Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - 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.: A4061035
PROTOCOL TITLE: Phase 2 Study of AG-013736 as Second-Line Treatment in Patientswith Metastatic Renal Cell Cancer
Study Centers: A total of 18 centers in Japan took part in the study and enrolled subjects.
Study Initiation Date, Primary Completion and Final Completion Dates:
First Subject First Visit (FSFV): 12 December 2007
Primary Completion date: 26 February 2010
Last Subject Last Visit (LSLV): 09 August 2013
Phase of Development: Phase 2
Study Objectives:
Primary Objective:

Evaluate objective tumor response of AG-013736 (axitinib) for metastatic renal
cell cancer (mRCC).

Secondary Objectives:


Evaluate the progression-free survival (PFS);

Evaluate time to tumor progression (TTP);

Evaluate duration of response (DR);

Evaluate overall survival (OS);

Evaluate the safety profile of axitinib;

Investigate the changes of the plasma concentration profiles of soluble vascularendothelial growth factor receptor 1 (s-VEGFR1), soluble vascular endothelial
growth factor receptor 2 (s-VEGFR2), soluble vascular endothelial growth factor
receptor 3 (s-VEGFR3), soluble stem cell factor receptor (s-KIT) and vascularendothelial growth factor (VEGF).

Template version 1.0

Page 1

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

METHODS
Study Design: This study was an axitinib single agent, open-label, non-randomized,
multicenter Phase 2 study in subjects with mRCC.
Axitinib 5 mg was administered orally twice daily (BID) on a continuous schedule. Cycle
length was 28 days. If the drug was well tolerated at 5 mg BID, the dose of axitinib was tobe titrated to 7 mg BID and then to a maximum of 10 mg BID. Treatment was continued
until the subject met the discontinuation criteria. The schedule of tests and procedures isgiven in Table 1.

Template version 1.0

Page 2

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 1.

Schedule of Tests and Procedures

Observation
Screening

Within14 Days
PredosingInformed consent
Subject backgrounde
Body weight, bodytemperature, pulse rate
Blood pressuref
Home blood pressure
monitoringg
ECOG performancestatusHematologyh
Coagulation testj
Chemistryk
Thyroid function testl

Urine analysism
12-lead ECGo
Blood sampling for
genotyping
Blood sampling for PK(for population PK
analysis)q
Blood sampling for PK(when dose isincreased)r

Template version 1.0

Cycle 1 (Days ± Acceptable range)aDay 1(Predosing)- 4 days

Cycle 2-4 (Days± Acceptable
Range) a

Day 8

Day 15

Day 22

Day 1

Day 15

±4
Days

±4
Days

±4
Days

±4
Days

±4
Days

X

X

X

X

X

X

X

X

X

X

Cycle 5 or
Latera(Days ±
Acceptable
Range)
Day 1

Post Treatment (Days ± Acceptable
Range)At End of Treatment/
Discontinuationb+ 4 days± 4 Days

Xd
X
X

X

X

X

X

X

X

X

X

X

X
X
X

X
X
X

X (Oddnumbercycles only

X

X

X

Throughout the study period
X

X

X
X
X

i

X
Xi
Xi

X

Xi

Xn
X

Xi

X

X

X

X

X

X
X
X
X

X
X
X
X

X
X
X
X

X
X
X
X
(Cycles
2,3
only)
X

X
X
X

X

X
Xp

X

X

X
Xq
(Cycles
3 only)X

Xq (Cycles
5,7 only)
When dose was titrated

Page 3

Follow Up
28 daysAfter Last
Dosec

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 1.

Schedule of Tests and Procedures

Observation
Screening

Within14 Days
PredosingBlood sampling forpharmacodynamic
markerss
Pregnancy test
Tumor assessmentu

Cycle 1 (Days ± Acceptable range)aDay 1(Predosing)- 4 days

Cycle 2-4 (Days± Acceptable
Range) a

Day 8

Day 15

Day 22

Day 1

Day 15

±4
Days

±4
Days

±4
Days

±4
Days

±4
Days

X
X
Xt

Xw
(Cycles
3 only)Xv

Cycle 5 or
Latera(Days ±
Acceptable
Range)
Day 1

Post Treatment (Days ± Acceptable
Range)At End of Treatment/
Discontinuationb+ 4 days± 4 Days
X (Until
Cycle 7)
Xw (Odd
numbercyclesonly)

Follow Up
28 daysAfter Last
Dosec

X

Xx

Bone scintigraphy
XvyBrain CT / MRI
Xv
Drug compliance
Concomitant
medications / therapies
Adverse events
Serious adverse events
Survivalz
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance imaging; PK =pharmacokinetic.
a.
A cycle length was 28 days.
b.
If the tests and procedures were performed after last dose, these were not repeated.
c.
Adverse event was assessed at the visit after 28 days or later from last dose.
d.
Within 28 days prior to registration on the study.
e.
Including the smoking status.
f.
Blood pressure was measured twice, separated by at least 1 hour, at each clinic visit (including screening visit). Blood pressure measurements weremade with the subject in the seated position after the subject had been seated quietly for 5 minutes.
g.
Blood pressure measurements were made at least twice daily prior to each axitinib dosing on an outpatient basis and recorded in a Subject Diary

Template version 1.0

Page 4

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 1.

Schedule of Tests and Procedures

Observation
Screening

Within14 Days
Predosing

h.
i.
j.
k.
l.
m.

n.
o.

p.
q.

