Clinical trial NCT02133742
Conditions: Renal Cell Carcinoma
Keywords: Axitinib and MK-3475 patients with advanced Renal Cell Cancer.
Sponsor: Pfizer
Start date: 2014-09-16; Completion date: 2019-07-03
Enrollment: 52 participants; Allocation: NA; Intervention model: 

Brief summary:
Despite substantial improvements of patients outcome in advanced RCC, durable and complete response is uncommon. The majority of patients eventually develop resistance and exhibit disease progression. Combining a PD-1 inhibitor, which has shown single-agent efficacy with axitinib may provide additional clinical benefit compared to axitinib alone.

Detailed description:

Arms: arm 1: To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose
Interventions: intervention 1: Axitinib intervention 2: MK-3475
Intervention descriptions: intervention 1: Axitinib at starting dose of 5 mg and 3 mg BID. intervention 2: MK-3475 with two dose levels: 2 mg/kg every three weeks to find the maximum tolerated dose and continue treatment in a dose expansion phase.

Protocol documents:
Prot_002.pdf: 
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CLINICAL PROTOCOL
A PHASE 1B, OPEN LABEL, DOSE FINDING STUDY TO EVALUATE SAFETY, 
PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) 
IN COMBINATION WITH PEMBROLIZUMAB (MK-3475) IN PATIENTS WITH 
ADVANCED RENAL CELL CANCER
Compounds:
AG-013736, MK-3475
Compound Names:
Axitinib, MK-3475
US IND Numbers:
Protocol Number:
A4061079
Phase:
1b
CCI


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Document History
Document
Version Date
Summary of Changes
Amendment 2
03 April 2018
Removed most of the efficacy assessments after 
completing collection of data for the primary and 
most secondary endpoints (see Appendix 6).
Administrative changes to sections such as 
banked biospecimens, adverse events, drug 
storage, and patient informed consent to align 
with latest Pfizer protocol template.
Further clarified dose modification sections and 
updated with new MK-3475 safety and 
management of toxicities guidelines.
Amendment 1
18 March 2015
Changed dose level -1 to axitinib 3 mg bid and 
MK-3475 to 2 mg/kg every 3 weeks to allow 
testing a lower dose level of axitinib while 
MK-3475 dose remains at 2 mg/kg.
Updated the protocol with new MK-3475 safety 
and management of toxicities guidelines.
Updated the protocol template with the updated 
Pfizer protocol template language.
Corrected typographical errors and improved 
consistency across the document.
Original protocol
20 March 2014
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs). 


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PROTOCOL SUMMARY
Background and Rationale:
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of 
all malignant tumors in adults.1  Until 2005, interferon-alpha (IFN-) and high-dose 
interleukin (IL)-2 therapies were the standard of care for patients with advanced RCC 
(aRCC), albeit with modest efficacy.  Since then, development and approval of multiple 
vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) 
inhibitors have significantly improved the outcomes of aRCC patients. These agents include 
the VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib 
and sorafenib; the mTOR inhibitors temsirolimus and everolimus, and the anti-VEGF 
monoclonal antibody bevacizumab. However, despite the substantial improvement of patient 
outcomes with these agents, durable and complete response in aRCC patents are uncommon; 
the majority of patients will eventually develop resistance exhibit disease progression while 
on therapy and succumb to death due to metastatic disease.
There is a strong rationale for considering immunotherapy in aRCC patients.  Cytokine-based 
immunotherapy, especially high-dose IL-2, exhibited durable responses in some aRCC 
patients. There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration in tumor tissues.2 These reports have 
generated considerable interest in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune-check point inhibitors such as anti-PD1 and 
anti-PD L1 antibodies in recent years. Upregulation of programmed death-1 (PD-1) receptor 
on tumor-infiltrating lymphocytes (TILs), and its ligand PD-L1 on tumors, are associated 
with more aggressive disease and poor prognosis.3,4
Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for aRCC 
which has shown single-agent efficacy in patients whose disease has progressed following 
VEGF pathway inhibitor therapy.6,7  BMS-936558, also named nivolumab, is a fully 
humanized anti-PD-1 antibody (Bristol-Myers Squibb) that has shown anti-tumor activity in 
296 patients with solid cancers.5. Among these 296 patients, 33 patients had aRCC and were 
heavily pretreated before nivolumab therapy. Nivolumab was given at a starting dose of 
1 mg/kg and then expanded to 10 mg/kg.  The objective response rate (ORR) was 27% (9/33) 
and another 9 patients (27%) had stable disease at the 24-week follow-up time-point.  Five 
patients had durable response longer than 1 year.5  MK-3475 is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  It is proposed in this study 
that the addition of the PD-1 inhibitor, MK-3475, to the VEGF pathway inhibitor axitinib 
may provide additional clinical benefit compared to treatment with axitinib alone.
Antitumor activity of single agent axitinib in treatment-naïve patients with clear cell aRCC 
was assessed against sorafenib in a randomized, open-label, Phase 3 trial.  Although the 
study did not demonstrate a statistically significant difference in median PFS (mPFS) 
between patients treated with axitinib or sorafenib, axitinib was associated with a longer 
mPFS value {median PFS of 10.1 months (95% CI 7.2,12.1) with axitinib vs. 6.5 months 
(95% CI 4.7, 8.3) with sorafenib, stratified hazard ratio 0.77, (95% CI 0.56, 1.05)}.  The 


