portion of the study for Child-Pugh Class B (score 7) subjects. If
2/6 or more subjects at 1 mg BID dose level experienced DLT during Cycle 1, alower dose level may have been explored with concurrence of the sponsor andinvestigator following examination of the PK data.

Provided there was no unacceptable safety or tolerability and with concurrence of theinvestigators and sponsor, subjects within each cohort were allowed to continue their current
dosing for the first cycle and then dose titration may have been performed according to thedose titration guideline until progressive disease (PD) was documented. All subjects enrolled
into the non-randomized portion were assessed and followed up following the same schedule(except for assessment of soluble proteins, RNA transcripts, and Subject Reported Outcomes[PROs]) as subjects in the randomized portion.
Randomized portion (all sites)
The randomized portion of the study was a multicenter, double-blind, parallel-arm clinical
trial to compare the efficacy of axitinib + BSC versus placebo + BSC in subjects withadvanced HCC whose disease had progressed after or were intolerant to one priorantiangiogenic therapy. Subjects were randomized (2:1 ratio) to receive either axitinib + BSC
or placebo + BSC and were stratified by tumor invasion (presence vs absence of extrahepatic
spread and/or vascular invasion) and geographic region (Asia vs non-Asia).
Schedule of activities can be found in Table 1.

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Protocol A4061058 – 27 January 2015 – Final

Table 1: Schedule of Activities

Note: Tests and procedures were to be done on schedule, but occasional changes by ±4 days (only +4 days for tests and procedures to be done at “Follow-up Day 28
after last dose” visit) were allowable for holidays, vacations, and other administrative reasons.
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Protocol A4061058 – 27 January 2015 – Final* Cycle length was 4 weeks. Subjects enrolled into the non-randomized portion were to follow the same schedule of activities as the randomized portion.
** Unnecessary to repeat before first dose if the assessment was performed within 7 days prior to first dosea
Informed consent: Prior to any procedures performed solely for this study.
bMedical history: Including information on prior systemic first-line treatment and pre-study tumor assessment data showing disease progression according to
RECIST criteria if applicable.
cConcomitant treatment: collected from screening to the follow-up period.
dPhysical exam: Examination of major body systems (including neurological examination). Abnormalities from subsequent history and physical examinations were
to be recorded as AEs.
e
Height was not required to be collected after the first measurement.
f
BP was to be measured with the subject in the seated position after the subject had been sitting quietly for 5 minutes; 2 BP readings were required at each clinic
visit. It was acceptable not to collect the second BP reading at follow-up clinic visit only if there were no BP elevations observed by home BP monitoring and thefirst BP reading in clinic was normal.
gHome BP monitoring: All subjects (in both study arms) were provided a BP monitoring device. Subjects were to take BP at least twice daily prior to taking eachdose of medication and BP was to be recorded in a subject diary. Subjects were to be instructed by the study staff to contact their physician for guidance if their
systolic BP rose above 140 mm Hg, diastolic BP rose above 90 mm Hg, or if they developed symptoms perceived to be related to elevated BP (eg, headache, visual
disturbance). A different BP threshold for contacting physician may have been used according to the physician’s clinical judgment.
hEastern Cooperative Oncology Group (ECOG) performance status.
i
Hematology: Hemoglobin, white blood cells with differential count, and platelets required within 7 days prior to the start of study treatment.
j
Chemistry, alpha-fetoprotein: blood urea nitrogen, creatinine, sodium (Na+), potassium (K+), chloride (Cl-), calcium (Ca+), alkaline phosphatase,
gamma-glutamyl-transpeptidase, lactate dehydrogenase, alanine aminotransferase (or serum Glutamate-Pyruvate Transferase), aspartate aminotransferase (or serum
Glutamate-Oxalate Transferase), total protein, albumin, total bilirubin, glucose, phosphate, and alpha-fetoprotein.
k
HBV panel, anti-HCV antibodies: HBsAg, HBe, anti-HBc, and anti-HCV.
l
Coagulation test: Prothrombin time or International Normalized Ratio required within 7 days prior to the start of study treatment.
m
Thyroid Function Tests (free T3, free T4, and thyroid stimulating hormone): was to be performed for all non-randomized and randomized subjects (in both studyarms) on Cycle 1 Day 1 before dosing or within 7 days of pre-dose. Subsequently, thyroid stimulating hormone was to be done at Cycle 1 Day 15, Cycle 2 Day 1,
Cycle 3 Day 1, Cycle 4 Day 1, then every 8 weeks thereafter starting from Cycle 6 Day 1. Free T3 and/or free T4 was to be performed when clinically indicated.
Subjects
were to be monitored for signs and symptoms of hypothyroidism, such as fatigue, deepening of voice, cold intolerance, constipation, anorexia, periorbital edema,
myxedema, or changes in skin or hair. Hypothyroidism was to be treated per standard medical practice to maintain euthyroid state.
nUrine analysis: Protein, glucose, and blood required within 7 days prior to the start of study treatment. If protein ≥2+ by semiquantitative method (eg, urine
dipstick) then quantitate by 24-hour urine collection. Dose adjustment may have been required (adjustment of the dose once subject is on trial. This did notdepend on baseline proteinuria).
o
ECGs: A single ECG measurement was collected at screening. If the mean QTc interval was prolonged (>500 msec), then the ECGs were to be re-read by a
cardiologist or other qualified person at the site for confirmation. Additional ECGs may have been performed as clinically indicated.
p
Tumor assessments including CT/MRI: Pre-study objective evidence of disease progression per RECIST or intolerance to prior therapy was to be confirmed by theinvestigator and documented in the subject’s medical record. Baseline (screening) tumor assessments required CT/MRI (no chest x-ray) of the chest and abdomen at
the minimum. A bone scan and CT/MRI of the pelvis may have been performed if clinically indicated at baseline and at follow up visits. If the interval between anyof the baseline tumor assessments and randomization was >28 days, the expired baseline tumor imaging was to be repeated. For all subjects, CT/MRI (covering thesame anatomy as the baseline scans) was required every 8 weeks by calendar from the date of randomization. Response (CR/PR) required confirmation with CT/MRIPage 5

Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final

at least 4 weeks after the response is first noted.
q
Serum or urine pregnancy test: Female subjects of childbearing potential must have had a negative pregnancy test within 7 days prior to treatment and all subjects
must have been using appropriate birth control or practicing abstinence. Pregnancy testing may have been repeated as per request of IRB/IECs or if required by local
regulations.
rEndoscopy or upper gastrointestinal imaging (screening): to exclude subjects with esophageal varices of greater than grade 2 according to Paquet classification oresophageal varices in the presence of any red signs (grade 2 allowed only if on prophylactic treatment).
s
Study randomization: Subject number, randomization, and axitinib bottle number assignments were obtained via centralized randomization. Required information:site and subject identifiers, demographic information, and stratification variables including tumor invasion (presence versus absence of extrahepatic spread and/or
vascular invasion), geographic region (Asia versus non-Asia). Study treatment was to begin within 7 days of randomization.
t
Pharmacokinetics:
Non-randomized portion (selected sites only): Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2,
3, 4, 6 and 8 hours after axitinib dosing. Subjects were instructed to hold the morning dose of axitinib until the pre-dose sample was drawn.
Randomized portion (all sites): Population PK samples for axitinib/placebo were to be obtained from subjects on Day 1 of Cycle 1, 2 and 3. On Cycle 1 Day 1, one
sample will be obtained 2 to 3 hours after the first axitinib/placebo dose in clinic. The exact time of the first dose was to be noted. On Day 1 of Cycle 2 and 3, twosamples were to be collected: 1 sample just before (within 15 minutes) the morning axitinib/placebo dose (taken in the clinic) and another 2 to 3 hours after themorning axitinib/placebo dose. The exact time of the clinic visit dose and the dose taken prior to that were to be noted.
uPlasma soluble proteins: Ang-2, MMP-2, VEGF-A, VEGF-C, sVEGFR2, SVEGFR3, HGF, sMET, SCF, sKIT, NGAL, SDF-1, IL-6, IL-8, E-selectin, MCP-3,
MIF, CCL5 (also referred to as RANTES)were only measured in randomized subjects. On Cycle 1 Day 1 and at end of study treatment/withdrawal, samples were to
be collected at predose. On Cycle 2 Day 1, samples were to be collected at 2 to 3 hours after the morning axitinib/placebo dose.
v
Blood RNA samples: Blood samples for RNA analysis were to be collected from randomized subjects only. On Cycle 1 Day 1 and at end of study
treatment/withdrawal, samples were to be collected at predose. On Cycle 2 Day 1, samples were to be collected at 2 to 3 hours after the morning axitinib/placebo
dose.
w
Safety assessment: AEs were to be collected from the first day of study treatment throughout the study period until at least 28 days after the last dose of study drug
and followed until resolution or stabilization. SAEs were to be monitored and reported from the time the subject provided informed consent.
xSurvival: All subjects were to be followed for survival at least every 3 months after discontinuing study treatment until at least two years after randomization of thelast subject.
yPatient reported outcomes: FACT-Hep and EQ-5D (patient reported outcome) questionnaires were to be administered on Cycle 1 Day 1 before dosing and before
any other clinical assessments, then every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up, Day 28 after last dose in BOTH
treatment arms. PROs were to be administered to randomized subjects only.
Abbreviations: AFP=Alpha-fetoprotein; Ang-2=Angiopoietin 2; BP=Blood pressure; BCLC=Barcelona Clinic Liver Cancer; CCL5=Chemokine (C-C motif)
ligand 5; CLIP=Cancer of the Liver Italian Program; CT=Computed tomography; ECG=Electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EQ5D=EuroQoL 5 dimensions; FACT-Hep=Functional Assessment of Cancer Therapy –Hepatobiliary questionnaire; GI=Gastrointestinal; HBV=Hepatitis B virus;
HCV=Hepatitis C virus; HGF=Hepatocyte growth factor; IL-6=Interleukin 6; IL-8=Interleukin 8; MCP-3=Monocyte chemotactic protein; MIF=Migration inhibitory
factor; MMP-2=Matrix metalloproteinase 2; MRI=Magnetic resonance imaging; NGAL=Neutrophil gelatinase-associated lipocalin; PK=Pharmacokinetic;
RANTES=Regulated upon Activation Normal T cell Expressed and presumably Secreted; RECIST=Response Evaluation Criteria in Solid Tumors; RN=Ribonucleic
Acid; SAE=Serious adverse event; sKIT=Soluble stem cell factor receptor; SCF=Stem cell factor; SDF-1=stromal cell-derived factor 1 ; sVEGFR2=Soluble vascularendothelial growth factor receptor 2; sVEGFR3=Soluble vascular endothelial growth factor receptor 3; VEGF=Vascular endothelial growth factor;
VEGF-A=Vascular endothelial growth factor A; VEGF-C=Vascular endothelial growth factor C.

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Protocol A4061058 – 27 January 2015 – Final

Number of Subjects (Planned and Analyzed)
Non-randomized portion (selected sites only)
Planned: approximately 24 subjects (12 in the Child-Pugh A cohort and 12 in the Child-Pugh
B [score 7] cohort);
Analyzed: enrolled 22 subjects (15 in the Child-Pugh A cohort and 7 in the Child-Pugh B
cohort).
Randomized portion (all sites)
Planned: 198 subjects (132 in the axitinib arm and 66 in the placebo arm).
Analyzed: enrolled 202 subjects (134 in the axitinib arm and 68 in the placebo arm).
Diagnosis and Main Criteria for Inclusion
Subjects with locally advanced or metastatic HCC, failure of one prior antiangiogenic
therapy including sorafenib, bevacizumab and brivanib, and Child-Pugh disease A (score 5 or
6) or B (score 7 only) disease were enrolled in this study.
Study Treatment
Study treatment was to begin within 7 days of randomization. All subjects enrolled were toreceive treatment with axitinib or placebo during the study depending on their participationin either the non-randomized or randomized part of the study. Study treatment wasadministered in cycles of 4 weeks in duration. Axitinib/placebo was administered beginningon Day 1 of the study. Each medication dose was to be taken with food as close to 12 hours
apart as possible and at approximately the same times each day on a continuous schedule.
Test productNon-randomized Portion
Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the
non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.
Subjects with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled
only into the non-randomized portion of this study to determine the recommended starting
dose of axitinib for this population.
Randomized Portion
Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized
portion at a starting axitinib dose of 5 mg BID. Subjects with Child-Pugh Class B disease(score 7) were to begin enrollment into the randomized portion of the study following
determination of the recommended axitinib starting dose in the non-randomized portion.
Subjects were randomized (2:1 ratio) in a double-blind fashion (using a centralized
registration system) to receive axitinib+BSC (Arm A) or placebo+BSC (Arm B).

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Protocol A4061058 – 27 January 2015 – FinalRandomization was stratified by tumor invasion (presence versus absence of extra hepatic
spread, and/or vascular invasion) and geographic region (Asia versus non-Asia).
Reference Therapy
Matching placebo was supplied as 1 mg and 5 mg immediate-release, film-coated tablets fororal administration.
The criteria for dose modification for study drug-related AEs are summarized in Table 2.
Table 2: Criteria for Dose Modification for Study Drug-related Adverse Events
Related Adverse Event

Intervention/Management

Axitinib-related adverse events other than hypertension or proteinuria
Grade 1

Continued at same dose level

Grade 2

Continued at same dose level

Grade 3 hematologic treatment-related toxicity

Continued at same dose levela

Grade 3 nonhematologic treatment-related toxicity

Decreased dose to 1 lower dose level

Grade 4 nonhematologic treatment-related toxicity or
Grade 4 hematologic toxicityb

Interrupted dosing; restarted at 1 lower dose level as soon as
improvement to NCI CTCAE Grade ≤2Hypertension
2 BP readings separated by ≥1 hour showed systolic BP>140 mmHg or 2 BP readings separated by ≥1 hour showed
diastolic BP >90 mmHg

If not on maximal antihypertensive treatment, instituted new
or additional antihypertensive medication and maintained
dose of axitinib/placebo.
If on maximal antihypertensive treatment, reduced axitinib to
1 lower dose level/placebo.