Cycle 1 (Days ± Acceptable range)aDay 1(Predosing)- 4 days

Cycle 2-4 (Days± Acceptable
Range) a

Day 8

Day 15

Day 22

Day 1

Day 15

±4
Days

±4
Days

±4
Days

±4
Days

±4
Days

Cycle 5 or
Latera(Days ±
Acceptable
Range)Day 1± 4 Days

Post Treatment (Days ± Acceptable
Range)At End of Treatment/
Discontinuationb+ 4 days

Follow Up
28 daysAfter Last
Dosec

during outpatient period, using blood pressure cuff provided by the sponsor for home monitoring. Subjects were instructed by the study staff totemporarily hold doses and contact their investigator immediately for guidance if their systolic blood pressure was elevated above 150 mm Hg, or
diastolic blood pressure was elevated above 100 mm Hg, or if they developed symptoms perceived to be related to elevated blood pressure (eg,headache, visual disturbance). If subjects were unable to contact their investigator for guidance, subjects were to restart dosing when systolic bloodpressure fell below 140 mm Hg and diastolic blood pressure fell below 90 mm Hg, and all symptoms related to elevated blood pressure wereresolved.
Red blood cell count (RBC), hemoglobin, hematocrit, white blood cell count (WBC) and differential, platelet count.
If the tests at screening were performed within 7 days prior to treatment period, the tests on Cycle 1 Day 1 were not repeated.
Prothrombin time (PT) and activated partial thromboplastin time (APTT).
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total protein,
albumin, calcium (Ca), sodium (Na), potassium (K), chloride (Cl), total birilubin, blood urea nitrogen (BUN), creatinine, and glucose.
Thyroid function test for Free-T3, Free-T4, and thyroid stimulating hormone (TSH) was performed at screening, Cycle 1 Day 1, Day 8, Day 15,
Day 22, Cycle 2 Day 1, Cycle 3 Day 1 and subsequently Day 1 of odd number cycles. Hypothyroidism was to be treated per standard medical
practice to maintain euthyroid state.
Urine protein, urine glucose, urine occult blood (quantitative or semiquantitative for all), and urinary sediment (urinary sediment was performed atscreening and only Day 1 of each cycle). If urinalysis (semiquantitative testing, eg, dipstick) showed 2+ proteinuria, a 24-hour urine collection was
to be performed. In urinary sediment, erythrocyte morphology, and RBC cast were observed by microscopy.
If urinalysis (semiquantitative testing, eg, dipstick) showed 2+ proteinuria, a 24-hour urine collection was to be performed; subjects with total
protein <2 g/24 hours could be enrolled.
Three consecutive 12-lead ECGs were performed approximately 2 minutes apart to determine mean QTc interval. The ECGs were performed atscreening, approximately 1 to 3 hours following a dose of axitinib on Cycle 1 Day 15, and at end of treatment (EOT)/discontinuation. If the mean
QTc interval was prolonged (>500 msec), then the results of ECG were to be re-read by a cardiologist at the site for confirmation. Additional ECGs
were performed as clinically indicated.
ECG at Cycle 1 Day 15 was performed 1 to 3 hours post-treatment.
Blood sampling for PK (population PK analysis) was conducted on Day 1 of Cycles 1, 3, 5, and 7. Blood samples were collected at 2 hours postdose(taken in clinic) in the morning on Day 1 of Cycle 1, and prior to the morning dose (taken in clinic) and 2 hours after a dose of axitinib on Day 1 of

Template version 1.0

Page 5

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 1.

Schedule of Tests and Procedures

Observation
Screening

Within14 Days
Predosing

r.

s.
t.
u.
v.
w.

x.
y.
z.

Cycle 1 (Days ± Acceptable range)aDay 1(Predosing)- 4 days

Cycle 2-4 (Days± Acceptable
Range) a

Day 8

Day 15

Day 22

Day 1

Day 15

±4
Days

±4
Days

±4
Days

±4
Days

±4
Days

Cycle 5 or
Latera(Days ±
Acceptable
Range)Day 1± 4 Days

Post Treatment (Days ± Acceptable
Range)At End of Treatment/
Discontinuationb+ 4 days

Follow Up
28 daysAfter Last
Dosec

Cycles 3, 5 and 7. If blood samples could not be collected for some reasons such as that the subject had inadvertently taken their morning dose prior
to arriving at hospital, or dose interruption/dose reduction had been performed during 3 days before blood collection, blood collection was to berescheduled to the next visit.
Only for the subjects undergoing dose titration on Cycle 1 Day 15 or later, 4-hour serial PK sampling was performed at the visit 5 days or more after
dose increase (the day prior to next dose increase). The collection time points for the 4-hour serial PK sampling were: predose (prior to the morning
dose taken in the clinic), 1, 2, 3 and 4 hours postdose. If 4-hour serial pharmacokinetic sampling was performed once at a particular dose, it was not
required to perform another 4-hour serial PK sampling when the subject received the same dose following dose increase.
Plasma concentrations of s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT, and VEGF were determined on Day 1 of each cycle until Cycle 7 and at
EOT/discontinuation.
Pregnancy test was conducted within 7 days prior to the initiation of treatment.
At a minimum, CT/MRI of the chest, abdomen and pelvis and bone scan were required at baseline.
If tumor assessments were performed within 28 days (42 days for Bone scintigraphy) before starting the study treatment, the results could be used as
the screening assessment.
Tumor assessments were done on Day 1 of odd number cycles following Cycle 3 Day 1 (acceptable range was 7 days). If baseline scan showed bonemetastases, bone scan was required every 8 weeks. If responses (CR/PR) were observed, all assessments (CT/MRI and bone scan) were to be
performed immediately after 4 weeks had passed since a response was first noted to confirm the response. If the confirmation assessments were
performed, subsequent tumor assessments could be rescheduled at even number cycles.
If subject discontinued study treatment without progressive disease (PD) in accordance with Response Evaluation Criteria in Solid Tumors(RECIST), tumor assessments were to be performed after 28 days from last dosing (acceptable range is 7 days). If subject started a new anticancer
treatment within 28 days from last dosing, this tumor assessment was not necessary.
If the symptoms related to brain metastases were clinically indicated, subsequent brain CT/MRI were to be performed.
Survival follow-up was performed at least every 6 months from EOT/discontinuation. All subjects were followed for survival until at least 3 years
after the last subject started the study treatment.