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mPFS observed with axitinib in this study was similar to that demonstrated earlier in Phase 3 
clinical trials with other approved VEGF TKIs in the first-line treatment of aRCC patients.8
Toxicities in this clinical trial were manageable and similar to those observed in clinical trials 
with axitinib in pre-treated aRCC patients.9
This data supports the testing of MK-3475 in combination with axitinib in the first-line 
treatment of aRCC patients. The primary objective of this study will be to assess the safety 
and tolerability of the combination regimen in previously untreated aRCC patients.  
Secondary objectives of this study will include the assessment of objective response rate 
(ORR) and duration of response (DR); progression-free survival (PFS); overall survival (OS) 
up to five years.  In addition, secondary objectives will also include pharmacokinetics (PK) 
of axitinib and MK-3475 when administered in combination and the effect of MK-3475 on 
the PK of axitinib and translational component.  Specifically, assessments in tumor and/or 
blood will include characterization of drug target pathways (eg, PD-L1), and gene expression 
profiles. 
Once the tolerability of the combination has been confirmed, a preliminary assessment of its 
antitumor activity will be conducted in an expansion cohort of aRCC patients in the first-line 
treatment setting. 
Study Objectives:
Primary Objective

To assess the safety and tolerability of axitinib in combination with MK-3475 in 
patients with previously untreated advanced RCC in order to estimate the maximum 
tolerated dose (MTD) and select the recommended Phase 2 dose (RP2D).
Secondary Objectives

To evaluate the overall safety profile of axitinib in combination with MK-3475.

To assess the anti-tumor activity of axitinib in combination with MK-3475 in patients 
with advanced RCC in the first-line treatment setting.

To characterize the pharmacokinetics (PK) of axitinib and axitinib plus MK-3475 
when administered in combination, and to assess the effect of MK-3475 on the PK of 
axitinib.

To characterize, using translational approaches, genes and proteins such as PD-L1, 
VEGF-A and IL-8 relevant to angiogenesis drug target pathway, renal cell carcinoma 
biology, and sensitivity/resistance mechanisms to axitinib in combination with 
MK-3475 in tumor and/or blood. 

To explore the pharmacodynamic effect of axitinib in combination with MK-3475 in 
blood and tumor by assessment of gene, RNAs and proteins including but not limited 
to VEGF-A, IL-8 and VEGFR2 and T-cell receptors.


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
To assess the immunogenicity of MK-3475.
Study Design:
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and pharmacodynamic 
study of axitinib in combination with MK-3475 in adult patients with previously untreated 
advanced RCC.  This clinical study will be composed of a Dose Finding Phase and a Dose 
Expansion Phase.  The Dose Finding Phase will estimate the MTD in patients with advanced 
RCC patients with clear cell histology who did not receive prior systemic therapy for the 
advanced disease, using the modified toxicity probability interval (mTPI) method.
The Dose Finding Phase will lead to the identification of an Expansion Test Dose for axitinib 
in combination with MK-3475 in patients with aRCC who did not receive prior systemic 
therapy.  The Expansion Test Dose will be either the MTD (ie, the highest dose of axitinib 
and MK-3475 associated with the occurrence of DLTs in <33% of patients) or the RP2D, 
ie, the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor.  
Once the Expansion Test Dose is identified, the Dose Expansion Phase will be opened and 
axitinib in combination with MK-3475 will be tested in patients with previously untreated 
aRCC. Approximately 60 patients (including Dose Finding Phase and Dose Expansion 
Phase) are expected to be enrolled in the study.
Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline, 
12 weeks, and every 6 weeks thereafter, using RECIST version 1.1.  In addition, radiological 
tumor assessments will also be conducted whenever disease progression is suspected (eg, 
symptomatic deterioration), and at the time of End of Treatment/Withdrawal (if not done in 
the previous 6 weeks).  Brain CT or MRI scans are required at baseline and when there is a 
suspected brain metastasis.  Bone scan (bone scintigraphy) or 18F-FDG-PET/CT is required 
at baseline then every 12 weeks only if bone metastases are present at baseline.  Otherwise 
bone imaging is required only if new bone metastases are suspected.  Bone imaging is also 
required at the time of confirmation of response for patients who have bone metastases. 
If radiologic imaging shows progressive disease (PD), tumor assessment should be repeated 
4 weeks later in order to confirm PD.  Assigned study treatment may be continued at the 
investigator’s discretion while awaiting radiologic confirmation of progression.  If PD is 
confirmed (Section 5.2.4.2.1) patients may be discontinued from study treatment.  However, 
if a patient with evidence of PD is still experiencing clinical benefit according to the 
investigator’s judgment, he/she may be eligible for continued treatment with one or both 
study drugs (after discussion between the investigator and the Sponsor).  The details of the 
criteria for study drug continuation in these patients are described in the Sections 3.1 and 
5.2.4.2.1.
Discontinuation from MK-3475 treatment may be considered at the investigator’s discretion 
for patients who have attained a confirmed CR, that have been treated for at least 24 weeks 
with MK-3475 and have received at least two treatments with MK-3475 beyond the date the 
initial CR was declared.  Axitinib may be continued in those patients.  Patients who then 
experience radiologic disease progression will be eligible for re-treatment with MK-3475 at 