2 BP readings separated by ≥1 hour showed systolic BP>160 mmHg or 2 BP readings separated by ≥1 hour showed
diastolic BP >105 mmHg

Interrupted dosingc; adjusted antihypertensive medication; assoon as BP was less than 140/90 mmHg, restarted
axitinib/placebo at 1 lower dose level.

Proteinuria>2+ proteinuria (dipstick)

Performed 24-hour urine collection. Dosing could continue
while waiting for test results.

≤3.5 g proteinuria/24 hours

Continued dosing at the same dose level.

>3.5 g proteinuria/24 hours

Held dosing and repeated 24-hour urine collection forproteinuria and creatinine clearance (interval at investigator
discretion) until proteinuria was ≤3.5 g/24 hours. Restarted
axitinib/placebo at the same dose or 1 lower dose level at thediscretion of the investigator.
aSubjects who developed Grade 3 nonhematologic toxicities that were controlled with symptomatic medications or who
developed Grade 3 asymptomatic biochemistry laboratory abnormalities continued at the same dose level at the discretion of
the investigator.
b
Subjects who developed Grade 4 lymphopenia or Grade 4 asymptomatic biochemistry laboratory abnormalities continued
study treatment without interruption.
c
If axitinib/placebo was held, subjects receiving antihypertensive medications were to be monitored closely forhypotension. The plasma half-life of axitinib is 2 to 4 hours and BP usually decreases within 1 to 2 days following doseinterruption.
Abbreviations: BP=Blood pressure; NCI CTCAE=National Cancer Institute Common Terminology Criteria For Adverse
Events.

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Protocol A4061058 – 27 January 2015 – Final

Efficacy, Pharmacokinetic, Pharmacodynamic, or Outcomes Research Endpoints
Non-randomized Portion•

Plasma PK [maximum plasma concentration (Cmax); area under the plasma
concentration-time curve (AUC) from time 0 to 24 hours (AUC0-24); area under theplasma concentration-time curve from time 0 to the time of the last measurable
concentration (AUClast); time to first occurrence of Cmax (Tmax); terminal phaseelimination half-life (t1/2); apparent oral clearance (CL/F); apparent volume of
distribution of the drug during the elimination Phase (Vz/F)], and tolerability ofsingle-agent axitinib following continuous dosing.

Randomized Portion
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PrimaryOS.
Secondary
PFS;
TTP;
ORR;
DR;
CBR;
Axitinib population PK analysis;
Patient-Reported Outcomes (PRO) of HRQoL and disease-related symptoms as
measured by the Functional Assessment of Cancer Therapy – Hepatobiliary
Questionnaire (FACT-Hep) and health status measured by the EuroQol EQ-5D
Self-Report Questionnaire (EQ-5D);
Plasma soluble proteins (angiopoietin 2 [Ang-2], matrix metalloproteinase 2[MMP-2], VEGF-A, VEGF-C, soluble vascular endothelial growth factor receptor 2[sVEGFR2], sVEGFR3, hepatocyte growth factor [HGF], c-MET, stem cell factor[SCF], soluble stem cell factor receptor [sKIT], neutrophil gelatinase-associatedlipocalin [NGAL], stromal cell-derived factor 1 [SDF-1], interleukin 6 [IL-6],
interleukin 8 [IL-8], E-selectin, monocyte chemotactic protein [MCP-3], migration
inhibitory factor [MIF], chemokine (C-C motif) ligand 5 [CCL5; also referred to as
Regulated upon Activation Normal T cell Expressed and presumably Secreted(RANTES)];
Plasma micro-RNA transcripts associated with angiogenesis and tumor growth.

Safety Evaluations
Non-randomized portion••

First-cycle DLT; Child-Pugh Class B, score 7 population only.
Type, incidence, severity, timing, seriousness, and relatedness of AEs, laboratory
abnormalities based upon the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) Version 3.0.

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Protocol A4061058 – 27 January 2015 – FinalRandomized portion•

Type, incidence, severity (graded by the NCI CTCAE, Version 3.0), timing, seriousness,and relatedness of AEs and laboratory abnormalities.

Statistical Methods
Analysis Sets
Full Analysis Population:
The full analysis set (FAS) was to include all randomized subjects, and subjects wereclassified according to the randomized treatment arm regardless of what treatment, if any,
was received. This was to be the primary population for evaluating all efficacy endpoints aswell as subject characteristics.
Safety Analysis Population:
The safety analysis population was to include all randomized subjects who received at least
1 dose of study drug with treatment assignments designated according to actual study
treatment received. This population was to be the primary population for evaluating
treatment administration/compliance and safety.
Pharmacokinetic Analysis Sets:
The PK concentration set was to include all subjects who were treated and had at least 1
measured concentration on at least 1 day of PK assessment.
The PK parameter analysis set was to include all subjects treated who had at least 1 estimatedPK parameter of primary interest.
Pharmacodynamic Analysis Sets:
The soluble protein analysis set was to include all subjects in the safety analysis set who hada baseline soluble protein assessment.
The microRNA (miRNA) analysis set was to include all subjects in the safety analysis set
who had a baseline miRNA assessment.
Efficacy analyses
Primary Analysis
The primary objective of this study was to compare OS of axitinib+BSC versus
placebo+BSC in subjects with advanced HCC, whose disease had progressed on/after orwere intolerant to one prior antiangiogenic therapy. The study was designed to detect a
hazard ration (HR) of 0.6 in OS for axitinib over placebo.

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Overall survival: OS was defined as the time from the date of randomization to the date ofdeath due to any cause. OS (in months) was calculated as (date of death − first randomization
date +1)/30.4. OS was summarized in the FAS using Kaplan-Meier (KM) methods. A
stratified log-rank test (1-sided, α=0.025) was used to compare OS between the 2 treatment
arms. The median event time and 2-sided 95% CI for the median was to be provided. The HR
and its 95% CI were also estimated. The 1-year survival probability was also estimated using
the KM method and a 2-sided 95% CI for the log [-log (1-year survival probability)] wascalculated using a normal approximation and then back transformed to give a CI for the
1-year survival probability itself. A Cox regression model was used to explore the potential
influences of the stratification factors on the primary OS endpoint. OS was calculated using
the following censoring method: OS data were censored at the date of last contact at which
the subject was known to be alive, or the date the subject crossed to another chemotherapy,
whichever came first. Sensitivity analyses using an unstratified log rank test were also
performed.
Secondary Analyses
Progression-free survival: PFS was defined as the time from date of first dose of study drug
to first documentation of objective tumor progression, or to death due to any cause,
whichever occurred first. PFS (in months) was calculated as (first event date – date of firstdose of study drug+1)/30.4. PFS in each arm was assessed using the KM method in the FAS
and compared with a 1-sided stratified log-rank test at α=0.025 significance level. Medianand 95% CIs for each treatment arm were to be provided. As an additional sub-analysis, an
unstratified log-rank test was calculated along with the above mentioned supporting
summary statistics.
Time to progression: TTP was defined as the time from randomization to first documentationof objective tumor progression. TTP (in months) was calculated as (first event date − first
randomization date +1)/30.4. TTP in each arm was assessed using the KM method in the
FAS and compared with a 1-sided stratified log-rank test, at α=0.025 significance level.
Median and 95% CIs for each treatment arm were to be provided. As an additional subanalysis, an unstratified log-rank test was to be calculated along with the above mentioned
supporting summary statistics.
Overall response rate: ORR was defined as the percent of subjects with confirmed complete
response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria
in Solid Tumors (RECIST 1.1) criteria, relative to all randomized subjects who had baseline
measurable disease. ORR for the 2 treatment arms was compared with using CochranMantel-Haenszel (CMH) test for stratified analyses (α=0.025 significance level).
Duration of response: DR was defined as the time from the first documentation of objective
tumor response (CR or PR) that was subsequently confirmed to the first documentation of PD
or to death due to any cause, whichever occurs first. DR (in months) was calculated as (theend date for DR − first CR or PR that was subsequently confirmed +1)/30.4. Estimates of the
DR were evaluated using the KM method. Median and 95% CIs for each treatment arm were
provided.

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Clinical benefit rate: CBR was defined as the proportion of subjects with confirmed CR or
confirmed PR or a best response of stable disease ≥8 weeks according to RECIST criteria,
relative to all randomized subjects who had baseline measurable disease. CBR for the 2treatment arms was compared using CMH test for stratified analyses (α=0.025 significancelevel).
Pharmacokinetic analysis
Axitinib PK parameters were estimated using non-compartmental methods. The axitinib PK
data were summarized and reported based on Child-Pugh class as well as the dose
administered. Descriptive statistics (n, mean, standard deviation (SD), % coefficient ofvariation (CV), median, minimum, maximum) of plasma concentrations for axitinib were
presented in tabular form by study day, Child-Pugh class, dose and nominal time. PK
parameters for axitinib were listed and summarized using descriptive statistics (n, mean, SD,%CV, median, minimum, maximum, and geometric mean, its associated 95% CI andgeometric %CV) by Child-Pugh class. PK parameters with zero values were to be excluded
from the calculation of geometric means, its associated 95% CI and geometric %CV.
Population PK modeling using data from both serial (non-randomized portion) and sparse(randomized portion) sample collections in this study are intended to be reported separately,
and are not included in this document.
Biomarker analyses
Separately for miRNA and soluble proteins, p-values were assessed for significance for bothan unadjusted comparison (α=0.05) and the adjusted comparison where α=0.05/# of analytes
assayed.
RNA Transcript Analysis: Subjects were to be classified as clinical benefit responder/nonresponder based on achieving or failing to achieve clinical benefit. A responder was defined
as a subject with a confirmed CR or confirmed PR or a best response of stable disease≥8 weeks according to RECIST and a non-responder was defined as a subject with a best
response of stable disease <8 weeks, PD, symptomatic deterioration, early death, andinterminate response. Summaries by responder/non-responder were to be used to identify
biomarkers associated with clinical outcome. Probe sets with significant associations with
CBR were to be summarized by p-values, odds ratios, or other appropriate statistics. OS data
were to be summarized stratifying on baseline biomarkers using KM methods. A stratified
log-rank test (1-sided, α=0.025) was to be used to compare OS between the two baseline
biomarker categories within a treatment arm, if appropriate. The median event time and2-sided 95% CI for the median were to be provided, along with the HR and its 95% CI.
P-values from statistical hypothesis tests were to be compared to alpha using unadjusted andadjusted comparisons and the false discovery rate (FDR) were to be provided.
Presentations for all miRNA biomarkers were to include the following as data permitted:• Summary of baseline biomarkers by treatment group and the comparison of axitinib
to placebo using Wilcoxon Rank-Sum test.
• Summary of biomarker values versus CBR category by treatment arm.

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Protocol A4061058 – 27 January 2015 – Final

•
•
•
•
•
•

Analysis of OS using KM method with baseline biomarker by treatment arm.
P-value for comparison of biomarker category within treatment group.
Plots of survival curves were to be provided; the 4 groups were to be on one plot,
with the two p-values, HR, and 95% CI for HR.
For KM analyses significant at the 0.05 level (unadjusted) for axitinib,
sensitivity/specificity or receiver operating characteristic (ROC) curves predicting OS
from the biomarker (actual value) were to be provided.
Summary table of basic demographic and other characteristics for the biomarker
analysis set.
A listing of miRNA data including, at a minimum, center, subject identification,
randomization number, treatment code, accession number, analyte, visit, and result.

Soluble Protein Analysis: Presentations for all serum biomarkers were to include thefollowing as data permitted:
•
•
•
•
•

•
•

P-value comparisons to alpha were to be done using unadjusted and adjusted
comparisons.
Summary of baseline biomarkers by treatment group comparison of axitinib andplacebo for baseline using Wilcoxon Rank-Sum Test.
Summary of biomarker values versus CBR category by treatment arm.
Analysis of OS using KM method with baseline biomarker categorized.
A stratified log-rank test (1-sided, α=0.025) was to be used to compare OS between
the 2 baseline biomarker categories within treatment arms, if appropriate. The
median event time and 2-sided 95% CI for the median were to be provided. The HR
and its 95% CI were also to be estimated.
Plots of survival curves. For KM analyses significant at the 0.05 level (unadjusted)
for axitinib, ROC curves prediction OS from the biomarker (actual value) were to beprovided.
A listing of biomarker soluble protein data including, at a minimum, center, subject
identification, randomization number, treatment code, accession number, analyte,
visit, and result.