Template version 1.0

Page 6

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Number of Subjects (Planned and Analyzed): It was planned to enroll 63 subjects in the
study. Sixty-four (64) subjects were actually enrolled into the study. All 64 subjects wereenrolled in Japan and all were analyzed for efficacy and safety.
Diagnosis and Main Criteria for Inclusion: Male and female subjects aged 20 years andolder who were histologically diagnosed with mRCC with a component of clear cell cancer,
refractory to cytokine therapy as 1st line, had experienced nephrectomy, had at least 1 target
lesion, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) and who had
no uncontrolled hypertension were eligible for inclusion in this study. Subjects withgastrointestinal abnormalities, current use or anticipated inability to avoid potent CYP3A4
inhibitors or CYP1A2/3A4 inducers, active seizure disorder or evidence of brain metastases,
or with hemoptysis were excluded.
Study Treatment: The axitinib tablets were film-coated tablets that contained 1 mg or 5 mgof axitinib. The starting dose of axitinib was 5 mg BID administered orally with food.
Doses were to be taken as close to 12 hours apart as possible, and at approximately the sametime each day. One cycle was 28 days, and the treatment could be continued until the subject
met the discontinuation criteria.
Subjects who tolerated axitinib with no adverse events (AEs) related to axitinib above
Grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) for
consecutive 2-week periods could have their dose titrated to 7 mg BID and then to a
maximum of 10 mg BID unless systolic blood pressure (sBP) was >150 mmHg or diastolicblood pressure (dBP) was >90 mmHg, or the subject was receiving antihypertensive
medication. The dose could have been titrated every 2 weeks or longer interval. The clinicaljudgment of the treating physician was to be exercised regarding axitinib dose.
Efficacy, Safety and Pharmacodynamic Endpoints:
Primary EndpointObjective response rate (ORR)

Secondary Endpoints


PFS



TTP



DR



OS



Adverse events and abnormal change of laboratory test resultsPlasma concentration of s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT and VEGF

Template version 1.0

Page 7

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Safety Evaluations: Safety was assessed by monitoring AEs, and through laboratory test
results, blood pressure measurements, and electrocardiograms (ECGs).
Statistical Methods: The intent to treat (ITT) population was defined as all subjects
enrolled in the study who received at least 1 dose of study medication. This ITT population
was used for all efficacy and safety analyses.
In the analyses of ORR, PFS and TTP, subjects who had no baseline tumor assessment andwho had inadvertently enrolled in this study were to be excluded from analyses, and were
replaced with new subjects. The analyses of DR were conducted for all subjects whoachieved complete response (CR) or partial response (PR).
ORR was estimated with a 2-sided 95% confidence interval (CI) using the exact method
based on F distribution. PFS, TTP, DR and OS were summarized using the Kaplan-Meiermethod. Median and 95% CI for each of the durations were calculated using the method of
Brookmeyer and Crowley. The primary analyses of ORR, PFS, TTP and DR were based on
the Independent Review Committee (IRC) assessments, and the investigator assessments
were used for secondary analyses.
If a subject received subsequent therapy after discontinuation of study treatment, the datacollected after initiation of subsequent therapy was not used for efficacy analysis (except forOS).
Plasma concentrations of s-VEGFR1, s-VEGFR2, s-VEGFR3, s-KIT, and VEGF weresummarized using descriptive statistics.
RESULTSThe results presented here are based on data at the time of study completion (LSLV:
09 August 2013).
Subject Disposition and Demography: A total of 64 subjects were enrolled and treatedwith axitinib. The majority of subjects (59 subjects, 92.2%) out of 64 subjects who weretreated with axitinib discontinued the study. The commonest reason for discontinuation was“objective progression or relapse” in 42 subjects (65.6%), followed by “treatment-relatedAEs” in 16 subjects (25.0%). After the 3-year OS observation period (ie, end of study),
5 subjects who were still on the study were prescribed axitinib off-study. These 5 subjects
were recorded to have completed the study. Subject disposition is shown in Table 2.

Template version 1.0

Page 8

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 2.

Subject Disposition

Subject Category
Number of Subjects (%)
Assigned to study treatment
TreatedReplaced
Completed
Discontinued
Reason for discontinuation
Related to study drug
Adverse event
Not related to study drug
Global deterioration of health status
Objective progression or relapse

Axitinib64
64
0
5 (7.8)59 (92.2)
16 (25.0)
16 (25.0)
43 (67.2)
1 (1.6)42 (65.6)

Demographic characteristics are summarized in Table 3.

Template version 1.0

Page 9Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 3.