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the discretion of the investigator if no cancer treatment was administered other than study 
drugs since the last dose of MK-3475, the patient meets the safety parameters listed in the 
Inclusion /Exclusion criteria and the trial is open.  Patients will resume therapy at the same 
dose and schedule at the time of initial discontinuation.  MK-3475 treatment will be 
administered for up to one additional year.
Patients will be monitored closely for toxicity and in the event of significant toxicity dosing 
may be delayed and/or reduced (Section 5.2.7).  Based on the known safety profile of 
axitinib, blood pressure as well as thyroid function will be monitored throughout the 
treatment period.  Based on data emerging from trials of VEGF tyrosine kinase inhibitors 
given in combination with PD-1 inhibitors, liver function tests will be monitored closely for 
the first 3 cycles.49  MK-3475 dose modification and supportive care for drug related 
toxicities, including immune-related adverse events (irAEs) Section 5.2.7.4.  Patients with 
unacceptable toxicity attributed to one of the two drugs may be eligible for continued 
treatment with the other drug (after discussion between the Investigator and the Sponsor).
Intra-patient dose escalation for axitinib is permitted only after completing 12 weeks of 
treatment if the starting dose of axitinib is 5 mg BID (DL1), and after 6 weeks if axitinib 
starting dose is 3 mg BID (DL-1) (Section 5.2.7).
MK-3475 and axitinib do not have competing elimination/metabolism pathways, hence an 
overt PK interaction between the two drugs is not anticipated.  However, pharmacokinetic 
assessments will be conducted in this study to confirm the absence of drug-drug interactions.  
To understand the PK effects of MK-3475 on axitinib, a 7-day lead-in period with 
single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose Finding 
Phase and in at least 8 patients in the Dose Expansion Phases of the study.  On the contrary, 
the administration of single agent MK-3475 to this patient population is not considered in 
this trial.  The effect of axitinib on MK-3475 will be evaluated by comparing MK-3475 
trough concentrations at steady-state in the presence of axitinib with those reported for 
MK-3475 alone in prior studies.  MK-3475 has a long half-life (21-28 days) and an increase 
in trough concentration over time is expected. 
Archived tumor biospecimens, and baseline de novo biospecimens from metastatic lesions 
will be collected for all patients in the dose expansion cohort.  Every effort will be made to 
obtain a second biopsy at the time of first tumor assessment at 12 weeks.  Biomarker studies 
on tumor and blood biospecimens will be carried out to help understand the mechanism of 
action of the axitinib plus MK-3475 combination, as well as potential mechanisms of 
resistance.  Such results may help in the future development of this combination.  Analyses 
using translational approaches may also result in the identification of potential biomarkers of 
response to the axitinib plus MK-3475 combination, ultimately leading to the development of 
a patient selection strategy for further clinical investigation.  As such, collection of tumor and 
blood biospecimens at baseline and on study will be of paramount importance.


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After the collection of data for the primary study objective and most of the secondary 
objectives has been completed, this study (A4061079) will remain open to give patients an 
opportunity to continue to receive study treatment as described in Section 3 of this protocol. 
Guidance on the management of patients who continue on study (ie, patients who are still 
clinically benefiting from study treatment without unacceptable toxicity or disease 
progression and who have not withdrawn consent) is provided to investigators in Appendix 6. 
Clinical assessments will be reduced in scope and the required schedule of activities will be 
revised to maintain only those assessments that protect the well-being of the patient.
Study Treatment:
Axitinib will be given orally (PO) twice daily (BID) on a continuous dosing schedule.  
MK-3475 will be given as 30-minute intravenous infusion every 3-weeks.  In all patients, 
treatment with study drugs will continue until confirmed disease progression, patient refusal, 
patient lost to follow up, unacceptable toxicity, whichever occurs first, or the study is 
terminated by the Sponsor (see Section 6.4, Patient Withdrawal). 
The treatment duration with MK-3475 is 24 months calculated from the date of the first dose 
of MK-3475.  Continuation of treatment with MK-3475 beyond 24 months should be 
discussed with the sponsor and not go beyond 36 months.  Patients who stop MK-3475 for 
reasons other than confirmed disease progression may continue on treatment with axitinib 
single agent until disease progression (RECIST v. 1.1), patient refusal, unacceptable toxicity 
or the study is prematurely terminated by the Sponsor; whichever comes first.
Statistical Methods:
Up-and-Down Design with the mTPI Method
The escalation/de-escalation rules will follow the modified toxicity probability interval 
(mTPI) method.  Briefly, the mTPI method relies upon a statistical probability algorithm, 
calculated using all patients treated in prior and current cohorts at the same dose level) to 
determine when future cohorts should involve dose escalation, no change in dose, or dose 
de-escalation.
Rules for dose finding, using the mTPI method, include the following:

The target enrollment cohort size is 3 patients.  The first 3 patients at each dose level 
will initiate dosing sequentially, at least 2 days apart, to allow for the initial 
evaluation of toxicities and tolerability.  If the first 2 patients experience a DLT prior 
to enrollment of the third, the dose level will be deemed intolerable the dose level will 
be de-escalated.  If there are no safety concerns, any additional patients enrolled to 
this dose cohort will not be required to initiate dosing sequentially.