Patient Reported Outcomes
The EQ-5D questionnaires were to be scored according to the EQ-5D User’s Guide. At each
assessment time point and for each treatment arm, the proportion of individuals scoring at
each of the 3 levels (no, some, extreme problems) on each of the 5 health dimensions and thescore on the EQ-VAS were calculated.
The FACT-Hep questionnaire was scored in accordance with the FACIT Measurement
System Manual (Version 4). Overall between treatment comparisons of functional
assessment of cancer therapy – hepatobiliary questionnaire (FACT-Hep), EQ-5D, euroQoL
visual analogue scale (EQ-VAS), fact hepatobiliary symptom index (FHSI-8), functional
assessment of cancer therapy – general (FACT-G), FACT-G subscales, FACT Hep- cancer
subscale (CS) 18, and Hep- (trial outcome index) TOI based on the Repeated Measures

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Protocol A4061058 – 27 January 2015 – Final

Mixed Effects Model is presented in this report. Additionally, time to deterioration analysis
has also been presented for FHSI-8.
For the FACT-Hep and EQ-5D, an ambiguous answer to a question was assigned the worst
score of the answers circled. For the individual domains of FACT-Hep and FACT-G, aprorated subscale score was calculated as long as more than 50% of the items were answered.
The overall FACT-G and FACT-Hep were scored if the overall item response rate was >80%(eg, for FACT-G, at least 22 of the 27 items). Prorated subscale score=[Sum of item scores] x[N of items in subscale] / [N of items answered]. For the EQ-5D, questions not answered
were considered to be missing items, and were neither imputed nor utilized. For the EQ-5D,
since each dimension had a single item, responses to all 5 items were needed to calculate anindex-based summary score.
Safety analyses
Safety data was summarized for the Safety Analysis Set overall. All AEs reported during thestudy (including 28 days after the final dose of treatment) were considered as treatmentemergent adverse events (TEAEs). All AEs were coded by system organ class (SOC) andpreferred term using Medical Dictionary for Regulatory Activities (MedDRA) Version 17.0.
The number and percentage of subjects who experienced any adverse event (AE), who
experienced any serious adverse event (SAE), who experienced non-serious all causality andtreatment related TEAEs, who experienced any treatment-related SAE, and who discontinued
because of an AE were presented. Safety data were summarized using descriptive statistics.

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Protocol A4061058 – 27 January 2015 – Final

RESULTS
Subject Disposition and Demography
Subject disposition data in non-randomized and randomized subjects are presented in Table 3
and Table 4 respectively.
Non-randomized:
A total of 13 centers from 4 countries screened and assigned 22 subjects (15 in theChild-Pugh A cohort and 7 in the Child-Pugh B cohort) to study treatment between
06 Dec 2010 and 23 Aug 2013. None of them completed the non-randomized phase;
however, one subject was ongoing at date of cut-off. The primary reasons for discontinuationfrom study in the Child-Pugh A and B cohorts were: subject died (14 [93.3%] and6 [85.7%] subjects, respectively) and subject refused further follow-up (1 [6.7%] and 0
subjects, respectively).
Randomized:
A total of 70 centers from 13 countries screened and assigned 202 subjects (134 in theaxitinib arm and 68 in the placebo arm) to study treatment between 06 Dec 2010 and
12 Jul 2012. None of them completed the randomized phase. A total of 14 subjects in theaxitinib arm and 13 subjects in the placebo arm were ongoing at data cut-off. The primaryreasons for discontinuation from study in the axitinib and placebo arms were: subject died(101 [75.4%] and 52 [76.5%] subjects), subject refused further follow-up (11 [8.2%] and2 [2.9%] subjects) and lost to follow-up (1 [0.7%] and 0 subjects, respectively).

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Table 3: Subject Disposition: Non-randomized Subjectsn (%)
Child-Pugh A(N=15)

Child-Pugh B
(N=7)

Total
(N=22)

Screened

22

22

Assigned to study treatment

15

7

22

Treated15

7

22

Completed

000

Ongoing at date of cut-off

0

1 (14.3)

1 (4.5)

Ongoing in Follow-up

0

1 (14.3)

1 (4.5)

Subject died14 (93.3)

6 (85.7)

20 (90.9)

Subject refused further follow-up

1 (6.7)0

1 (4.5)

Objective progression or relapse

11 (73.3)

5 (71.4)

16 (72.7)

Global deterioration of health status

1 (6.7)0

1 (4.5)Adverse event

1 (6.7)

1 (14.3)

2 (9.1)

Subject died2 (13.3)

02 (9.1)0

1 (14.3)

1 (4.5)Adverse events

15 (100.0)

7 (100.0)22 (100.0)

Laboratory data

15 (100.0)

7 (100.0)22 (100.0)

Full Analysis Set[1]15 (100.0)

7 (100.0)22 (100.0)

15 (100.0)

7 (100.0)22 (100.0)

Primary reason for discontinuation from study

Primary reason for discontinuation from study
treatment

No longer willing to participate in study
Analyzed for Safety

Safety Analysis Set[2]

Number of Subjects Evaluable for adverse events is total number of subjects who received at least one dose of study
treatment. Number of Subjects Evaluable for lab is the total number of subjects with at least one post-baseline non missing
lab result collected who also received at least one dose of study treatment.
Subjects were treated with axitinib 5 mg BID for Child-Pugh A and 2 mg BID for Child-Pugh B.
[1]: Full Analysis Set includes all subjects who are enrolled with study drug assignment designated, regardless of whether
subjects receive study drug or receive different drug from that to which they are randomized.
[2]: Safety Analysis set consists of all subjects who received at least 1 dose of study medication.

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Table 4: Subject Disposition: Randomized Subjectsn (%)
Axitinib(N=134)

Placebo(N=68)

Screened

Total(N=202)202

Assigned to study treatment

134

68

202

Treated

133

68

201

Completed000Discontinued from Study

113 (84.3)

54 (79.4)

167 (82.7)

Ongoing at date of cut-off

21 (15.7)

14 (20.6)

35 (17.3)

Ongoing on Treatment

7 (5.2)

1 (1.5)8 (4.0)Ongoing in Follow-up

14 (10.4)

13 (19.1)

27 (13.4)

Subject died

101 (75.4)

52 (76.5)

153 (75.7)

Subject refused further follow-up

11 (8.2)2 (2.9)13 (6.4)

Lost to follow-up

1 (0.7)0

1 (0.5)

Objective progression or relapse

70 (52.2)

50 (73.5)

120 (59.4)

Global deterioration of health status

6 (4.5)2 (2.9)8 (4.0)Adverse event

31 (23.1)

8 (11.8)

39 (19.3)

Subject died

5 (3.7)3 (4.4)8 (4.0)No longer willing to participate in study

11 (8.2)2 (2.9)13 (6.4)Other

4 (3.0)2 (2.9)6 (3.0)Adverse events

133 (99.3)

68 (100.0)

201 (99.5)

Laboratory data

133 (99.3)

67 (98.5)200 (99.0)

134 (100.0)

68 (100.0)

202 (100.0)

133 (99.3)

68 (100.0)

201 (99.5)

Primary reason for discontinuation from study

Primary reason for discontinuation from study
treatment

Analyzed for safety

Full Analysis Set[1]

Safety Analysis Set

[2]

[1]

:Full Analysis Set includes all subjects who are randomized with study drug assignment designated, regardless of whether
subjects receive study drug or receive different drug from that to which they are randomized.
[2]: Safety Analysis set consists of all subjects who received at least 1 dose of study medication at that cycle with treatment
assignment designated according to actual study treatment received.

Demographic and baseline characteristics are presented in Table 5 and Table 6 for the nonrandomized and randomized subjects respectively. Mean age of the subjects were balanced
between the treatment groups in both the phases. Most of the subjects were male in both the
non-randomized and randomized phases (77.3% in the non-randomized portion and 82.2% in
randomized portion).

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Table 5: Demographic and Baseline Characteristics Based on CRF Data:
Non-randomized Subjects
Child-Pugh A Child-Pugh B(N=15)(N=7)

Total(N=22)

Age (years)
Mean (SD)57.8 (13.09)

59.9 (7.06)

58.5 (11.38)

Median

59.00

62.00

59.00

Min, Max38, 8051, 7038, 80<65

9 (60.0)

5 (71.4)

14 (63.6)>=65

6 (40.0)

2 (28.6)

8 (36.4)Male

12 (80.0)

5 (71.4)

17 (77.3)

Female3 (20.0)

2 (28.6)

5 (22.7)

Present

12 (80.0)

4 (57.1)

16 (72.7)

Absent3 (20.0)

3 (42.9)

6 (27.3)

Asian Sites

11 (73.3)

5 (71.4)

16 (72.7)

Hong Kong

1 (6.7)0

1 (4.5)Japan

4 (26.7)

3 (42.9)

7 (31.8)Korea

6 (40.0)

2 (28.6)

8 (36.4)

Non-Asian Sites

4 (26.7)

2 (28.6)

6 (27.3)USA

4 (26.7)

2 (28.6)

6 (27.3)

Age (years) [n (%)]

Sex [n (%)]

Vascular Invasion and/or Extrahepatic Spread

Geographic Region[1]Abbreviations: CRF = case report form; SD = standard deviation; USA = United States of America.
1
Country information is derived from IMPALA data.

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Table 6: Demographic and Baseline Characteristics (Full Analysis Set): Randomized
Subjects
Axitinib (N=134)

Placebo (N=68)

Total (N=202)

61.2 (11.30)

62.2 (11.81)

61.5 (11.45)

Median

61.00

63.00

61.00

Min, Max25, 8426, 8325, 84<65

81 (60.4)

36 (52.9)

117 (57.9)>=65

53 (39.6)

32 (47.1)

85 (42.1)

Male

110 (82.1)

56 (82.4)

166 (82.2)

Female24 (17.9)

12 (17.6)

36 (17.8)

102 (76.1)

52 (76.5)

154 (76.2)

32 (23.9)

16 (23.5)

48 (23.8)

97 (72.4)

50 (73.5)

147 (72.8)

37 (27.6)

18 (26.5)

55 (27.2)

Asian Sites

83 (61.9)

41 (60.3)

124 (61.4)

China

13 (9.7)

7 (10.3)

20 (9.9)

Hong Kong

6 (4.5)6 (8.8)12 (5.9)Japan

26 (19.4)

11 (16.2)

37 (18.3)

Korea

25 (18.7)

11 (16.2)

36 (17.8)

Taiwan13 (9.7)

6 (8.8)19 (9.4)

Non-Asian Sites

51 (38.1)

27 (39.7)

78 (38.6)

Belgium

1 (0.7)0

1 (0.5)

France19 (14.2)

14 (20.6)

33 (16.3)

Germany

5 (3.7)3 (4.4)8 (4.0)Hungary

3 (2.2)0

3 (1.5)Italy

7 (5.2)

1 (1.5)8 (4.0)Slovakia

2 (1.5)2 (2.9)4 (2.0)USA

10 (7.5)

3 (4.4)13 (6.4)

United Kingdom

4 (3.0)4 (5.9)8 (4.0)Age (years)
Mean (SD)Age (years) [n (%)]

Sex [n (%)]

Vascular Invasion and/or Extrahepatic Spread
Present
AbsentVascular Invasion and/or Extrahepatic Spread[1]

Present
Absent[1]

Geographic Region

Abbreviation: IVRS=Interactive Voice Response System; SD = standard deviation; USA = United States of America.1 FromIVRS data; Country information is derived from IMPALA data.

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Protocol A4061058 – 27 January 2015 – Final

Efficacy, Pharmacokinetic, Pharmacodynamic, or Outcomes Research Results
Efficacy endpoints were not evaluated in the non-randomized subjects. Tabular summaries ofthe secondary endpoints in randomized subjects are presented in below sections.
Efficacy results
Primary endpoint
Overall survival:
The OS in HCC subjects receiving axitinib+BSC or placebo+BSC are presented in Table 7.
Controlling for baseline stratification factors, tumor invasion (presence versus absence of
extrahepatic spread and/or vascular invasion) and geographic region (Asian versus non-Asiansites), the estimated stratified HR (axitinib versus placebo) was 0.907 (95% CI: 0.646, 1.274;
one-sided p=0.2872). The median OS was 12.7 months (95% CI: 10.2, 14.9) in the axitinibarm and 9.7 months (95% CI: 5.9, 11.8) in the placebo arm. The Axitinib didn’t show OS
benefit.

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Table 7: Overall Survival (Overall Stratified Analysis; Full Analysis Set): Randomized
Subjects
Axitinib (N=134)

Placebo (N=68)

101 (75.4)

52 (76.5)

Disease Under Study91 (90.1)

47 (90.4)

Unknown

4 (4.0)2 (3.8)6 (5.9)4 (7.7) [6]

33 (24.6)

16 (23.5)

Alive

21 (63.6)

14 (87.5)

Subject No Longer Willing To Participate

11 (33.3)

2 (12.5)

Lost To Follow-Up

1 (3.0)054.8 [45.7, 62.9]

37.9 [26.4, 49.4]

25%

5.5 [4.3, 6.9]

3.5 [2.7, 5.2]

50%

12.7 [10.2, 14.9]

9.7 [5.9, 11.8]

22.8 [19.0, 26.2]

19.1 [13.3, -]Number of deaths [n (%)]
Cause of death [n (%)]

Other
Number censored [n (%)]

[1]

Reason for censorship [n (%)]

1-year Survival Probability (95% Confidence Interval) [2]Kaplan-Meier estimates of Time to Event (Months)
Quartiles (95% Confidence Interval) [3]75%
Hazard Ratio(Axitinib Versus Placebo)

[4]

0.907

95% Confidence Interval for Hazard Ratio
P-value[0.646, 1.274][5]0.2872Abbreviation: IVRS= Interactive Voice Response System.
Subjects with multiple reasons for death are counted separately for each individual reason in the sub-category counts.
[1]
Subjects still alive on the PCD (primary outcome completion) date are censored on PCD date. Subjects with unknown
survival status at the PCD date are censored on the date they were last known to be alive prior to PCD date.
[2]
Calculated from the log[-log(12-month survival probability)] using a normal approximation and back transformation.
[3]
Based on the Brookmeyer and Crowley Method.
[4]
Assuming proportional hazards, a hazard ratio <1 indicates reduction in hazard rate to favor Axitinib; hazard ratio >1
indicates reduction to favor Placebo.
[5]
For the Overall Stratified Analysis the p-value is from a 1-sided log-rank test of treatment stratified by Tumor Invasion
and Geographic Region.
Tumor Invasion is from IVRS data; Geographic region includes Asian Sites/Non-Asian Sites.
[6]
Details about death ‘other’ are reported in Table 29.