Demographic Characteristics
Male
44

Number (%) of subjects
Age (years)
<18
0
18-44
4
45-64
21
19
65
Mean
62.1
SD
11
Range
37-80
Race
Asian
44
Weight (kg)
Mean
66.8
SD
11.8
Range
47.7-105.4
N
44
Height (cm)
Mean
166.3
SD
5.9
Range
152.5-178.0
N
44
Smoking
Never smoked
6
Smoker5
Ex-smoker
33
AllergyYes
7No37
N = number of evaluable subjects; SD = standard deviation.

Template version 1.0

Page 10

Axitinib
Female
20

Total
64

0
2
9
9
61
10.7
34-77

0
6
30
28
61.8
10.8
34-80

20

64

53.1
8.7
37.0-72.0
20

62.5
12.6
37.0-105.4
64

152.8
6.7
139.2-165.0
20

162.1
8.8
139.2-178.0
64

16
0
4

22
5
37

3
17

10
54

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

All 64 subjects were analyzed for efficacy and safety.
Efficacy and Pharmacodynamic Results:
Primary Endpoint: According to the IRC assessment, no subject had a CR, 33/64 subjects(51.6%) had a PR including 1 subject who had a response after the primary analysis; theoverall ORR was 51.6% (95% CI: 38.7 % to 64.2%). Among the non-responders,
28 subjects (43.8%) had a best response of stable disease (SD), 1 subject (1.6%) had a best
response of PD, and 2 subjects (3.1%) were indeterminate (no on-study disease assessment).
Best overall response is given in Table 4.
Table 4.

Best Overall Response (Independent Review Committee Assessment)

Number of Subjects (%)
Complete response (CR)
Partial response (PR)
Stable/No response
Objective progression
Symptomatic deterioration
Early deathIndeterminate
Objective response rate (CR+PR)
95% CIa
CI = confidence interval; N = total number of subjects.
a.
Using exact method based on binomial distribution.

Axitinib
N = 64033 (51.6)
28 (43.8)
1 (1.6)00
2 (3.1)33 (51.6)[38.7, 64.2]

According to Investigator-assessment, no subject had a CR, 36/64 subjects (56.3%) had a PR
including 1 subject who had a response after the primary analysis; the overall ORR was
56.3% (95% CI: 43.3% to 68.6%). Among the non-responders, 25 subjects (39.1%) had abest response of SD, 1 subject (1.6%) had a best response of PD, and 2 subjects (3.1%) wereindeterminate (no on-study disease assessment).
Secondary Endpoints:
Progression-Free Survival (PFS)At the study completion, there were 48 events among 64 subjects according to the
IRC-assessment and the median PFS was 11 months (95% CI: 9.2 to 12.0 months). All theevents were PD. A similar result was obtained based on the Investigator-assessment. The
Kaplan-Meier plot for PFS is shown in Figure 1.

Template version 1.0

Page 11

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Figure 1. Kaplan-Meier Plot of Progression-Free Survival (Independent Review
Committee Assessment)

Time to Progression (TTP)The TTP outcome was identical to the PFS outcome since no subject died prior toexperiencing PD.
Duration of Objective Response (DR)Of the 33 subjects with a response (confirmed PR) according to the IRC-assessment,
25 subjects (75.8%) subsequently progressed. The median DR was 11.1 months (95% CI:
8.2 to 13.7 months). Of the 36 subjects with a response according to the Investigatorassessment, 30 subjects (83.3%) subsequently progressed; the median DR was 12.8 months(95% CI: 7.7 to 17.5 months).
Overall Survival (OS)A total of 43 deaths (67.2%) were reported at the study completion. All deaths were due todisease under the study. Survival probability at Month 12, Month 24, Month 36, andMonth 48 were 92.1%, 68.3%, 55.6%, and 41.3%, respectively. The median OS was
37.3 months (95% CI: 28.6 to 49.9 months).
The summary of OS is shown in Table 5. The Kaplan-Meier plot for OS is shown in
Figure 2.

Template version 1.0

Page 12

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 5.

Overall Survival
Axitinib
N=64
43 (67.2)

Number of deaths n (%)
Cause of death n (%)
Disease under study

43 (67.2)

Number censoredn (%)
Reason for censorship n (%)
Alive
Lost to follow-up

21 (32.8)
20 (31.3)
1 (1.6)

Survival probability at Month 6 a (95% CI b)
Survival probability at Month 12 a (95% CI b)
Survival probability at Month 24 a (95% CI b)
Survival probability at Month 36 a (95% CI b)
Survival probability at Month 48 a (95% CI b)

98.4 (89.4, 99.8)
92.1 (82.1, 96.6)
68.3 (55.3, 78.3)
55.6 (42.5, 66.8)
41.3 (29.1, 53.1)

Kaplan-Meier Estimates of time to event (Month)
Quartiles (95% CI) c
25%
19.4 (14.6, 27.8)
50%
37.3 (28.6, 49.9)
75%
NE (51.2, NE )CI = confidence interval; N =total number of subjects; n = number of subject; NE = not estimable.
a.
Estimated from the Kaplan-Meier curveb.
Calculated from the product-limit methodc.
Based on the Brookmeyer and Crowley Method

Template version 1.0

Page 13

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Figure 2. Kaplan-Meier Plot of Overall Survival