The next cohort (target 3 patients) can be enrolled when all patients at the current 
dose cohort have been evaluated for 6 weeks (ie, the first two treatment cycles), or 
experience a DLT, whichever comes first.


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
If a patient withdraws from study treatment before receiving at least 75% of the 
planned first two cycles (6 weeks) doses of axitinib or two infusions of MK-3475 
within the DLT observation period for reasons other than study drug-related toxicity, 
another patient will be enrolled to replace that patient at the current dose level.

The dose-finding component of the trial is completed when at least 10 DLT-evaluable 
patients have been treated at the highest dose associated with a DLT rate <0.33.  It is 
estimated that approximately 20 DLT-evaluable patients will need to be enrolled to 
reach 10 DLT-evaluable patients at the estimated MTD.

The proposed doses, schedule and PK time points may be reconsidered and modified 
during the study based on the emerging safety and PK data.
Sample Size Determination
Due to the dynamic nature of the cohort allocation procedure used in this study, the sample 
size of the Up-and-Down design using the mTPI approach cannot be determined in advance.  
It is estimated that 20 DLT-evaluable patients will be enrolled in the Dose Finding Phase in 
order to have a reliable and accurate estimate of the MTD.  The expansion cohort will enroll 
up to 40 patients at the estimated MTD.  The sample size estimate for the expansion cohort 
takes into consideration the key tumor biomarker PD-L1 endpoints and historical data 
assuming 20% of RCC patients as tumor PD-L1 positive: if the observed rate of tumor 
PD-L1 positives patients is 20% then approximately 40 patients would be required to enroll 
8 PD-L1 tumor positive patients.
Dose Finding Criteria:
Dose escalation and de-escalation will follow an “Up-and-Down” design, using doses of 
MK-3475 and axitinib as shown in the Dose Levels in Dose Finding Phase Table 1. 
Dose Levels in Dose Finding Phase
Dose Level
MK-3475
Axitinib
1 (Starting Dose Level)
2 mg/kg IV q3wk
5 mg BID
-1
2 mg/kg IV q3wk
3 mg BID
BID: twice daily; q3wk: every 3 weeks
Dose level (DL) -1 will be explored only if the MTD is already exceeded at DL1. 
Alternative doses, schedule(s) and PK time points may be considered during the study based 
on the emerging safety and PK data. 


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table (SOA) provides an overview of the protocol visits and 
procedures.  Refer to STUDY PROCEDURES and ASSESSMENTS section of the protocol 
for detailed information on each assessment required for compliance with the protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities, in order to conduct evaluations or assessments required to protect the 
well-being of the patient.  Please refer to Appendix 6 for a revised Schedule of Activities 
associated with Amendment #2.


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SCHEDULE OF ACTIVITIES
Protocol Activities[1]
Screening
Lead-in
PK Period[2]
Study Treatment
(1 cycle = 21 days)
Post-Treatment
Cycle 1
Cycles 2
28 Days 
Prior to 
Registration
Day 1 
(2 days)
Day 7
Day 1
(3 days)
Day 5
(2 days)
Day 1
(3 days)
End of 
Treatment
/Withdrawal 
(3 days)[3]
Follow-up
Day 28 (+7 days) 
After Last Dose[4]
Documentation
Informed Consent[5]
X
Medical/Oncological History [6]
X
Baseline Signs/Symptoms[7]
X
(X)
Physical Examination [8]
X
X
X
X
ECOG Performance Status
X
X
X
X
X
In Clinic Blood Pressure, Pulse 
Rate[9]
X
X
X
X
X
X
Home Blood Pressure 
Monitoring [10]
X
X
Follow-up for Axitinib Dosing 
Compliance [11]
X
As needed based on 
axitinib dose 
modifications
Laboratory Studies
Hematology[12]
X
(X)
X
X
X
Blood Chemistry[12]
X
(X)
X
X
X
Coagulation[12]
X
(X)
X
X
X
Urinalysis[13]
X
(X)
X
X
X
12-lead ECG[14]
X
X
X
Thyroid Function Tests [15]
X
(X)
X
X
Pregnancy Test [16]
X
X
X
X
X
Disease Assessments


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Protocol Activities[1]
Screening
Lead-in
PK Period[2]
Study Treatment
(1 cycle = 21 days)
Post-Treatment
Cycle 1
Cycles 2
28 Days 
Prior to 
Registration
Day 1 
(2 days)
Day 7
Day 1
(3 days)
Day 5
(2 days)
Day 1
(3 days)
End of 
Treatment
/Withdrawal 
(3 days)[3]
Follow-up
Day 28 (+7 days) 
After Last Dose[4]
Tumor Assessments (including 
scans)[17]
X
X
(at 12 weeks and 
then every 6 weeks)
X
Other Clinical Assessments
Adverse Events[19]
X
Survival[18]
X
Concomitant 
Medications/Treatments[20]
X
(X)
X
X
X
X
X
Registration and Study 
Treatment [21]
MK-3475[22]
X[22]
X[22]
Axitinib[22]
X
Other Samplings
Pharmacokinetics[23]
X
X
X
X
(Cycles 3, 5, 7, 11 
and then q12w)
Serum Biomarkers[24]
X
X (Cycle 2 only)
X
Whole Blood Biomarkers[25]
X
X (Cycle 2 only)
X
Banked Biospecimen[26]
X
Archival Tumor Tissue27
X
De Novo Tumor 
Biospecimen[28]
X
X[28]
Anti-MK-3475 Antibodies[29]
X
X[29]
X[29]