Secondary endpoints
Progression-free Survival:
Summary of PFS by treatment (stratified analysis) is presented in Table 8. The estimated HR(axitinib versus placebo) was 0.618 (95% CI: 0.438, 0.871; one-sided p=0.0039) stratified bytumor invasion (present, absent) and geographic region (Asian, non-Asian sites), representing
a decrease of 38.2% in risk of progression or death before progression for axitinib overplacebo. PFS was statistically significant between the groups (p=0.0039).
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Protocol A4061058 – 27 January 2015 – FinalTime to Progression:
A summary of time to tumor progression by treatment (stratified analysis; derived
investigator’s assessment) for the FAS is presented in Table 9. The HR (axitinib versus
placebo) was 0.621 (95% CI: 0.434, 0.889) indicating TTP was statistically significant
between the groups (p=0.006).
Overall Response Rate:
A summary of ORR by treatment (stratified analysis) for the FAS is presented in Table 10.
The risk ratio (axitinib versus placebo) was 3.172 (95% CI: 0.759, 13.265). ORR between the
two treatment arms were not statistically significant (p=0.0914).
Duration of Response:
A summary of DR among responders by treatment (unstratified analysis; derived
investigator's assessment) for the FAS is presented in Table 11. The median DR was
6.4 months (95% CI: 3.7, 9.3) in the axitinib arm and not evaluable in the placebo arm.
Clinical Benefit Rate:
A summary of CBR by treatment (stratified analysis) for the FAS is presented in Table 12. A
total of 42 (31.3%) subjects in the axitinib arm and 8 (11.8%) subjects in the placebo arm had
an overall clinical benefit response rate (CR+PR+stable disease with ≥8 weeks to treatment
failure). The risk ratio (axitinib versus placebo) was 2.650 (95% CI: 1.319, 5.326) and
p=0.0025. The difference between the axitinib and placebo arms was statistically significant(p = 0.0025).

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Table 8: Progression-Free Survival (Overall Stratified Analysis; Derived Investigator’s
Assessment; Full Analysis Set): Randomized Subjects
Axitinib (N=134)

Placebo (N=68)

105 (78.4)

54 (79.4)

Objective progression

99 (94.3)

49 (90.7)

Increase in Existing Lesion (Target or Non-Target)

54 (54.5)

22 (44.9)

New Lesion

24 (24.2)

7 (14.3)

Increase and a New Lesion

21 (21.2)

20 (40.8)

Death without objective Progression

6 (5.7)5 (9.3)

Subject did not progress or die due to any cause while on study [n(%)] [1]29 (21.6)

14 (20.6)

No adequate baseline assessments

1 (3.4)1 (7.1)

No on-study disease assessments

6 (20.7)

3 (21.4)

Given new anti-cancer treatment prior to tumor progression

1 (3.4)1 (7.1)

Off treatment prior to progression

14 (48.3)

6 (42.9)

Withdrew consent for follow-up

0

1 (7.1)

Progressive disease or death occurs after >=2 consecutive, missed
assessments

3 (10.3)

1 (7.1)

In follow-up for progression

4 (13.8)

1 (7.1)25%

1.9 [1.8, 1.9]

1.8 [1.7, 1.8]50%

3.6 [2.3, 4.6]

1.9 [1.9, 3.5]

7.4 [7.3, 9.1]

3.7 [3.5, 6.8]

Subject observed to have progressed or died due to any cause whileon study [n (%)] [1]Type of event [n (%)]

Reason for censorship [n (%)]

Kaplan-Meier estimates of Time to Event (Months)
Quartiles (95% Confidence Interval) [2]75%
Hazard Ratio(Axitinib Versus Placebo)

[3]

0.618

95% Confidence Interval for Hazard Ratio
P-value[0.438, 0.871][4]0.0039Abbreviation: IVRS= Interactive Voice Response System.
Subjects are considered to have adequate baseline assessments if all target and non-target lesions with non-missing lesion
site are collected within 28 days prior to first treatment date and if all target lesions are measurable.
[1]
On study includes treatment plus 28-day follow-up period.
[2]
Based on the Brookmeyer and Crowley Method.
[3]
Assuming proportional hazards, a hazard ratio <1 indicates a reduction in hazard rate in favor of Axitinib; a hazard ratio>1 indicates a reduction in favor of Placebo.
[4]
For the Overall Stratified Analysis the p-value is from a 1-sided log-rank test of treatment stratified by Tumor invasion
and Geographic Region.
Tumor invasion is from IVRS data; Geographic region includes Asian Sites/Non-Asian Sites.

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Table 9: Time to Tumor Progression (Overall Stratified Analysis; Derived
Investigator’s Assessment; Full Analysis Set): Randomized Subjects
Axitinib (N=134)

Placebo (N=68)

134

68

99 (73.9)

49 (72.1)

35 (26.1)

19 (27.9)

No adequate baseline assessments

1 (2.9)1 (5.3)

No on-study disease assessments

11 (31.4)

6 (31.6)

Given new anti-cancer treatment prior to tumor progression

1 (2.9)1 (5.3)

Death on treatment without progression

2 (5.7)

2 (10.5)

Off treatment prior to progression

12 (34.3)

5 (26.3)

Withdrew consent for follow-up

2 (5.7)

2 (10.5)

PD or death occurs after >=2 consecutive, missed assessments

2 (5.7)1 (5.3)

In follow-up for progression

4 (11.4)

1 (5.3)25%

1.9 [1.8, 1.9]

1.8 [1.7, 1.9]50%

3.7 [2.8, 5.6]

1.9 [1.9, 3.6]

7.4 [7.3, 9.2]

3.9 [3.6, 7.4]

Overall stratified analysis
Number with event [n (%)]
Number censored [n (%)]

[1]

[1]

Reason for censorship [n (%)]

Kaplan-Meier estimates of Time to Event (Months)
Quartiles (95% Confidence Interval) [2]75%
Hazard Ratio(Axitinib Versus Placebo)

[3]

0.621

95% Confidence Interval for Hazard Ratio
P-value[0.434, 0.889]

[4]

0.006

Abbreviation: IVRS = Interactive Voice Response System; PD = Progressive disease.
[1]
On study includes treatment plus 28-day follow-up period.
[2]
Based on the Brookmeyer and Crowley Method.
[3]
Assuming proportional hazards, a hazard ratio <1 indicates a reduction in hazard rate in favor of Axitinib; a hazard ratio>1 indicates a reduction in favor of Placebo.
[4]
For the Overall Stratified Analysis the p-value is from a 1-sided log-rank test of treatment stratified by Tumor invasion
and Geographic Region.
Tumor invasion is from IVRS data; Geographic region includes Asian Sites/Non-Asian Sites.

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Table 10: Objective Response Rate (Overall Stratified Analysis, Derived Investigator'sAssessment; Full Analysis Set): Randomized Subjects
Axitinib (N=134)

Placebo (N=68)

Subjects with Baseline Assessment [n (%)]

133 (99.3)

67 (98.5)

Subjects with Measurable Disease at Baseline [n (%)]

131 (97.8)

66 (97.1)

Complete Response

1 (0.7)0Partial Response

12 (9.0)

2 (2.9)Stable Disease49 (36.6)

20 (29.4)

Progressive Disease55 (41.0)

38 (55.9)

Symptomatic deterioration

1 (0.7)0[1]

5 (3.7)3 (4.4)

Indeterminate

11 (8.2)

5 (7.4)Overall Confirmed Objective Response Rate (Complete
Response + Partial Response)

13 (9.7%)

2 (2.9%)[5.3%, 16.0%][0.4%, 10.2%]

Best Overall Response [n (%)]

Early Death

95% Exact Confidence Interval [2]Treatment Comparison (Axitinib vs Placebo)[3]

95% Confidence Interval [3]p-value

3.172[0.759, 13.265][4]

0.0914[1]

Early death is defined as death occurring within 8 weeks from start date and prior to new anti-cancer treatment.
Using exact method based on F-distribution.
[3]
Risk Ratio and CI based on the Mantel-Haenszel estimator; risk ratio is adjusted for Geographical Region and Vascular
Invasion and Extra Hepatic Spread.
[4]
P-value is from Cochran-Mantel-Haenszel test of treatment stratified by Geographical Region and Vascular Invasion and
Extra Hepatic Spread.
[2]

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Table 11: Duration of Response (Overall Unstratified Analysis, Derived Investigator'sAssessment (Full Analysis Set): Randomized Subjects
Axitinib (N=13)

Placebo (N=2)

10 (76.9)

0

10 (100.0)

0

0

0

3 (23.1)

2 (100.0)25%

5.6 [ 1.9, 6.4]50%

6.4 [ 3.7, 9.3]

NR
NR

75%

9.3 [ 5.7, NR ]NR

Subject observed to have progressed or died due to any
cause while on study [n (%)] [1]Type of event [n (%)]
Objective progression
Death without objective Progression
Subject did not progress or die due to any cause while on
study [n (%)] [1]Kaplan-Meier estimates of Time to Event (Months)
Quartiles (95% Confidence Interval) [2]Abbreviation: NR= not reached[1] On study includes treatment plus 28-day follow-up period.
[2] Based on the Brookmeyer and Crowley Method.

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Table 12: Clinical Benefit Response (Overall Stratified Analysis, Derived Investigator'sAssessment; Full Analysis Set): Randomized Subjects
Axitinib (N=134)

Placebo (N=68)

Subjects with Baseline Assessment [n (%)]

133 (99.3)

67 (98.5)

Subjects with Measurable Disease at Baseline [n (%)]

131 (97.8)

66 (97.1)

Complete Response

1 (0.7)0Partial Response

12 (9.0)

2 (2.9)Stable Disease49 (36.6)

20 (29.4)

Progressive Disease55 (41.0)

38 (55.9)

Symptomatic deterioration

1 (0.7)0[1]

5 (3.7)3 (4.4)

Indeterminate

11 (8.2)

5 (7.4)Overall Clinical Benefit Response Rate (Complete Response +Partial Response + Stable Disease with >= 8 weeks to treatment
failure)42 (31.3%)

8 (11.8%)[23.6% - 39.9%][5.2% - 21.9%]

Best Overall Response [n (%)]

Early Death

95% Exact Confidence Interval [2]Treatment Comparison (Axitinib vs Placebo)
95% Confidence Interval
p-value

[3]

[4]

2.650
[1.319, 5.326][5]0.0025[1]

Early death is defined as death occurring within 8 weeks from start date and prior to new anti-cancer treatment.
Using exact method based on F-distribution.
[3]
Risk Ratio and CI based on the Mantel-Haenszel estimator; risk ratio is adjusted for Geographical Region and Vascular
Invasion and Extra Hepatic Spread.
[4]
For the Overall Stratified Analysis the p-value is from Cochran-Mantel-Haenszel test of treatment stratified byGeographical Region and Vascular Invasion and Extra Hepatic Spread.
[2]

Pharmacokinetic results
Axitinib pharmacokinetics on cycle 1 day 15 from non-randomized portion:
PK parameter data from n=12 Child-Pugh A (5 mg BID axitinib dose) and from n=7Child-Pugh B (2 mg BID axitinib dose) HCC subjects are summarized in Table 13.

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Protocol A4061058 – 27 January 2015 – Final

Table 13: Summary of Axitinib Steady-State Pharmacokinetic Parameters Following
Administration of Multiple Doses of Axitinib in Subjects with Advanced
Hepatocellular Carcinoma
Hepatic Impairment
statusAxitinib
Dose

Cmax(ng/mL)

AUC0-24(ng.hr/mL)

Tmax
(hr)

CL/F
(L/hr)

Vz/F
(L)

t1/2
(hr)

Child-Pugh A; mild
hepatic impairment(n=12)a

5 mg
BID

35.7
(59)

311
(63)

2.50
(0.00-7.98)

32.2
(63)

150
(46)

4.12
(±3.55)

Child-Pugh B; moderate
hepatic impairment(n=7)b

2 mg
BID

21.2
(164)

316
(118)

1.05
(0.00-4.00)

12.7
(118)

81.2
(89)

4.79
(±2.42)Abbreviations: AUC0-24=area under the plasma concentration versus time curve from 0 to 24 hr; Cmax=maximum observed
plasma concentration; CL/F=apparent oral clearance; %CV=percent coefficient of variation; SD=standard deviation;
t1/2=terminal plasma elimination half-life; Tmax=time to first occurrence of Cmax; Vz/F=apparent oral volume of distribution of
the drug during the elimination phase.
Geometric mean (geometric %CV) for Cmax, AUC0-24, CL/F and Vz/F; arithmetic mean (±SD) for t1/2; median with range forTmax
a AUC0-24, CL/F, Vz/F and t1/2 were not reported for 4 subjects due to nonestimable half-life.
b AUC0-24, CL/F, Vz/F and t1/2 was not reported for 1 subject due to nonestimable half-life.