Pharmacodynamic results: Soluble protein plasma concentration percent change from
Cycle 1 up to the end of study is presented in Table 6.
A decrease in median s-VEGFR1 was observed throughout the study with median percent
change from Cycle 1 Day 1 of -12.78% to -30.95% (up to Cycle 7). The degree of change
was smaller at end of treatment (EOT)/discontinuation compared to other visits with themedian percent change of -9.75%.
A decrease in median s-VEGFR2 was observed throughout the study with median percent
change from Cycle 1 Day 1 of -32.90% to -41.19% (up to Cycle 7). The degree of change
was smaller at EOT/discontinuation compared to other visits with the median percent changeof -27.18%.
A decrease in median s-VEGFR3 was observed throughout the study with median percent
change from Cycle 1 Day 1 of -23.76% to -39.71% (up to Cycle 7). Increased medianpercent change of 5.37% from Cycle 1 Day 1 was observed at EOT/discontinuation.
The largest decrease in median s-KIT was observed at Cycle 2 Day 1, then a trend to revert
to the baseline was observed and the median percent change was 3.49% at Cycle 7 Day 1 and
0.24% at EOT/discontinuation. An increase in median VEGF-A was observed throughout
the study with median percent change from Cycle 1 Day 1 of 80.89% to 166.85% (up to
Cycle 7). The degree of change was smaller at EOT/discontinuation compared to other visitswith the median percent change of 54.00%.

Template version 1.0

Page 14

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 6.

Soluble Protein Plasma Concentration Percent Change From Cycle 1
Day 1
Axitinib
Percent Change From Baseline
Median (Minimum, Maximum)–-26.41 (-100.0, 23.4)-24.48 (-61.8, 507.8)-12.78 (-70.5, 90.6)-22.67 (-100.0, 101.6)-29.27 (-65.1, 48.9)-30.95 (-100.0, 29.2)-9.75 (-100.0, 1705.2)

Soluble Proteins-VEGFR1

Visit/Day
Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3 Day 1
Cycle 4 Day 1
Cycle 5 Day 1
Cycle 6 Day 1
Cycle 7 Day 1
At EOT/Discon

n
64
63
60
59
57
52
48
55

s-VEGFR2

Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3 Day 1
Cycle 4 Day 1
Cycle 5 Day 1
Cycle 6 Day 1
Cycle 7 Day 1
At EOT/Discon

64
63
60
59
57
52
48
55

–
-33.50 (-71.6, 92.7)-32.90 (-68.4, 92.7)-34.81 (-61.5, 149.4)-35.39 (-63.4, 261.8)-38.89 (-71.5, 225.6)-41.19 (-60.7, 296.9)-27.18 (-64.3, 165.6)

s-VEGFR3

Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3 Day 1
Cycle 4 Day 1
Cycle 5 Day 1
Cycle 6 Day 1
Cycle 7 Day 1
At EOT/Discon

64
63
60
59
57
52
48
55

–
-39.69 (-80.8, 2.5)
-39.71 (-76.8, 66.5)-25.63 (-100.0, 65.7)-23.76 (-100.0, 54.8)-25.92 (-83.0, 109.0)-35.75 (-100.0, 51.1)
5.37 (-100.0, 240.0)

s-KIT

Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3 Day 1
Cycle 4 Day 1
Cycle 5 Day 1
Cycle 6 Day 1
Cycle 7 Day 1
At EOT/Discon

64
63
60
59
57
52
48
55

–
-12.10 (-38.7, 28.5)-8.10 (-39.8, 25.1)-9.20 (-43.2, 30.8)-2.20 (-37.4, 48.1)-1.15 (-43.5, 44.0)
3.49 (-23.1, 65.3)
0.24 (-41.1, 63.3)

VEGF-A

Cycle 1 Day 1
64–
Cycle 2 Day 1
63
117.89 (-66.6, 996.8)
Cycle 3 Day 1
60
91.81 (-54.2, 634.0)
Cycle 4 Day 1
59
80.89 (-48.6, 656.0)
Cycle 5 Day 1
57
114.89 (-66.0, 825.7)
Cycle 6 Day 1
52
141.56 (-69.2, 900.0)
Cycle 7 Day 1
48
166.85 (-39.7, 1163.8)
At EOT/Discon
55
54.00 (-89.7, 415.6)
discon = study discontinuation; EOT = end of treatment; n = number of subjects with the given soluble protein
at each visit; s-KIT = soluble stem cell factor receptor; s-VEGFR = soluble vascular endothelial growth factor
receptor; VEGF-A = vascular endothelial growth factor A.

Template version 1.0

Page 15

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Safety Results:
Treatment emergent AEs (all causalities and treatment related) are shown in Table 7.
Table 7.

Treatment Emergent Adverse Events Occurring in ≥5% of Subjects by
System Organ Class and Preferred Terma

Number (%) of Subjects With Adverse Events by:
System Organ Class
and MedDRA Preferred Term
At least 1 adverse event
Any AEs
Blood and lymphatic system disorders
Anaemia
Ear and labyrinth disorders
Tinnitus
Endocrine disorders
Hypothyroidism
Gastrointestinal disorders
Abdominal pain
Abdominal pain upper
Cheilitis
Constipation
Dental caries
Diarrhoea
Dyspepsia
Gastritis
Haemorrhoids
NauseaStomatitis
Vomiting
General disorders and administration site conditions
Chest pain
Face oedema
Fatigue
Malaise
Mucosal inflammation
OedemaOedema peripheral
Pyrexia
Hepatobiliary disorders
Hepatic function abnormal
Infections and infestations
Cystitis
Gastroenteritis
Gingivitis
Herpes zoster
Nasopharyngitis
Periodontitis
Injury, poisoning and procedural complications
Fall
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased

Template version 1.0

Page 16

Axitinib (N=64)
All-Causality
TreatmentRelated
All Cycles
All Cycles
64 (100)
63 (98.4)
64 (100)
63 (98.4)
10 (15.6)
7 (10.9)5 (7.8)2 (3.1)
12 (18.8)
12 (18.8)
5 (7.8)4 (6.3)31 (48.4)
31 (48.4)
31 (48.4)
31 (48.4)
59 (92.2)
56 (87.5)
9 (14.1)
9 (14.1)
9 (14.1)
7 (10.9)6 (9.4)5 (7.8)14 (21.9)
10 (15.6)
5 (7.8)3 (4.7)44 (68.8)
42 (65.6)
5 (7.8)5 (7.8)6 (9.4)5 (7.8)4(6.3)
2(3.1)
22 (34.4)
18 (28.1)
15 (23.4)
15 (23.4)
14 (21.9)
12 (18.8)
49 (76.6)
48 (75.0)
10 (15.6)
9 (14.1)
4 (6.3)3 (4.7)36 (56.3)
36 (56.3)
10 (15.6)
9 (14.1)
4 (6.3)4 (6.3)6 (9.4)5 (7.8)7 (10.9)6 (9.4)10 (15.6)
5 (7.8)14 (21.9)
11 (17.2)
8 (12.5)
7 (10.9)
43 (67.2)
24 (37.5)
4 (6.3)
1 (1.6)4 (6.3)2 (3.1)4 (6.3)2 (3.1)4 (6.3)3 (4.7)25 (39.1)
5 (7.8)9 (14.1)
9 (14.1)
11 (17.2)
3 (4.7)6 (9.4)
1 (1.6)48 (75.0)
46 (71.9)
15 (23.4)
15 (23.4)
15 (23.4)
15 (23.4)

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 7.

Treatment Emergent Adverse Events Occurring in ≥5% of Subjects by
System Organ Class and Preferred Terma

Number (%) of Subjects With Adverse Events by:
System Organ Class
and MedDRA Preferred Term
Blood albumin decreased
Blood alkaline phosphatase increased
Blood creatinine increased
Blood lactate dehydrogenase increased
Blood thyroid stimulating hormone decreased
Blood thyroid stimulating hormone increased
Blood urea increased
Blood urine present
C-reactive protein increased
Haemoglobin decreased
Neutrophil count decreased
Platelet count decreased
Protein urine
Weight decreased
Metabolism and nutrition disorders
Decreased appetite
Hyperlipidaemia
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain
Musculoskeletal pain
Musculoskeletal stiffness
Myalgia
Neck pain
Nervous system disorders
Dizziness
Dysgeusia
HeadacheHypoaesthesia
Psychiatric disorders
Insomnia
Renal and urinary disorders
Proteinuria
Respiratory, thoracic and mediastinal disorders
Cough
Dysphonia
Epistaxis
Oropharyngeal pain
Upper respiratory tract inflammation
Skin and subcutaneous tissue disorders
Alopecia
Hyperkeratosis
Palmar-plantar erythrodysaesthesia syndrome
Pruritus
Rash
Vascular disorders
Hypertension

Template version 1.0

Page 17

Axitinib (N=64)
All-Causality
TreatmentRelated
All Cycles
All Cycles
7 (10.9)6 (9.4)13 (20.3)
12 (8.8)5 (7.8)5 (7.8)8 (12.5)
7 (10.9)4 (6.3)4 (6.3)21 (32.8)
21 (32.8)
6 (9.4)6 (9.4)5 (7.8)4 (6.3)7 (10.9)2 (3.1)5 (7.8)4 (6.3)4 (6.3)4 (6.3)8 (12.5)
7 (10.9)5 (7.8)5 (7.8)21 (32.8)
20 (31.3)
31 (48.4)
30 (46.9)
27 (42.2)
26 (40.6)
6 (9.4)5 (7.8)40 (62.5)
27 (42.2)
15 (23.4)
13 (20.3)
13 (20.3)
7 (10.9)9 (14.1)
6 (9.4)5 (7.8)4 (6.3)4 (6.3)3 (4.7)5 (7.8)4 (6.3)32 (50.0)29 (45.3)
7 (10.9)6 (9.4)12 (18.8)
12 (18.8)
18 (28.1)
16 (25.0)
5 (7.8)4 (6.3)6 (9.4)3 (4.7)4 (6.3)2 (3.1)35 (54.7)
35 (54.7)
33 (51.6)
33 (51.6)
49 (76.6)
46 (71.9)
14 (21.9)9 (14.1)
34 (53.1)
34 (53.1)
17 (26.6)
16 (25.0)
9 (14.1)
7 (10.9)4 (6.3)2 (3.1)55 (85.9)
53 (82.8)
5 (7.8)5 (7.8)4 (6.3)4 (6.3)48 (75.0)
48 (75.0)
6 (9.4)5 (7.8)17 (26.6)
13 (20.3)
56 (87.5)
56 (87.5)
56 (87.5)
56 (87.5)

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 7.

Treatment Emergent Adverse Events Occurring in ≥5% of Subjects by
System Organ Class and Preferred Terma

Number (%) of Subjects With Adverse Events by:
System Organ Class
and MedDRA Preferred Term

Axitinib (N=64)
All-Causality
TreatmentRelated
All Cycles
All Cycles

Adverse events and serious adverse events are not separated out.
MedDRA = Medical Dictionary for Regulatory Activities; N = number of subjects assessed.
a.
According to incidence of all-causality adverse events in all cycles.

Treatment emergent serious adverse events (all causality and treatment related) are shown in
Table 8.

Template version 1.0

Page 18

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 8.