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Footnotes for Schedule of Activities
1.
Protocol Activities: All assessments should be performed prior to dosing with study medications unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headings.  
2.
Lead-in PK Period: All patients in the Dose Finding Phase, and at least 8 patients in the Dose Expansion Phase. 
3.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessment which need not be repeated if 
performed within the prior 6 weeks.
4.
Follow-up Day 28 after last dose: To occur at least 28 days, and no more than 35 days, after discontinuation of treatment. See footnote 19 and
Section 8.1.1.
5.
Informed Consent: Must be obtained prior to undergoing any trial specific procedure.
6.
Medical/Oncological History: To include information on prior systemic adjuvant or neoadjuvant therapy regimens, surgery and radiation therapy.
7.
Baseline Signs/Symptoms: To be documented and recorded at Lead-in Day 1 or Cycle 1 Day 1 predose for all patients.
8.
Physical Examination: Includes an examination of major body systems, assessment of ECOG performance status, and weight (height included at screening 
only).
9.
In Clinic Blood pressure, pulse rate: Blood pressure, and pulse rate should be taken with the patient in the seated position after the patient has been sitting 
quietly for at least 5 minutes.  Two blood pressure readings will be taken at least 1 hour apart at each clinic visit.
10. Home blood pressure monitoring: All patients will receive home blood pressure monitoring devices and blood pressure will be monitored at home.  While 
on axitinib (as single agent during the Lead-in, or combined with MK-3475) patients will monitor their blood pressure at least twice daily (before taking 
each dose of axitinib) and blood pressure should be recorded in a patient diary.  Patients should be instructed to contact the site immediately for guidance if 
their systolic blood pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or if they develop symptoms perceived to be related 
to elevated blood pressure (eg, headache, visual disturbance) although a different blood pressure threshold for contacting the site may be used according to 
the Investigator’s clinical judgment (see Section 5.2.7.3).
11. Follow-up for Dosing Compliance: Follow-up by telephone will be done to confirm patient understanding and compliance with dosing instructions.  If 
needed, patient will be retrained. 
12. Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 8.  Blood Chemistry may be performed weekly during the first 
3 cycles.  All laboratory tests may be performed also when clinically indicated. Dose adjustment may be required (see Section 5.2.7).
13. Urinalysis (Table 8): If protein 2+ by semiquantitative method (eg, urine dipstick), protein will have to be quantified by 24 hour urine collection.  Dose 
adjustment may be required (see Section 5.2.7.2).  May be performed also when clinically indicated.
14. 12-lead ECG: See Section 7.1.5 for details.  Single ECG measurement will be obtained at screening, on Cycle 1 Day 1 and End of Treatment/Withdrawal. 
Clinically significant abnormal findings in baseline ECGs will be recorded as medical history.  Additionally, ECGs should be performed when clinically 
indicated.  Clinically significant findings seen on follow-up ECGs should be recorded as adverse events.
15. Thyroid Function Tests: Free T3, free T4 and TSH will be performed at baseline/screening, Lead-in Day 1; or at baseline (Cycle 1 Day 1 pre-dose for 
patients with no lead in dose or within 7 days of Cycle 1 Day 1) for all patients.  Subsequently, TSH should be assessed at Cycle 2 Day 1, Cycle 4 Day 1, 
Cycle 6 Day 1, and every 6 weeks thereafter starting from Cycle 8 Day 1.  Free T3 and free T4 should additionally be performed when clinically indicated.  
Hypothyroidism should be treated per standard medical practice to maintain euthyroid state.  See Table 8. 


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16. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed 
on two occasions prior to starting study therapy: once at the start of screening (all patients), and once at Lead-in Day 1 (patients in Lead-in) immediately 
before axitinib administration, or at the baseline visit (all other patients) immediately before the administration of axitinib in combination with MK-3475.  
Following a negative pregnancy result at screening, appropriate contraception must be commenced.  Pregnancy tests will also be routinely repeated at every 
cycle during the active treatment period, at the end of study treatment and additionally whenever one menstrual cycle is missed or when potential pregnancy 
is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations (see Section 7.1.1).
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI 
scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone scans (required at baseline then every 12 weeks only if 
bone metastases are present at baseline) see Section 7.5.  The CT scans should be performed with contrast agents unless contraindicated for medical reasons. 
The same imaging technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments.  
Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, 12 weeks then every 6 weeks, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of End of Treatment/Withdrawal (if not done in the previous 6 weeks).  Follow up 
bone scans is required every 12 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is required only if new bone metastasis are 
suspected and at the time of confirmation of response for patients who have bone metastases.  Assessment of response will be made using RECIST 
version 1.1.
18. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment. Survival monitoring will continue until 
5 years after Cycle 1 Day 1 of the last patient enrolled in the study.
19. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  For SAEs, the active reporting period 
to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 90 calendar 
days after the last administration of the investigational product and before initiation of a new anti-cancer treatment.  The prolonged follow up is due to the 
pharmacokinetic properties of the investigational product MK-3475.  SAEs experienced by a patient after the active reporting period (see Section 8.1.1) has 
ended should be reported to the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the Investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.  AEs (serious and non serious) should be recorded on the Case Report 
Form (CRF) from the time the patient has taken at least one dose of study treatment through last patient visit (Day 28 after last dose).  If a patient begins a 
new anticancer therapy, the AE reporting period for non serious AEs ends at the time the new treatment is started.  Pregnancy or breast feeding that occur 
during the trial, within 120 days of discontinuing treatment with MK-3475, or within 28 days after the cessation of study treatment if the patient begins a 
new anticancer therapy, whichever is earlier, should be reported as in Section 8.4 (Exposure During Pregnancy).
20. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 28 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions). 
21. Registration: Patient number and dose level allocation operated by Pfizer Inc.  Required information: site and patient identifiers and demographic 
information.  Study treatment (either single agent axitinib for patients in Lead-in or axitinib in combination with MK-3475 for all other patients) should 
begin within 7 days of registration.  
22. Study Treatment: Axitinib will be given orally twice daily PO on a continuous schedule.  MK-3475 will be given as a 30-minute intravenous infusion 
every 3 weeks.  (one Cycle = 3 weeks) (see Section 5).  Patients with disease progression who are continuing to derive clinical benefits from the study 
treatment will be eligible to continue with study drugs provided that the treating physician has determined that the benefit/risk for doing so is favorable.