Randomized portion:
Results from population PK modeling using data from both serial and sparse sample
collections in this study are intended to be reported separately, and are not included in thisdocument.
Pharmacodynamic Results:
Pharmacodynamic results were evaluated in the randomized portion of this study.
Micro-RNA Results:
Baseline samples were analyzed for miRNA transcript analysis. From 181 samples collected,
RNA of sufficient quality for Agilent micro-array analysis was generated from 170 subjects.
The false discovery rate (a statistical method for adjusting for level of significance with 100sor 1000s of analytes) for potential differences in presence/absence of baseline miRNAs
between treatment groups was >0.8 for all 174 miRNAs, indicating high confidence of nodifferences.
Soluble Proteins:
Baseline levels of the soluble proteins analyzed were similar between treatment arms
(Table 14).

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Table 14: Concentration of Soluble Proteins at Baseline: Soluble Proteins Analysis Set
Axitinib(N=120)

Placebo(N=61)

P-valueunadjusted[1]P-value
Bonferroniadjusted[2]50.67 (102.86)

50.72 (106.74)

0.46991.000052313.94 (32603.18)

55430.76 (26723.43)

0.20601.0000IL-833.35 (47.72)

27.23 (44.46)

0.37191.0000

HGF

478.84 (712.43)

406.06 (376.04)

0.84561.0000MMP-2355715.66 (137663.04)

350979.72 (146323.29)

0.70541.0000SCF

1352.75 (1534.41)

1439.71 (2260.89)

0.78481.0000Ang-2

662.40 (623.87)

577.82 (354.42)

0.82101.0000

VEGF-A

102.56 (128.09)

173.59 (472.19)

0.23301.0000

VEGF-C----sVEGFR2

17675.76 (7218.95)

18273.65 (6836.16)

0.61351.0000sVEGFR3

287429.28 (117583.24)

290338.69 (97830.36)

0.47041.0000SDF11190.08 (823.03)

1150.10 (681.04)

0.94191.0000NGAL

134861.80 (152492.96)

141383.00 (121747.35)

0.44011.0000MIF

33057.15 (28256.00)

32302.99 (21485.01)

0.47331.00001664.96 (834.36)

1641.08 (704.38)

0.97421.0000RANTES

26412.12 (38682.81)

26917.76 (27094.12)

0.26841.0000

MCP-3

-

-

Mean (SD)IL-6
E-Selectinc-MET ELISA‘-‘% < LLQ was greater than 75% and no summary statistics was provided and those analytes were not included in the countof statistical comparisons for the Bonferroni correction.
[1]
P-values from comparison of treatment groups based on the exact two-sided Wilcoxon test, estimated using 1,000,000
Monte Carlo realizations.
[2]
Bonferroni-adjusted p-values < 0.05 (or unadjusted p-values < 0.05/15=0.0033) are considered significant.

Other Results – Patient Reported Outcomes
Patient-Reported Outcomes were evaluated in the randomized portion of this study and arepresented in Table 15 and Table 16.
The overall between-treatment comparison for axitinib versus placebo based on the repeatedmeasures mixed effects model was statistically significant favoring placebo for all the PROvariables presented in Table 15 except for FACT-G Subscales SWB and EWB. However, theresults were similar between the treatment groups for SWB and EWB.
The time to deterioration based on the composite outcome (death or tumor progression or
FHSI-8 mean score decrease ≥3 points, whichever occurred first ) or FHSI-8 mean score
decrease alone showed no significant difference between treatment arms (Table 16).

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Table 15: Patient-Reported Outcomes - Overall between Treatment Comparison of
FACT-Hep, EQ-5D, EQ-VAS, FHSI-8, FACT-G, FACT-G subscales, FACT Hep-CS18,
and Hep-TOI Based on the Repeated Measures Mixed Effects Model - Full Analysis Set

FACT-Hep; Estimated Mean (95% CI)

Axitinib (N=134)

Placebo (N=68)

123.33 (120.17, 126.50)

135.22 ( 129.17, 141.27)

Overall Comparisons
Estimated Mean (95% CI)-11.89 (-18.70, -5.08)

P-Value
EQ-5D; Estimated Mean (95% CI)

0.00060.67 ( 0.63, 0.70)

0.79 ( 0.72, 0.86)

Overall Comparisons
Estimated Mean (95% CI)-0.12 (-0.20, -0.04)

P-Value
EQ-VAS; Estimated Mean (95% CI)

0.002468.67 (66.11, 71.23)

75.70 (70.40, 81.00)

Overall Comparisons
Estimated Mean (95% CI)-7.03 (-12.91, -1.15)

P-Value
FHSI-8; Estimated Mean (95% CI)

0.019323.42 (22.77, 24.07)

26.69 (25.35, 28.03)

Overall Comparisons
Estimated Mean (95% CI)-3.27 (-4.76, -1.78)

P-Value
FACT-G; Estimated Mean (95% CI)<.000171.20 (69.00, 73.41)

78.81 (74.68, 82.93)

Overall Comparisons
Estimated Mean (95% CI)-7.60 (-12.27, -2.94)

P-Value
FACT-G Subscale PWB; Estimated Mean
(95% CI)

0.001419.39 (18.72, 20.07)

23.13 (21.76, 24.50)

Overall Comparisons
Estimated Mean (95% CI)-3.74 (-5.26, -2.21)

P-Value
FACT-G Subscale SWB; Estimated Mean
(95% CI)<.000118.94 (18.05, 19.83)

20.21 (18.66, 21.77)

Overall Comparisons
Estimated Mean (95% CI)-1.27 (-3.07, 0.52)

P-Value
FACT-G Subscale EWB; Estimated Mean
(95% CI)

0.1642
17.23 (16.63, 17.84)

Overall Comparisons
Estimated Mean (95% CI)-0.48 (-1.80, 0.84)

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
P-Value
FACT-G Subscale FWB; Estimated Mean
(95% CI)

0.475915.76 (14.88, 16.65)

17.83 (16.19, 19.47)

Overall Comparisons
Estimated Mean (95% CI)-2.07 (-3.92, -0.21)

P-Value
FACT Hep-CS18; Estimated Mean (95% CI)

0.028851.78 (50.46, 53.10)

56.74 (54.08, 59.39)

Overall Comparisons
Estimated Mean (95% CI)-4.96 (-7.93, -1.99)

P-Value
FACT Hep-TOI; Estimated Mean (95% CI)

0.001187.28 (84.98, 89.58)

97.73 (93.24, 102.23)

Overall Comparisons
Estimated Mean (95% CI)-10.45 (-15.49, -5.42)

P-Value<.0001

Larger values are associated with better health status. Analysis based on repeated measures mixed-effects model with anintercept term, treatment, time, treatment-by-time, and baseline as covariate.
Abbreviations: EQ-5D = EuroQoL 5 Dimensions; EQ-VAS = EuroQoL visual analogue scale; EWB: Emotional well-being;
FACT-Hep = Functional assessment of cancer therapy – hepatobiliary questionnaire; FACT Hep-CS18: Functional
assessment of cancer therapy - hepatobiliary cancer subscale; FACT-G : Functional assessment of cancer therapy – general;
FHSI-8= Fact hepatobiliary symptom index; FWB: Functional well-being; PWB= Physical well-being; SWB= Social/family
well-being; TOI = Trial outcome index.

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Table 16: Time to Deterioration (TTD) Based on Composite Endpoint (Death or Tumor
Progression or FHSI-8 Mean Score Decrease ≥3 Points, Whichever ComesFirst) in Randomized Portion: Overall Between-Treatment Comparison
Based on Repeated Measures Mixed Effects Model - Full Analysis Set
Axitinib (N=134)

Placebo (N=68)

Subject had composite endpoint (death or tumor progression or
FHSI-8 decrease >=3 points) while on study [n (%)]

131 (97.8)

63 (92.6)

Subject did not have composite endpoint while on study [n (%)]

3 (2.2)5 (7.4)0

0

Off treatment prior to composite endpoint

1 (33.3)

1 (20.0)

Subject alive and on study without composite event

2 (66.7)

4 (80.0)25%

1.0 [ 1.0, 1.0 ]1.7 [ 1.0, 1.8 ]50%

1.9 [ 1.8, 1.9 ]1.9 [ 1.8, 2.7 ]75%

3.7 [ 2.8, 4.4 ]3.7 [ 3.3, 6.8 ]Reason for censorship [n (%)]
No adequate assessment of composite endpoint

Kaplan-Meier estimates of Time to Event (Months)
Quartiles (95% Confidence Interval) [1]Axitinib Versus Placebo
Hazard Ratio [2]95% CI for Hazard Ratio
P-value

1.252[2]0.923 - 1.698[3]

0.9182[1]

Based on the Brookmeyer and Crowley Method.
Assuming proportional hazards, a hazard ratio <1 indicates reduction in hazard rate to favor Axitinib, hazard ratio >1
indicates reduction to favor Placebo.
[3]p-value is from a 1-sided, unstratified log-rank test.
[2]

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Protocol A4061058 – 27 January 2015 – Final

Safety Results:
Safety overview
Overall summary of all-causality TEAEs in non-randomized and randomized portions arepresented in Table 17 and Table 18 respectively. Overview of treatment-related AEs issummarized in Table 19 for the non-randomized subjects and in Table 20 for the randomized
subjects.
Non-randomized: All subjects in the non-randomized portion experienced TEAEs out of
which 14 subjects in the Child-Pugh A cohort and 6 subjects in the Child-Pugh B cohort
experienced treatment-related TEAEs.
Randomized: TEAEs, SAEs, Grade ≥3 AEs were more frequent in the axitinib arm than in
the placebo arm, while the Grade 5 AEs were similar in the two arms. One hundred
twenty-eight (128) (96.2%) subjects in the axitinib arm and 40 (58.8%) subjects in theplacebo arm experienced treatment-related TEAEs.
Table 17: Overall Summary of Treatment-Emergent Adverse Events (All Causalities):
Non-randomized Subjects
Child-Pugh A(N=15)n (%)

Child-Pugh B
(N=7)
n (%)

Subjects evaluable for adverse events

15

7

Subjects with adverse events

15 (100.0)

7 (100.0)

Subjects with serious adverse events

10 (66.7)

3 (42.9)

Subjects with ≥Grade 3 adverse events

13 (86.7)

5 (71.4)

Subjects with Grade 5 adverse events

4 (26.7)

1 (14.3)

Subjects who discontinued treatment due to adverse events

4 (26.7)

1 (14.3)

Subjects with dose reduced due to adverse events

5 (33.3)

0 (0.0)Subjects with temporary discontinuation due to adverse
events13 (86.7)

5 (71.4)

Subjects were treated with axitinib 5 mg BID for Child-Pugh A and 2 mg BID for Child-Pugh B.
Includes data up to 28 days after last dose of study drug.
CTCAE version 3.
MedDRA (version 17.0) coding dictionary applied.
Abbreviations: BID=Twice daily; CTCAE= Common Terminology Criteria for Adverse Events; MedDRA=Medical
Dictionary for Regulatory Activities.

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Table 18: Overall Summary of Treatment-Emergent Adverse Events (All Causalities) in
Randomized Portion: Safety Analysis Set
Axitinib(N=133)n (%)

Placebo(N=68)n (%)

Subjects evaluable for adverse events

133

68

Subjects with adverse events131 (98.5)

63 (92.6)

Subjects with serious adverse events

62 (46.6)

16 (23.5)

Subjects with Grade ≥3 adverse events

109 (82.0)

26 (38.2)

Subjects with Grade 5 adverse events

16 (12.0)

8 (11.8)

Subjects who discontinued treatment due to adverse events

38 (28.6)

9 (13.2)

Subjects with dose reduced due to adverse events46 (34.6)

5 (7.4)

Subjects with temporary discontinuation due to adverse
events87 (65.4)

17 (25.0)

Subjects were treated with axitinib+BSC or placebo+BSC.
Includes data up to 28 days after last dose of study drug.
Subjects were counted only once per treatment in each row.
CTCAE version 3.
MedDRA (version 17.0) coding dictionary applied.
Abbreviations: BSC=Best supportive care; CTCAE= Common Terminology Criteria for Adverse Events;
MedDRA=Medical Dictionary for Regulatory Activities.

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Table 19: Overall Summary of Treatment-Related Treatment-Emergent Adverse
Events: Non-randomized Subjects
Child-Pugh A(N=15)n (%)

Child-Pugh B
(N=7)
n (%)

Subjects evaluable for adverse events

15

7

Subjects with adverse events

14 (93.3)

6 (85.7)

Subjects with serious adverse events

2 (13.3)

2 (28.6)

Subjects with ≥Grade 3 adverse events

9 (60.0)

4 (57.1)

Subjects with Grade 5 adverse events

0 (0.0)0 (0.0)Subjects who discontinued treatment due to adverse events

0 (0.0)1 (14.3)

Subjects with dose reduced due to adverse events

5 (33.3)

0 (0.0)Subjects with temporary discontinuation due to adverse
events9 (60.0)

4 (57.1)

Subjects were treated with axitinib 5 mg BID for Child-Pugh A and 2 mg BID for Child-Pugh B.
Includes data up to 28 days after last dose of study drug.
CTCAE version 3.
MedDRA (version 17.0) coding dictionary applied.
Abbreviations: BID=Twice daily; CTCAE= Common Terminology Criteria for Adverse Events; MedDRA=Medical
Dictionary for Regulatory Activities.