Treatment Emergent Serious Adverse Events

3

M/73
M/61
M/62
M/56

4

M/64

5

F/75

6

F/62

Dose at
Onset of
b
AE
5 mg
5 mg
5 mg
5 mg
3 mg
3 mg
5 mg
5 mg
5 mg
5 mg
3 mg
2 mg
2 mg
0 mg

7

M/60

5 mg

8
9

F/65
F/46

3 mg
0 mg

10

M/77

0 mg

Serial
No.
1
2

11
12
13

Sex/
a
Age

M/37
M/50
M/43

2 mg
5 mg
5 mg
5 mg
5 mg
5 mg

14

M/67

2 mg

15

F/64
F/65
F/68

3 mg
2 mg
2 mg

M/39
F/68

10 mg
5 mg

16
17

5 mg
18

M/50
M/51

3 mg
3 mg
3 mg
3 mg

19
20

M/62
M/64

3 mg
0 mg

M/55

5 mg

Template version 1.0

Adverse Event
Event
c
d
MedDRA version Grade Onset Causality
16.0 Preferred TermDay
Cholecystitis
3
40 Not related
Dehydration
2
42
RelatedPneumothorax
2365
RelatedProteinuria
2
71
Related
Decreased appetite
3
124
RelatedMalaise3
124
RelatedDiarrhoea
2251
RelatedVomiting
2
252
Related
Dehydration
3
253
RelatedDiarrhoea
3189
RelatedBalance disorder
3299
Related
Peptic ulcer
3319
Related
Duodenal stenosis
3
340
RelatedAnaphylactic
31401 Not relatedereaction
Myocardial
41160
RelatedeInfarction
Hyponatraemia
3114
Relatede31220 Not related
DiverticulitishStudy Drug
ActionOutcome

Temporarily withdrawn
Temporarily withdrawn
Temporarily withdrawn
Temporarily withdrawn
Permanently withdrawn
Permanently withdrawn
Temporarily withdrawn
Temporarily withdrawn
Temporarily withdrawn
Dose reduced
Dose reduced
Temporarily withdrawn
Temporarily withdrawn
Post-therapyfResolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved
Resolved

Permanently withdrawn

Resolving

Dose not changedgResolved
Resolved

i

Fatal

i

Fatal

Post-therapy

564

Not related

564

Not related

2
4
3

136
692
698

RelatedTemporarily withdrawn
Not related Temporarily withdrawn
Not related Temporarily withdrawn

4
3
2
2

7

RelatedPermanently withdrawn

Resolving

13

RelatedPermanently withdrawn

Resolving1

13

RelatedPermanently withdrawn

Resolving2753

Not related Temporarily withdrawn

Resolved

3
3
2

113
Related
Dose not changed
450
Related
Dose not changed
1461 Not related Temporarily withdrawn

Resolved
Resolved
Resolved

2
2

312
144

RelatedRelatedTemporarily withdrawn
Temporarily withdrawn

Resolved
Resolved

3

144

RelatedTemporarily withdrawn

Resolved

3
2

401
813

Not related Temporarily withdrawn
RelatedTemporarily withdrawn

Resolved
Resolved

Renal failure acute ,3821

Not related Temporarily withdrawn

Resolved

Vomiting
Angina unstable2819

Temporarily withdrawn

Resolved

3

621
RelatedTemporarily withdrawnm1208 Not related
Post-therapy
152
RelatedTemporarily withdrawn

Resolved
Resolved

Disease progression
Renal cellhcarcinoma
Pneumonia
AppendicitiseBile duct stone
Hypertension

Subarachnoid
haemorrhage
Posterior reversible
encephalopathyjsyndromeePneumonia
Cryptococcosis
HypertensionePyelonephritis
Haemoptysis
Gastrointestinal
haemorrhage
Loss ofconsciousness
Duodenal ulcereDiarrhoea

ek

e

el

Angina unstable
Gastroenteritis

3

Page 19

RelatedPost-therapy
Post-therapy

Resolving
Resolved
Resolved

ResolvedPublic Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 8.
Serial
No.

Sex/
a
Age
M/56

21

M/60

22

M/61

Treatment Emergent Serious Adverse Events
Dose atAdverse Event
Event
Study DrugcdOnset of
MedDRA version Grade Onset Causality
Actionb
16.0 Preferred Term
Day
AE
5 mg
Upper
3
356
RelatedTemporarily withdrawn
gastrointestinal
haemorrhage
7 mg
Acute myocardial
4
528
RelatedTemporarily withdrawneinfarction
3 mg
Hyperthyroidism
4
142
RelatedPermanently withdrawn

OutcomeResolved
Resolved
Resolved

AE = adverse event; F = female; M = male; MedDRA = Medical Dictionary for Regulatory Activities;
No. = Number.
a.
Age at adverse event onset.
b.
Dose per administration at onset or the last dose prior to the onset of AE.
c.
According to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
d.
Investigator causality.
e.
Newly reported after the primary analysis.
f.
Therapy was stopped on Day 1400.
g.
Therapy was stopped on Study Day 1176.
h.
Single event term “disease progression” was entered in the project database.
i.
Therapy was stopped on Study Day 62.
j.
This event was entered as “Leukoencephalopathy” in the project database.
k.
Reported as “renal failure” in the project database.
l.
Angina was initially entered as non-serious in the project database. After the active reporting period,ie, >28 days after the last study drug administration, the angina became serious and it was entered asserious into the safety database only.
m.
Therapy was stopped on Study Day 1149.