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23. Pharmacokinetics: Samples will be collected at the time points indicated in the Schedule for Pharamcokinetic Samples Collection Table. Pharmacokinetic 
samples for MK-3475 will be collected from all patients in the study.  Pharmacokinetic samples for axitinib will be collected from all patients in the Dose 
Finding Phase and at least 8 patients in the Dose Expansion Phase.  Details are outlined in Section 7.2.  
24. Serum Biomarkers: Blood biospecimens (10 mL) will be obtained to measure DNA, RNA or protein markers known or suspected to be of relevance to the 
mechanism of action, the development of resistance or the identification of those patients who might benefit from treatment with axitinib in combination 
with MK-3475.  Blood biospecimens will be collected at screening, Cycle 2 Day 1 predose, and End of Treatment/Withdrawal whichever comes first.  See 
Section 7.3.2.
25. Whole Blood Biomarkers: Blood biospecimen (10 mL) will be obtained to measure DNA, RNA or protein markers known or suspected to be of relevance 
to the mechanism of action, the development of resistance or the identification of those patients who might benefit from treatment with axitinib in 
combination with MK-3475.  Blood samples will be collected at screening, Cycle 2 Day 1 predose, and End of Treatment/Withdrawal whichever comes 
first.  See Section 7.3.2
26. Banked Biospecimen: A single 4 mL blood sample will be collected at screening.  Banked biospecimens will be collected for the purpose of conducting 
research; specific uses are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid (DNA), ribonucleic acid (RNA), protein, 
and metabolite variation patterns of patients who respond well and those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment.  Collecting biospecimens for exploratory pharmacogenomic/genomic/biomarker analyses and 
retaining them in the Biospecimen Banking System (BBS) make it possible to better understand the investigational product’s mechanism of action and to 
seek explanations for differences in, for example, exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.  Banked 
biospecimens retained in the BBS also can be used in research on RCC.  Providing these biospecimens is a required study activity for study sites and 
patients, unless prohibited by local regulations or ethics committee (EC) decision.  See Section 7.4.
27. Archival Tumor Tissue: Mandatory Archival Biospecimen from primary diagnosis for all patients enrolled in the study (Dose Finding and Dose Expansion 
Phases).  Formalin-fixed, paraffin-embedded (FFPE) block(s) from initial diagnosis.  If no FFPE block is available, then at least 12 unbaked, unstained 
slides containing FFPE tissue sections that are 4 microns (preferred) or 5 microns (acceptable) thick must be provided.  However FFPE blocks are strongly 
encouraged over slides.  See Section 7.3.1.
28. De Novo Tumor Biospecimens: Baseline de novo tumor biospecimens from metastatic tumor sites are mandatory for all patients enrolled in the Dose 
Expansion Phase.  Baseline de novo tissue biopsies taken from metastatic lesions prior to the date of screening are acceptable.  For all patients in the Dose 
Expansion cohort, a second biopsy is strongly encouraged at the time of first tumor assessment after 12 weeks.  If possible the tumor biospecimen at 
12 weeks should come from the same baseline anatomical location.  Formalin-fixed, paraffin-embedded (FFPE) block(s) of metastatic lesion tumor 
biospecimens from baseline de novo biopsies that contain sufficient tissue to generate at least 12 unstained slides are required, each with tissue sections that 
are 5-microns thick.  If no FFPE block is available, then at least 12 unbaked, unstained slides containing FFPE tissue sections that are 5 microns thick must 
be provided.  However FFPE blocks are strongly encouraged over slides.  See Section 7.3.1.
29. Anti-MK-3475 Antibodies (anti-drug antibodies, ADA): One blood sample (6 mL) for anti-MK-3475 antibodies will be collected pre-dose on Cycle 1, 3, 
5 and 11.  Subsequently, testing should be performed approximately every 12 weeks. All samples should be drawn within 24 hours before start of MK-3475 
infusion.  Additional samples for anti-MK-3475 antibodies (and simultaneous pharmacokinetic draws for measurement of MK-3475) will be collected at 
30 days, 3 months and 6 months after the end of MK-3475 treatment.  See Section 7.2.5.
a.
(X) = only if activity not performed in prior 7 days.