Table 20: Overall Summary of Treatment-Related Treatment-Emergent Adverse
Events in Randomized Subjects: Safety Analysis Set
Axitinib(N=133)n (%)

Placebo(N=68)n (%)

Subjects evaluable for adverse events

133

68

Subjects with adverse events

128 (96.2)

40 (58.8)

Subjects with serious adverse events24 (18.0)

1 (1.5)

Subjects with ≥Grade 3 adverse events90 (67.7)

12 (17.6)

Subjects with Grade 5 adverse events

1 (0.8)0 (0.0)Subjects who discontinued treatment due to adverse events

15 (11.3)

2 (2.9)Subjects with dose reduced due to adverse events46 (34.6)

4 (5.9)Subjects with temporary discontinuation due to adverse
events73 (54.9)

8 (11.8)

Subjects were treated with axitinib+BSC or placebo+BSC.
Includes data up to 28 days after last dose of study drug.
Subjects were counted only once per treatment in each row.
CTCAE version 3.
MedDRA (version 17.0) coding dictionary applied.
Abbreviations: BSC=Best supportive care; CTCAE= Common Terminology Criteria for Adverse Events;
MedDRA=Medical Dictionary.

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Analyses of non-serious TEAEs and SAEs (All causality and treatment related)
The treatment-emergent non-serious AEs reported in >=5% of subjects in any of thetreatment arm by preferred term and by SOC (all causality and treatment-related) aresummarized in Table 21 for the non-randomized subjects and in Table 22 for the randomized
subjects.
SAEs by preferred term and by SOC (all-causality and treatment-related) are summarized inTable 23 for the non-randomized subjects and in Table 24 for the randomized subjects.
Non-randomized:
The most frequently reported non-serious, all-causality TEAEs in the non-randomized
portion of the study were fatigue (80.0% and 28.6% in the Child Pugh A and Child Pugh B
cohorts respectively), diarrhoea (60.0% and 14.3% respectively), palmar-plantar
erythrodysaesthesia syndrome (53.3% and 28.6% respectively), hypertension (46.7% and42.9% respectively), decreased appetite (40.0% and 71.4% respectively), dizziness (40.0%
and 0% respectively), and dysphonia (40.0% and 42.9% respectively) (Table 21).
The most frequently reported non-serious, treatment-related TEAEs overall in the nonrandomized portion of the study were decreased appetite (40.0% and 71.4% in the ChildPugh A Child-Pugh B cohort), dysphonia (40.0% and 42.9% respectively), fatigue (60.0%
and 28.6% respectively), hypertension (46.7% and 42.9% respectively) and palmar-plantar
erythrodysaesthesia syndrome (53.3% and 28.6% respectively) (Table 21).
The most frequently reported SAE in subjects in the Child-Pugh A cohort was diseaseprogression (20.0% of subjects), and no SAE preferred term was reported by >1 subject in
the Child-Pugh B cohort. Treatment related SAEs were hyponatraemia, encephalopathy (onesubject each in the Child-Pugh B cohort) and enterocolitis haemorrhagic and hypertension(one subject each) in the Child-Pugh A cohort (Table 23).
Randomized:
The most frequently reported non-serious, all-causality TEAEs were diarrhoea (53.4% and11.8% in the axitinib and placebo arms respectively), hypertension (54.1% and 13.2%
respectively), and decreased appetite (46.6% and 20.6% respectively) (Table 22).
The most frequently reported non-serious, treatment-related TEAEs were hypertension(54.1% and 13.2% in the axitinib and placebo arms respectively), diarrhoea (45.1% and 7.4%
respectively), and decreased appetite (37.6% and 11.8% respectively) (Table 22)).
Sixty-two (62) (46.6%) subjects in the axitinib arm and 16 (23.5%) subjects in the placebo
arm experienced SAEs. The most frequently reported SAE in either treatment arm wasdisease progression (Table 24).

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Table 21: Treatment-Emergent Non-Serious Adverse Events Reported in ≥5% Subjects
in Any of the Treatment Arm by System Organ Class and Preferred Term
(All Causalities and Treatment-Related) - Non-randomized Subjects
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities
15 (100.0)

Treatment
related14 (93.3)

All
Causalities
7 (100.0)

Treatment
related6 (85.7)

1 (6.7)0

1 (6.7)-0-

Cardiac disorders

1 (6.7)-0-

Atrial fibrillation

1 (6.7)

-

0

-

0

0

1 (14.3)

1 (14.3)

00

1 (14.3)

1 (14.3)

1 (6.7)0

1 (14.3)

1 (14.3)

1 (6.7)0

1 (14.3)

1 (14.3)

Endocrine disorders

4 (26.7)

4 (26.7)

00

Hypothyroidism

4 (26.7)

01 (6.7)4 (26.7)-

00-Ocular surface disease

1 (6.7)-0-

Gastrointestinal disorders

13 (86.7)

10 (66.7)

4 (57.1)

4 (57.1)

Abdominal distension

2 (13.3)

1 (6.7)00Abdominal pain

6 (40.0)

3 (20.0)

1 (14.3)

1 (14.3)

Abdominal pain upper

2 (13.3)

2 (13.3)

1 (14.3)

0Anal inflammation

2 (13.3)

2 (13.3)

00

Ascites

1 (6.7)-

1 (14.3)-

Constipation

5 (33.3)

3 (20.0)

2 (28.6)

1 (14.3)

Diarrhoea

9 (60.0)

8 (53.3)

1 (14.3)

1 (14.3)

Dry mouth

1 (6.7)1 (6.7)00

Dyspepsia

5 (33.3)

2 (28.6)

Enterocolitis

01 (6.7)-

1 (14.3)

1 (14.3)-

Gastritis erosive0-

1 (14.3)-

Glossitis00

1 (14.3)

1 (14.3)

Nausea5 (33.3)

3 (20.0)

3 (42.9)

3 (42.9)

Stomatitis

3 (20.0)

3 (20.0)

0

0

0

-

1 (14.3)-

3 (20.0)

1 (6.7)00With adverse events
Blood and lymphatic system disorders
Anaemia

Congenital, familial and genetic disorders
Hydrocele
Ear and labyrinth disorders
Ear disorder

Eye disorders

Varices oesophageal
Vomiting

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Protocol A4061058 – 27 January 2015 – Final
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities

Treatment
relatedAll
Causalities

12 (80.0)

10 (66.7)

6 (85.7)

Treatment
related6 (85.7)002 (28.6)

2 (28.6)

Catheter site pain

1 (6.7)-0-

Chest discomfort

2 (13.3)-

0-

Chest pain

2 (13.3)

0Chills1 (6.7)1 (6.7)-

1 (14.3)

0-Face oedema

2 (13.3)-

0-

Fatigue

12 (80.0)

9 (60.0)

2 (28.6)

2 (28.6)

Influenza like illness

1 (6.7)

-

0

-

0

0

2 (28.6)

2 (28.6)

Mucosal inflammation

1 (6.7)1 (6.7)00Oedema1 (6.7)0

1 (14.3)

1 (14.3)

Oedema peripheral

4 (26.7)

1 (6.7)

1 (14.3)

0Pain

5 (33.3)

3 (20.0)00

Pyrexia

3 (20.0)-

1 (14.3)-

Hepatobiliary disorders0

1 (6.7)

1 (14.3)

1 (14.3)

Hyperbilirubinaemia

0

1 (14.3)

Infections and infestations

2 (13.3)0-2 (28.6)

1 (14.3)-

Bronchitis0-

1 (14.3)-

Cystitis

1 (6.7)

-

0

-

0

-

1 (14.3)-

1 (6.7)-0-

4 (26.7)

1 (6.7)00Contusion

1 (6.7)0

Fall

1 (6.7)1 (6.7)-00-Laceration

1 (6.7)-0-

Procedural pain

1 (6.7)-0-

9 (60.0)

8 (53.3)

3 (42.9)

3 (42.9)

Alanine aminotransferase increased

2 (13.3)0Alpha 1 foetoprotein increased

1 (6.7)

2 (13.3)-

00-Ammonia increased

1 (6.7)-0-

Aspartate aminotransferase increased

4 (26.7)

2 (13.3)

00General disorders and administration site
conditions
Asthenia

MalaiseNasopharyngitis
Pneumonia
Injury, poisoning and procedural complications

Investigations

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities
2 (13.3)

Treatment
related1 (6.7)

All
Causalities
0

Treatment
related0Blood bilirubin increased

1 (6.7)-0-

Blood creatinine increased00

1 (14.3)

1 (14.3)

Blood thyroid stimulating hormone increased

1 (6.7)1 (6.7)00Gamma-glutamyltransferase increased

3 (20.0)

2 (13.3)

00

Neutrophil count decreased

1 (6.7)1 (6.7)00Platelet count decreased

2 (13.3)

2 (13.3)

00Weight decreased

5 (33.3)

4 (26.7)

3 (42.9)

3 (42.9)9 (60.0)

7 (46.7)

5 (71.4)

5 (71.4)

Decreased appetite

6 (40.0)

6 (40.0)

5 (71.4)

5 (71.4)

Hypercalcaemia

00

1 (14.3)

1 (14.3)

Hyperkalaemia

00

1 (14.3)

1 (14.3)

Hypoalbuminaemia

4 (26.7)

1 (6.7)2 (28.6)

1 (14.3)

Hypocalcaemia

1 (6.7)0

1 (14.3)

1 (14.3)

Hypokalaemia

00

1 (14.3)

1 (14.3)

Hyponatraemia

1 (6.7)0

3 (42.9)

3 (42.9)

Hypophosphataemia

1 (6.7)1 (6.7)00

11 (73.3)

4 (26.7)

2 (28.6)

1 (14.3)

Arthralgia

2 (13.3)-0-Arthropathy

1 (6.7)1 (6.7)00Back pain

4 (26.7)-

1 (14.3)-

Bone pain

1 (6.7)1 (6.7)00

Flank pain

4 (26.7)-

0-Muscle spasms

1 (6.7)1 (6.7)000

1 (14.3)
0

1 (14.3)-

Blood alkaline phosphatase increased

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Muscular weakness
Musculoskeletal chest pain

1 (6.7)0-Musculoskeletal discomfort

1 (6.7)-0-Musculoskeletal pain

2 (13.3)-

0-Musculoskeletal stiffness

1 (6.7)-0-

Myalgia

1 (6.7)1 (6.7)0

0

Neck pain

1 (6.7)-

0-

Pain in extremity

2 (13.3)

1 (6.7)0

0

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities

Treatment
relatedAll
Causalities0-

1 (14.3)

Tumour associated fever0-

1 (14.3)-

Nervous system disorders

8 (53.3)

7 (46.7)

3 (42.9)

3 (42.9)

Dysgeusia

0

-

0

-

Dizziness

6 (40.0)

5 (33.3)

00

Headache

5 (33.3)

3 (20.0)

2 (28.6)

2 (28.6)

Hepatic encephalopathy00

1 (14.3)

1 (14.3)

Neuropathy peripheral

1 (6.7)-0-

Peripheral sensory neuropathy

2 (13.3)

1 (6.7)

0

0

0

0

1 (14.3)

1 (14.3)

6 (40.0)

3 (20.0)

1 (14.3)

0Agitation

1 (6.7)-0-

Confusional state

1 (6.7)1 (6.7)00Depression

1 (6.7)1 (6.7)00Insomnia

2 (13.3)

1 (6.7)

1 (14.3)0

Irritability

1 (6.7)-0-

6 (40.0)

4 (26.7)

1 (14.3)

1 (14.3)

Chromaturia

1 (6.7)0

Dysuria

1 (6.7)1 (6.7)-00-

Pollakiuria

1 (6.7)-0-

Proteinuria

4 (26.7)

4 (26.7)

1 (14.3)

1 (14.3)

10 (66.7)

8 (53.3)

4 (57.1)

4 (57.1)Cough

3 (20.0)

1 (6.7)00Dysphonia

6 (40.0)

6 (40.0)

3 (42.9)

3 (42.9)

Dyspnoea

3 (20.0)

1 (6.7)

1 (14.3)

0

Epistaxis

1 (6.7)1 (6.7)00Haemoptysis

1 (6.7)0

1 (14.3)

1 (14.3)

Interstitial lung disease

1 (6.7)1 (6.7)00Nasal congestion

1 (6.7)1 (6.7)00Nasal inflammation

1 (6.7)1 (6.7)00Oropharyngeal pain

2 (13.3)

1 (6.7)00

Productive cough00

1 (14.3)

1 (14.3)

Neoplasms benign, malignant and unspecified(incl cysts and polyps)

Tremor
Psychiatric disorders

Renal and urinary disorders

Respiratory, thoracic and mediastinal disorders

Page 40

Treatment
related-Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

Upper respiratory tract inflammation

All
Causalities
1 (6.7)

Treatment
related1 (6.7)

All
Causalities
0

Treatment
related0Skin and subcutaneous tissue disorders

11 (73.3)

11 (73.3)

3 (42.9)

3 (42.9)

Blister

2 (13.3)

2 (13.3)

00

Dry skin

1 (6.7)1 (6.7)00Facial wasting

1 (6.7)-0-Nail disorder

1 (6.7)1 (6.7)0

0

Night sweats

1 (6.7)1 (6.7)00Palmar-plantar erythrodysaesthesia syndrome

8 (53.3)

8 (53.3)

2 (28.6)

2 (28.6)

Petechiae

1 (6.7)1 (6.7)00Pruritus00

1 (14.3)

1 (14.3)Rash

2 (13.3)

2 (13.3)

2 (28.6)

2 (28.6)

00

1 (14.3)

1 (14.3)

Vascular disorders

8 (53.3)

7 (46.7)

3 (42.9)

3 (42.9)

Hypertension

7 (46.7)

7 (46.7)

3 (42.9)

3 (42.9)

Hypotension

1 (6.7)-0-

Skin ulcer

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Note: The symbol ‘-’ in the table indicates data not provided in the source table as the subject had not experienced thatparticular event.
MedDRA (v17.0) coding dictionary applied.