A total of 41 SAEs were reported in 22 subjects. A total of 30 SAEs reported in 16 subjects
were considered treatment-related. SAEs that were reported in >1 subject included diarrhea,
hypertension, dehydration, and vomiting. One death due to disease progression was reported
and was not-related to the study drug.
Discontinuations due to AEs are presented in Table 9. A total of 16 subjects (25.0%)
discontinued the study due to AEs. Protein in urine (Medical Dictionary for Regulatory
Activities [MedDRA] term: proteinuria [7 subjects], protein urine [1 subject], protein urinepresent [1 subject]) was the most common AE leading to study discontinuation and wasreported in 9 subjects (14.1%). Other AEs that resulted in discontinuation werepolycythaemia, malaise, myocardial infarction, subarachnoid hemorrhage, anxiety, weightdecreased, and hyperthyroidism (each reported in 1 subject).

Template version 1.0

Page 20

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

Table 9.
Serial
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Discontinuations Due to Adverse Events
Adverse Events
MedDRA
Version 16.0

Sex/Age
M/64
M/56
M/60
M/70
F/54
M/74
M/57
M/65
M/43
M/63
M/77
M/79
M/72
F/61
M/79
M/61

Polycythaemia
MalaiseProteinuria
Protein urine present
Proteinuria
Protein urine
Myocardial infarction
Proteinuria
Subarachnoid haemorrhage
Proteinuria
Anxiety
Weight decreased
Proteinuria
Proteinuria
Proteinuria
Hyperthyroidism

Cycle (Day)Start/Stop

Study Day
Start/Stop a

Cycle 1 (15)/ 2 (7)Cycle 5 (12)/ 5 (19)Cycle 9 (15)/ Follow-up (2)Cycle 6 (18)/ 6 (29)
Cycle 2 (1)/ Follow-up (2)Cycle 1 (8)/ 8 (50)
Cycle 42 (33)/ Follow-up(12)
Cycle 1 (22)/ 15 (29)
Cycle 1 (13)/ 1 (34)
Cycle 42 (1)/ Follow-up (1)Cycle 1 (15)/ Follow-up (20)Cycle 4 (1)/ Follow-up (10)Cycle 1 (8)/ 5 (15)Cycle 2 (14)/ 2 (36)
Cycle 1 (22)/ 7 (19)Cycle 6 (2)/ 6 (14)15/35
124/131239/(>645)
158/169
29/141
8/(>246)

2
3
2
3
2
2

RelatedRelatedRelatedRelatedRelatedRelated1181/(>1198)
22/(>421)
13/(>34)
1148/(>1372)
15/(>79)
85/(>155)
8/(>127)
42/64
22/187142/154

2
2
2
2
2
2
2
3
2
4

RelatedRelatedRelatedRelatedRelatedRelatedRelatedRelatedRelatedRelated

Grade Causality

F = female; M = male; No. = number; MedDRA = Medical Dictionary for Regulatory Activities.
a.
Day relative to start of study treatment. First day of study treatment = Day 1.

Nine (9) subjects (14.1%) had a dose reduction without temporary discontinuation due to
AEs and 58 subjects (90.6%) had both dose reductions and temporary discontinuations or
temporarily discontinuations only due to AEs
One death due to disease progression was reported and was not-related to the study drug.
A total of 62 subjects (97%) had 1 postdose abnormal laboratory test value regardless of thebaseline abnormality. The most commonly reported laboratory abnormalities were thyroid
stimulating hormone (TSH) increased >1.2 × upper limit of normal (ULN) (54 subjects,84%) and urine protein (41 subjects, 64%). Both increases and decreases in TSH were
measured in some subjects during the study treatment.
CONCLUSIONS:

No subject had CR, 33/64 subjects (51.6%) had a PR, and the overall ORR based on IRC
assessment was 51.6% (95% CI: 38.7 % to 64.2%). The ORR based on Investigatorassessment was 56.3% (05% CI: 43.3% to 68.6%).

The median PFS was 11 months (95% CI: 9.2 to 12.0 months). A total of 43 deaths(67.2%) were reported at the study completion. All deaths were due to disease under the
study. Survival probability at Month 12, Month 24, Month 36, and Month 48 were
92.1%, 68.3%, 55.6%, and 41.3%, respectively. The median OS was 37.3 months (95%
CI: 28.6 to 49.9 months).



The most commonly-reported all-causality adverse events (≥50%) were hypertension,palmar-plantar erythrodysaesthesia syndrome, diarrhoea, and dysphonia. In general,treatment-emergent adverse events were clinically manageable with no unexpectedTemplate version 1.0

Page 21

Public Disclosure Synopsis
Protocol – A4061035 – 12 June 2019 - Final

toxicities. There was no apparent increase of toxicity in subjects who underwent dose
titration above a starting dose of 5 mg BID; however, the number of subjects who
underwent dose titration was limited (7.8%).


Elevation of TSH (with/without transient decrease) was frequently observed.

Proteinuria was the most common adverse event leading to treatment discontinuation.

Axitinib decreased s-VEGFR1, s-VEGFR2, s-VEGFR3, increased VEGF, and had little
effect on s-KIT concentrations.



Exploratory analysis suggested subjects with a larger degree of decrease in s-VEGFR2
were likely to show a higher ORR, longer PFS and longer OS. Also, subjects withdiastolic BP 90 mmHg showed longer OS than subjects with diastolic BP <90 mmHg
after Cycle 1 Day 1 to Cycle 2 Day 1.

Template version 1.0

Page 22