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SCHEDULE FOR PHARMACOKINETIC SAMPLE COLLECTION
Axitinib
Axitinib in Combination with MK-3475
Lead-in
Day7
Cycle 1
Cycles 3 and 5
Cycle 7
Cycle 11 and every 12 weeks 
thereafter
Day 1
Day 5
Day 1
Day 1
Day 1
PK Samples for 
axitiniba
PK Samples for 
MK-3475b
Sample for 
anti-MK-3475-
antibodies 
(ADA)c
PK
Sample for 
MK-3475b
PK Sample for 
MK-347b
Sample for 
anti-MK-3475-
antibodies 
(ADA)c
PK
Samples for 
axitiniba
PK Sample for 
MK-3475b
Sample for 
anti-MK-3475-
antibodies (ADA)c
Prior to
axitinib morning 
dose
Prior to
MK-3475 dose
Prior to MK-3475 
dose
One sample collected 
at any time between 
Cycle 1 Day 3 and 
Cycle 1 Day 7 for 
MK-3475; the exact 
time/day of sample 
collection to be noted 
in Case Report Form.
Prior to MK-3475 
dose
Prior to MK-3475 
dosec
Prior to
axitinib morning dose
Prior to 
MK-3475 dose
Prior to
MK-3475 dose
1 hr post
axitinib morning 
dose
End of MK-3475
infusiond
1 hr post
axitinib morning dose
2 hrs post
axitinib morning 
dose
2 hrs post
axitinib morning dose
3 hrs post
axitinib morning 
dose
3 hrs post
axitinib morning dose
4 hrs post
axitinib morning 
dose
4 hrs post
axitinib morning dose
6 hrs post
axitinib morning 
dose
6 hrs post
axitinib morning dose
8 hrs post
axitinib morning 
dose
8 hrs post
axitinib morning dose
K= pharmacokinetics; ADA= anti-drug antibodies
Note that PK samples for MK-3475 and anti-MK-3475-antibodies (ADA) will be collected from all patients in the study.  Axitinib PK samples will be collected from all patients in 
the Dose Finding phase and at least 8 patients in the Dose Expansion Phase. 
a.
One sample (3 mL) collected at each time point for axitinib.
b.
One sample (3 mL) collected at each time point for MK-3475.  Additionally PK samples will be collected at 1 month, 3 months and 6 months after end of MK-3475 treatment.
c.
One sample (6 mL) collected at each time point for MK-3475-antibodies. 
d.
Sample may be collected within 30 minutes after end of MK-3475 infusion.


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TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................3
LIST OF TABLES...................................................................................................................21
LIST OF FIGURES .................................................................................................................21
APPENDICES .........................................................................................................................21
1. INTRODUCTION ...............................................................................................................22
1.1. Indication.................................................................................................................22
1.2. Background and Rationale ......................................................................................22
1.2.1. Renal Cell Cancer.......................................................................................22
1.2.2. Pharmaceutical and Therapeutic Background ............................................23
1.2.2.1. Axitinib (INLYTA, AG-013736)............................................23
1.2.2.2. Clinical Safety and Efficacy of Axitinib...................................23
1.2.2.3. Pembrolizumab(MK-3475) .......................................................24
1.2.2.4. Clinical Safety and Efficacy of MK-3475..................................25
1.2.3. Rationale for Studying Axitinib in Combination with MK-3475 in 
Patients with Advanced Renal Cell Carcinoma...............................................26
1.2.4. Rationale for Axitinib and MK-3475 Starting Doses in This Trial............27
1.2.4.1. Axitinib Starting Dose...............................................................27
1.2.4.2. MK-3475 Starting Dose and Regimen......................................27
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................28
2.1. Objectives................................................................................................................28
2.2. Endpoints.................................................................................................................29
3. STUDY DESIGN.................................................................................................................29
3.1. Study Overview.......................................................................................................29
3.1.1. Dose Finding Phase ....................................................................................33
3.1.1.1. Starting Doses for Axitinib and MK-3475 (Dose Level 1).......33
3.1.1.2. Criteria for Dose Finding ..........................................................33
3.1.2. DLT Definition...........................................................................................36
3.2. Maximum Tolerated Dose Definition .....................................................................36
3.3. Dose Expansion Phase Test Dose Definition..........................................................36
3.3.1. Dose Expansion Phase................................................................................37
3.4. Recommended Phase 2 Dose Definition.................................................................37