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Protocol A4061058 – 27 January 2015 – Final

Table 22: Treatment-Emergent Non-Serious Adverse Events Reported in ≥5% Subjects
in Any of the Treatment Arm by System Organ Class and Preferred Term
(All Causalities and Treatment-Related) - Randomized Subjects
System Organ Class

Axitinib(N=133)n (%)

Preferred Term

Placebo(N=68)n (%)

All
Causalities

Treatment
relatedAll
Causalities

Treatment
related130 (97.7)

125 (94.0)

55 (80.9)

33 (48.5)

8 (6.0)8 (6.0)00Thrombocytopenia

8 (6.0)8 (6.0)00Endocrine disorders

33 (24.8)

31 (23.3)

00

Hypothyroidism

33 (24.8)

31 (23.3)

00Gastrointestinal disorders

102 (76.7)

84 (63.2)

33 (48.5)

17 (25.0)

Abdominal distension

5 (3.8)-7 (10.3)-

Abdominal pain

45 (33.8)

23 (17.3)

12 (17.6)

2 (2.9)Abdominal pain upper

17 (12.8)

7 (5.3)3 (4.4)3 (4.4)

Constipation

21 (15.8)

11 (8.3)

8 (11.8)

4 (5.9)Diarrhoea

71 (53.4)

59 (44.4)

8 (11.8)5 (7.4)

Dry mouth

7 (5.3)-2 (2.9)-Dyspepsia

10 (7.5)

10 (7.5)

6 (8.8)4 (5.9)

Nausea35 (26.3)

24 (18.0)

7 (10.3)

4 (5.9)Stomatitis

19 (14.3)

19 (14.3)

00Vomiting

26 (19.5)

20 (15.0)

7 (10.3)

89 (66.9)

72 (54.1)

26 (38.2)

3 (4.4)15 (22.1)

Asthenia

27 (20.3)

24 (18.0)

3 (4.4)3 (4.4)

Fatigue46 (34.6)

40 (30.1)

18 (26.5)

11 (16.2)

Malaise13 (9.8)

10 (7.5)

1 (1.5)

1 (1.5)

Mucosal inflammation

8 (6.0)8 (6.0)00Oedema peripheral

14 (10.5)

10 (14.7)

Pyrexia

16 (12.0)

7 (5.3)-3 (4.4)3 (4.4)-9 (6.8)-8 (11.8)-9 (6.8)-8 (11.8)-

55 (41.4)

6 (8.8)2 (2.9)1 (1.5)-

With adverse events
Blood and lymphatic system disorders

General disorders and administrationsite conditions

Infections and infestations
Nasopharyngitis
Investigations
Alanine aminotransferase increased

8 (6.0)29 (21.8)-

Aspartate aminotransferase increased

10 (7.5)-

4 (5.9)-Blood bilirubin increased

7 (5.3)-0-

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ Class

Axitinib(N=133)n (%)

Preferred Term

Placebo(N=68)n (%)

All
Causalities
9 (6.8)Treatment
related8 (6.0)All
Causalities
0

Treatment
related0

36 (27.1)

23 (17.3)

2 (2.9)1 (1.5)72 (54.1)

50 (37.6)

17 (25.0)

8 (11.8)

Decreased appetite

62 (46.6)

14 (20.6)

Dehydration

9 (6.8)50 (37.6)-

0

8 (11.8)-

Hyperkalaemia

9 (6.8)-2 (2.9)-Hypoalbuminaemia

8 (6.0)-1 (1.5)-

Hyponatraemia

8 (6.0)-3 (4.4)-30 (22.6)-

13 (19.1)-

Arthralgia

7 (5.3)-

1 (1.5)-Back pain

11 (8.3)-

11 (16.2)-

Musculoskeletal pain

8 (6.0)-4 (5.9)-Musculoskeletal pain

8 (6.0)-4 (5.9)-Pain in extremity

7 (5.3)-

1 (1.5)-27 (20.3)

19 (14.3)

3 (4.4)

1 (1.5)Dysgeusia

9 (6.8)8 (6.0)0

0

Headache21 (15.8)

13 (9.8)

3 (4.4)

1 (1.5)12 (9.0)

7 (5.3)3 (4.4)

1 (1.5)12 (9.0)

7 (5.3)3 (4.4)

1 (1.5)27 (20.3)

27 (20.3)

1 (1.5)

1 (1.5)27 (20.3)

27 (20.3)

1 (1.5)52 (39.1)

39 (29.3)

12 (17.6)

1 (1.5)3 (4.4)Cough

16 (12.0)-

6 (8.8)-Dysphonia

33 (24.8)

32 (24.1)

00

Dyspnoea

13 (9.8)

7 (5.3)6 (8.8)1 (1.5)

Epistaxis

10 (7.5)

8 (6.0)2 (2.9)2 (2.9)64 (48.1)

62 (46.6)

17 (25.0)

14 (20.6)

Alopecia

6 (4.5)6 (4.5)7 (10.3)

Palmar-plantar erythrodysaesthesia
syndrome

45 (33.8)

45 (33.8)

4 (5.9)6 (8.8)2 (2.9)Pruritus

11 (8.3)

7 (5.3)8 (11.8)

7 (10.3)

Blood thyroid stimulating hormone
increased
Weight decreased
Metabolism and nutrition disorders

Musculoskeletal and connective tissue
disorders

Nervous system disorders

Psychiatric disorders
Insomnia
Renal and urinary disorders
Proteinuria
Respiratory, thoracic and mediastinal
disordersSkin and subcutaneous tissue disorders

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ Class

Axitinib(N=133)n (%)

Preferred Term

Placebo(N=68)n (%)

All
Causalities
23 (17.3)

Treatment
related22 (16.5)

All
Causalities
2 (2.9)Vascular disorders

72 (54.1)

9 (13.2)

Hypertension

72 (54.1)

71 (53.4)
71 (53.4)

Treatment
related2 (2.9)8 (11.8)

9 (13.2)

8 (11.8)

Rash

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities
Note: The symbol ‘-’ in the table indicates data not provided in the source table as the subject had not experienced thatparticular event.
MedDRA (v17.0) coding dictionary applied.

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final

Table 23: Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All Causalities and Treatment-Related) - Non-randomized
Subjects
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities

Treatment
relatedAll
Causalities

Treatment
related10 (66.7)

2 (13.3)

3 (42.9)

2 (28.6)

2 (13.3)

1 (6.7)

1 (14.3)

0Abdominal pain

1 (6.7)-0-Enterocolitis haemorrhagic

1 (6.7)1 (6.7)

0

0

0

-

1 (14.3)-

4 (26.7)-0-

Disease progression

3 (20.0)-0-

Fatigue

1 (6.7)-0-

Hepatobiliary disorders

4 (26.7)-0-Bile duct stenosis

1 (6.7)-0-Cholecystitis acute

2 (13.3)-

0-

Hepatic function abnormal

1 (6.7)-0-

Infections and infestations

2 (13.3)-

1 (14.3)-

1 (6.7)

-

0

-

0

-

1 (14.3)-

1 (6.7)-0-

1 (6.7)02 (28.6)

Decreased appetite

1 (6.7)-0

1 (14.3)-

Electrolyte imbalance

1 (6.7)

-

0

-

0

0

1 (14.3)

1 (14.3)

0-

1 (14.3)-

Hepatocellular carcinoma0-

1 (14.3)-

Nervous system disorders

1 (6.7)0

1 (14.3)

1 (14.3)

Cerebral infarction

1 (6.7)-0-

Encephalopathy00

1 (14.3)

1 (14.3)

Psychiatric disorders

1 (6.7)-0-Completed suicide

1 (6.7)-0-

1 (6.7)-0-With serious adverse events
Gastrointestinal disorders

Varices oesophageal
General disorders and administration site
conditions

Appendicitis
Peritonitis bacterial
Pneumonia
Metabolism and nutrition disorders

Hyponatraemia
Neoplasms benign, malignant and unspecified(incl cysts and polyps

Respiratory, thoracic and mediastinal disorders

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ ClassChild Pugh A(N=15)n (%)

Preferred Term

Child Pugh B
(N=7)
n (%)

All
Causalities
1 (6.7)

Treatment
related-All
Causalities
0

Treatment
related-Vascular disorders

2 (13.3)

1 (6.7)00Hypertension

1 (6.7)1 (6.7)

0

0

Hypotension

1 (6.7)-0

Dyspnoea

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Note: The symbol ‘-’ in the table indicates data not provided in the source table as the subject had not experienced thatparticular event.
MedDRA (v17.0) coding dictionary applied.

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final

Table 24: Treatment-Emergent Serious Adverse Events Reported by System OrganClass and Preferred Term (All Causalities and Treatment-Related) Randomized Subjects
System Organ Class

Axitinib (N=133)

Placebo (N=68)

Preferred Term

n (%)

n (%)

All
Causalities

Treatment
relatedAll
Causalities

Treatment
related62 (46.3)

24 (17.9)

16 (23.5)

1 (1.5)1 (0.7)0

1 (1.5)

1 (1.5)00

1 (1.5)

1 (1.5)1 (0.7)-0-

3 (2.2)2 (1.5)00Acute myocardial infarction

1 (0.7)1 (0.7)00Bradycardia

1 (0.7)-0-Ventricular tachycardia

1 (0.7)1 (0.7)00

Eye disorders

2 (1.5)2 (1.5)00Cataract

1 (0.7)1 (0.7)0

0

Retinal vein occlusion

1 (0.7)1 (0.7)0

0

Gastrointestinal disorders

16 (11.9)

5 (7.4)3 (2.2)6 (4.5)-2 (2.9)0-

Ascites0-

2 (2.9)-Colitis1 (0.7)-0-

Diarrhoea

7 (5.2)5 (3.7)0

0

Gastric ulcer

1 (0.7)0

Gastrointestinal disorder

1 (0.7)1 (0.7)-0

0-

Gastrointestinal haemorrhage

1 (0.7)-0-

Haematochezia

1 (0.7)

-

0

-

0

-

1 (1.5)-1 (0.7)-

1 (1.5)-16 (11.9)

4 (3.0)6 (8.8)Asthenia

4 (3.0)0

Disease progression

8 (6.0)3 (2.2)-4 (5.9)0-General physical health deterioration

3 (2.2)-0-

Inflammation

1 (0.7)00

1 (0.7)-

1 (1.5)0-

1 (0.7)-

1 (1.5)-

With serious adverse events
Blood and lymphatic system disorders
Anaemia
Febrile neutropenia
Cardiac disorders

Abdominal pain

Rectal haemorrhage
Upper gastrointestinal haemorrhage
General disorders and administration site
conditions

Oedema peripheral
Pyrexia

Page 47

0

Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ Class

Axitinib (N=133)

Placebo (N=68)

Preferred Term

n (%)

n (%)

All
Causalities
8 (6.0)Treatment
related2 (1.5)

All
Causalities
2 (2.9)Treatment
relatedBile duct stone

1 (0.7)-0-Cholangitis

4 (3.0)1 (0.7)00Cholangitis acute

1 (0.7)-0-

Hepatic failure

2 (1.5)00

1 (0.7)-

1 (1.5)0-

Hepatorenal syndrome0-

1 (1.5)-

Jaundice cholestatic

1 (0.7)-0-

Infections and infestations

9 (6.7)-4 (5.9)-Abscess rupture0-1 (1.5)-Gastroenteritis

2 (1.5)-0-Otitis media

1 (0.7)

-

0

-

0

-

1 (1.5)-

Pneumonia

1 (0.7)-

1 (1.5)-

Sepsis1 (0.7)-0-Upper respiratory tract infection

1 (0.7)-

1 (1.5)-

Urinary tract infection

3 (2.2)-0-

3 (2.2)-0-

Femur fracture

1 (0.7)-0-

Humerus fracture

1 (0.7)-0-Road traffic accident

1 (0.7)-0-

1 (0.7)1 (0.7)00Alanine aminotransferase increased

1 (0.7)1 (0.7)0

0

Aspartate aminotransferase increased

1 (0.7)1 (0.7)00Metabolism and nutrition disorders

8 (6.0)3 (2.2)00Cachexia

1 (0.7)-0-Decreased appetite

1 (0.7)1 (0.7)00Dehydration

3 (2.2)1 (0.7)00Hyperkalaemia

2 (1.5)1 (0.7)

00

Hypovolaemia

1 (0.7)-0-

3 (2.2)1 (0.7)00

Muscular weakness

1 (0.7)1 (0.7)0

0

Necrotising myositis

1 (0.7)-0-

Hepatobiliary disorders

Hepatic function abnormal

Ovarian abscess

Injury, poisoning and procedural complications

Investigations

Musculoskeletal and connective tissue disorders

Page 480

Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final
System Organ Class

Axitinib (N=133)

Placebo (N=68)

Preferred Term

n (%)

n (%)

All
Causalities
1 (0.7)

Treatment
related-All
Causalities
0

Treatment
related-2 (1.5)-

1 (1.5)-Hepatocellular carcinoma

1 (0.7)-

0-

Malignant neoplasm progression

1 (0.7)

-

0

-

0

-

1 (1.5)-

Nervous system disorders

9 (6.7)4 (3.0)3 (4.4)0

Brain stem infarction

1 (0.7)-0-Coma hepatic

1 (0.7)1 (0.7)

0

0

0

-

1 (1.5)-

Encephalopathy

2 (1.5)1 (0.7)00

Epilepsy

1 (0.7)-0-

Hepatic encephalopathy

4 (3.0)1 (1.5)
1 (1.5)0-

Osteoporotic fracture
Neoplasms benign, malignant and unspecified(incl cysts and polyps)

Tumour rupture

Dizziness

Ischaemic stroke0

2 (1.5)-

Quadriparesis0-1 (1.5)-

Psychiatric disorders

1 (0.7)-0-

Dysthymic disorder

1 (0.7)-0-

3 (2.2)2 (1.5)

1 (1.5)0Renal failure

1 (0.7)1 (0.7)

1 (1.5)0Renal impairment

1 (0.7)1 (0.7)00

Ureteric obstruction

1 (0.7)-0-

7 (5.2)

1 (1.5)0

1 (0.7)-

1 (1.5)0-

Dyspnoea

3 (2.2)-0-

Epistaxis

1 (0.7)-0-

Lung disorder

1 (0.7)

-

0

-

0

-

1 (1.5)-

Pulmonary alveolar haemorrhage

1 (0.7)0

Respiratory failure

2 (1.5)1 (0.7)-00-

1 (0.7)-0-

1 (0.7)-0-

Renal and urinary disorders

Respiratory, thoracic and mediastinal disorders
Bronchospasm

Obstructive airways disorder

Skin and subcutaneous tissue disorders
Drug eruption

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Note: The symbol ‘-’ in the table indicates data not provided in the source table as the subject had not experienced thatparticular event.
MedDRA (v17.0) coding dictionary applied.

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final

Permanent discontinuation due to AEs
Non-randomized:
Overall, 4 (26.7%) subjects in the Child-Pugh A cohort and 1 (14.3%) subject in the ChildPugh B cohort experienced TEAEs that led to treatment discontinuation. The AEs that caused
permanent treatment discontinuations are presented in Table 25.
Randomized:
Overall, 38 (28.6%) subjects in the axitinib arm and 9 (13.2%) subjects in the placebo arm
experienced TEAEs that led to treatment discontinuation. The AEs that caused permanent
treatment discontinuations are presented in Table 26.
Table 25: Number (Percentage) of Subjects with Treatment Emergent Adverse Events
Leading to Treatment Discontinuation- Non-randomized Subjects
System Organ ClassChild Pugh A(N=15)n (%)

Child Pugh B
(N=7)
n (%)

Any AEs

4 (26.7%)

General disorders and administration site conditions
Asthenia

2 (13.3)
0

1 (14.3%)0

Disease progression

2 (13.3)

0

Psychiatric disorders
Completed suicide

1 (6.7)1 (6.7)0

Infections and infestations
Pneumonia

1 (6.7)1 (6.7)0Preferred Term

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Includes data up to 28 days after last dose of study drug.
% = (n/N)*100.
MedDRA (v17.0) coding dictionary applied.

Page 50

1 (14.3)

00Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final

Table 26: Number (Percentage) of Subjects with Treatment Emergent Adverse Events
Leading to Treatment Discontinuation – Safety Analysis Set
System Organ Class

Axitinib (N=133)

Placebo (N=68)

Preferred Term

n (%)

n (%)

Any AEs

38 (28.6)

Blood and lymphatic system disorders

1 (0.8)9 (13.2)01 (0.8)02 (1.5)0Acute myocardial infarction

1 (0.8)0Ventricular tachycardia

1 (0.8)0

1 (0.8)0Retinal vein occlusion

1 (0.8)0

Gastrointestinal disorders

4 (3.0)1 (1.5)

Diarrhoea

2 (1.5)0

Gastrointestinal haemorrhage

1 (0.8)0Intestinal fistula

1 (0.8)00

1 (1.5)12 (9.0)

4 (5.9)Asthenia

1 (0.8)0Disease progression

6 (4.5)3 (4.4)

Fatigue

1 (0.8)1 (1.5)General physical health deterioration

3 (2.3)0

Malaise1 ( 0.8)03 (2.3)0Cholangitis

1 (0.8)0

Hepatic failure

2 (1.5)0

1 (0.8)0

Alanine aminotransferase increased

1 (0.8)0Metabolism and nutrition disorders

1 (0.8)0

1 (0.8)02 (1.5)0Muscular weakness

1 (0.8)0

Necrotising myositis

1 (0.8)02 (1.5)

1 (1.5)Hepatocellular carcinoma

1 (0.8)

0

Malignant neoplasm progression

1 (0.8)0Thrombocytopenia
Cardiac disorders

Eye disorders

Upper gastrointestinal haemorrhage
General disorders and administration site conditions

Hepatobiliary disorders

Investigations

Dehydration
Musculoskeletal and connective tissue disorders

Neoplasms benign, malignant and unspecified (incl cysts
and polyps)

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System Organ Class

Axitinib (N=133)

Placebo (N=68)

Preferred Term

n (%)

n (%)

Tumour rupture01 (1.5)4 (3.0)1 (1.5)Coma hepatic

1 (0.8)0

Encephalopathy

1 (0.8)0

Hepatic encephalopathy

2 (1.5)0Ischaemic stroke0

1 (1.5)

Psychiatric disorders

1 (0.8)0

Confusional state

1 (0.8)0

3 (2.3)2 (2.9)1 (0.8)0

Obstructive airways disorder0

1 ( 1.5)

Pneumonitis0

1 ( 1.5)

Pulmonary alveolar haemorrhage

1 ( 0.8)0Respiratory failure

1 (0.8)0

3 (2.3)0

3 (2.3)0

Vascular disorders0

1 (1.5)Hypertension0

1 (1.5)

Nervous system disorders

Respiratory, thoracic and mediastinal disorders
Lung disorder

Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome

Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities.
Includes data up to 28 days after last dose of study drug.
% = (n/N)*100.
MedDRA (v17.0) coding dictionary applied.

Dose-limiting toxicities
Dose-limiting toxicities in non-randomized subjects are presented in Table 27. In the ChildPugh B disease (score 7) cohort (axitinib 2 mg BID) a total of 2 out of 7 subjects experienced
DLTs. One subject had proteinuria >3.5 g/24 hours in Cycle 1. The other subject had a Cycle
1 compliance <75% because of treatment-related toxicity, however, upon further review, thissubject was considered not fully evaluable for Cycle 1 DLT and was replaced with anothercandidate.

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Table 27: Subjects with Dose Limiting Toxicity – Non-randomized Subjects
Subjects

Cycle

Done/Not Done

Did Subject experience
DLT

Subject AA
Subject BB
Subject CC

Cycle 1
Cycle 1
Cycle 1

Done
Done
Done

No
No
Yes

Subject DD
Subject EE
Subject FF
Subject GG

Cycle 1
Cycle 1
Cycle 1
Cycle 1

Done
Done
Done
Done

No
No
No
Yes

Child Pugh B

DLT Details-

2011.12.27
Urine protein 5.64 G-

DeathsThe number of subjects who died on the study and during the follow-up and the reasons forthe deaths are presented in Table 28 for the non-randomized portion and in Table 29 for the
randomized portion.
Table 28: Summary of Deaths: Non-randomized Subjects
Child-Pugh A(N=15)n (%)

Child-Pugh B
(N=7)
n (%)

Total
(N=22)n (%)

14 (93.3)

6 (85.7)

20 (90.9)

4 (26.7)

1 (14.3)

5 (22.7)

Disease Under Study

3 (20.0)

1 (14.3)

4 (18.2)Other

1 (6.7)0

1 (4.5)1 (6.7)0

1 (4.5)

10 (66.7)

5 (71.4)

15 (68.2)

Disease Under Study

10 (66.7)

4 (57.1)

14 (63.6)

Unknown0

1 (14.3)

1 (4.5)Other

0

1 (14.3)

1 (4.5)Biliary Sepsis0

1 (14.3)

1 (4.5)

Subjects Who Died
Subjects Who Died On-study[1]

SuicideSubjects Who Died During Follow-up[2]

Subjects were treated with axitinib dose 5 mg BID for Child-Pugh A and 2 mg BID for Child-Pugh B.
A subject with multiple reasons for death was counted separately for each individual reason in the sub-category counts.
%=(n/N)×100.
[1]
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.
[2]
Follow-up deaths are those that occurred more than 28 days after the last dose of study drug.
Abbreviations: BID=Twice daily.

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Protocol A4061058 – 27 January 2015 – Final

Table 29: Summary of Deaths: Safety Analysis Set (in randomized portion of the study)
Axitinib(N=133n (%)

Placebo(N=68)n (%)

Total(N=201)n (%)

Subjects Who Died

100 (75.2)

52 (76.5)

152 (75.6)

Subjects Who Died On-study [1]

16 (12.0)

8 (11.8)

24 (11.9)

Disease Under Study

13 (9.8)6 (8.8)19 (9.5)

Other

3 (2.3)2 (2.9)5 (2.5)

Acute Renal And Liver Failure0

1 (1.5)1 (0.5)

AE Pneumopathy

1 (0.8)0

1 (0.5)

Liver Function Failure

1 (0.8)0

1 (0.5)

Obstruction Of Airway With Blood Phlegm0

1 (1.5)1 (0.5)

Septicaemia

1 (0.8)0

1 (0.5)

Subjects Who Died During Follow-up [2]84 (63.2)

44 (64.7)

128 (63.7)

Disease Under Study77 (57.9)

41 (60.3)

118 (58.7)

Unknown

4 (3.0)2 (2.9)6 (3.0)Other

3 (2.3)2 (2.9)5 (2.5)Hepatic Failure

1 (0.8)0

1 (0.5)Hepatic Insufficiency0

1 (1.5)1 (0.5)

Hospitalisation For Fracture Neck Of Femur. Death After
Multiple Organ Failure0

1 (1.5)1 (0.5)

Pneumonia

1 (0.8)0

1 (0.5)

Sepsis1 (0.8)0

1 (0.5)

Subjects were treated with axitinib+BSC or placebo+BSC.
A subject with multiple reasons for death was counted separately for each individual reason in the sub-category counts.
%=(n/N)×100.
[1]
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.
[2]
Follow-up deaths are those that occurred more than 28 days after the last dose of study drug.
Abbreviations: AE=Adverse event; BSC=Best supportive care.

Clinical laboratory evaluations
Abnormal values in the clinical laboratory data that the investigator determined to beclinically significant were reported as AEs and were summarized in Table 21 throughTable 24.
CONCLUSIONS:
Non-randomized• Axitinib steady-state plasma exposures in Child-Pugh B (score 7) subjects receiving 2 mg
BID axitinib and Child-Pugh A subjects receiving 5 mg BID axitinib are comparable.

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Public Disclosure Synopsis
Protocol A4061058 – 27 January 2015 – Final• The safety findings collected in the 6 Child-Pugh Class B (score 7) subjects evaluable for
Cycle 1 DLT suggest that 2 mg BID is an appropriate axitinib starting dose for thispopulation.
• The safety profile of axitinib in Child-Pugh A and Child-Pugh B subjects with advanced
HCC in this study was consistent with the known safety profile of axitinib or expectedbased on underlying disease. No new safety signals were identified in this population.
Randomized• The primary endpoint of OS in all randomized subjects did not meet statisticalsignificance. The estimated HR (axitinib versus placebo) was 0.907 (one-sided p=0.2872).
The median OS was 12.7 months in the axitinib arm and 9.7 months in the placebo arm.
• The difference between the axitinib and placebo arms was statistically significant for thefollowing secondary endpoints: PFS, TTP and CBR but was not statistically significant for
ORR.
• The time to deterioration based on the composite outcome of death, tumor progression,
decrease of ≥3 points in FHSI-8 score, whichever occurred first, showed no significant
difference between treatment arms. The overall comparison for axitinib versus placebo
based on the repeated measures mixed effects model for the estimated mean FHSI-8
scores by cycle post-baseline significantly favored placebo. The PRO data suggest that the
expected side effects of axitinib contributed to reduction of HRQoL based on results from
FACT-Hep and associated subscales; the only exceptions were the FACT-G subscales
social/family well-being and emotional well-being for which results were similar between
the treatment groups. In addition, subject responses to disease-related symptoms, or
symptoms of liver failure, whether or not the tumor stabilized or regressed, may each havecontributed to the time to deterioration outcomes.
• Low levels of IL-6, E-selectin, IL-8, Ang-2, MIF and c-MET were associated withfavorable prognosis (OS) for HCC. Low levels of E-selectin and SDF-1 may havebaseline predictive value for HCC subjects receiving axitinib.
• Overall, the safety profile of axitinib in subjects with advanced HCC in this study wasconsistent with the known safety profile of axitinib or expected based on underlying
disease. No new safety signals were identified in this population.

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