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4. PATIENT SELECTION......................................................................................................37
4.1. Inclusion Criteria.....................................................................................................37
4.2. Exclusion Criteria....................................................................................................39
4.3. Life Style Guidelines...............................................................................................41
4.3.1. Contraception..............................................................................................41
4.4. Sponsor Qualified Medical Personnel.....................................................................42
5. STUDY TREATMENTS.....................................................................................................43
5.1. Allocation to Treatment ..........................................................................................43
5.2. Drug Supplies..........................................................................................................43
5.2.1. Formulation and Packaging........................................................................44
5.2.1.1. Axitinib......................................................................................44
5.2.1.2. MK-3475 ...................................................................................44
5.2.2. Preparation and Dispensing........................................................................44
5.2.3. Administration............................................................................................44
5.2.3.1. Axitinib......................................................................................45
5.2.4. MK-3475.....................................................................................................45
5.2.4.1. MK-3475 Timing of Dose Administration................................45
5.2.4.2. MK-3475 Treatment Duration...................................................46
5.2.5. Medication Errors .......................................................................................47
5.2.6. Food Requirements.....................................................................................48
5.2.7. Recommended Dose Modifications............................................................48
5.2.7.1. Axitinib Intra-Patient Dose Increase.........................................49
5.2.7.2. Axitinib Dose Modifications in Case of Drug-Related 
Toxicity..............................................................................................49
5.2.7.3. Management of Axitinib-Related Hypertension .......................49
5.2.7.4. MK-3475 Immune-Related Adverse Events.............................52
5.2.8. Compliance.................................................................................................55
5.3. Drug Storage and Drug Accountability...................................................................55
5.4. Concomitant Medication(s).....................................................................................57
5.4.1. Inhibitors and Inducers of CYP Enzymes (Axitinib) .................................57
5.4.2. Hematopoietic Growth Factors...................................................................58
5.4.3. Concomitant Surgery..................................................................................58


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5.4.3.1. Axitinib......................................................................................58
5.4.3.2. MK-3475 ...................................................................................58
5.4.4. Concomitant Radiotherapy.........................................................................58
5.4.5. Concomitant Medications/Vaccinations (allowed & prohibited)...............59
5.4.6. Prohibited Concomitant Medications .........................................................59
5.5. Rescue Medications & Supportive Care .................................................................59
5.5.1. Supportive Care Guidelines........................................................................59
5.5.2. Management of MK-3475 Infusion Reactions ...........................................60
6. STUDY PROCEDURES .....................................................................................................62
6.1. Screening.................................................................................................................62
6.1.1. Tumor Biospecimens..................................................................................62
6.2. Study Period ............................................................................................................62
6.3. End of Treatment/Withdrawal and Follow-up Visits..............................................62
6.4. Patient Withdrawal..................................................................................................62
7. ASSESSMENTS..................................................................................................................64
7.1. Safety Assessment...................................................................................................64
7.1.1. Pregnancy Testing ......................................................................................64
7.1.2. Adverse Events...........................................................................................65
7.1.2.1. MK-3475 Adverse Events of Clinical Interest..........................65
7.1.3. Laboratory Safety Assessment ...................................................................66
7.1.4. Vital Signs and Physical Examination........................................................67
7.1.5. ECG Measurements....................................................................................67
7.2. Pharmacokinetics Assessments...............................................................................67
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis ...........................67
7.2.2. Collection of Axitinib PK Samples ............................................................68
7.2.3. Processing, Storage and Shipment of Axitinib PK Samples ......................68
7.2.4. Collection and processing of MK-3475 PK Samples.................................69
7.2.5. Collection and Processing of Anti-MK-3475 Antibody Samples ..............69
7.3. Translational and Pharmacodynamic Assessments.................................................69
7.3.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies.................69
7.3.2. Peripheral Blood.........................................................................................70
7.4. Banked Biospecimens .............................................................................................70


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7.4.1. Markers of Drug Response.........................................................................70
7.4.2. Additional Research....................................................................................71
7.5. Tumor Response Assessments ................................................................................71
8. ADVERSE EVENT REPORTING......................................................................................72
8.1. Requirements...........................................................................................................72
8.1.1. Additional Details on Recording Adverse Events on the CRF...................73
8.1.2. Eliciting Adverse Event Information..........................................................73
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal section).............................................................................73
8.1.4. Time Period for Collecting AE/SAE Information......................................73
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................74
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................74
8.1.5. Causality Assessment .................................................................................74
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................75
8.2. Definitions...............................................................................................................75
8.2.1. Adverse Event.............................................................................................75
8.2.2. Abnormal Test Findings .............................................................................76
8.2.3. Serious Adverse Events ..............................................................................76
8.2.4. Hospitalization............................................................................................77
8.3. Severity Assessment................................................................................................78
8.4. Special Situations ....................................................................................................79
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................79
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................80
8.4.2.1. Exposure During Pregnancy......................................................80
8.4.2.2. Exposure During Breastfeeding ................................................82
8.4.2.3. Occupational Exposure .............................................................82
8.4.3. Medication Errors .......................................................................................82
8.4.3.1. Medication Errors......................................................................82
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................83
9.1. Analysis Sets ...........................................................................................................83
9.2. Statistical Methods and Properties ..........................................................................84
9.2.1. Statistical Methods for Dose Escalation/De-Escalation: mTPI..................84


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9.2.2. Statistical Method for Estimating the MTD ...............................................85
9.3. Sample Size Determination.....................................................................................85
9.4. Efficacy Analysis ....................................................................................................86
9.4.1. Analysis of Efficacy Endpoints (Dose Expansion Phase Cohort)..............86
9.5. Analysis of Other Endpoints ...................................................................................87
9.5.1. Analysis of Pharmacokinetics.....................................................................87
9.5.1.1. Pharmacokinetic Analysis of MK-3475 and Axitinib...............87
9.5.1.2. Effect of MK-3475 on Axitinib Pharmacokinetics ...................88
9.5.1.3. Immunogenecity Assessment....................................................88
9.5.1.4. Population Pharmacokinetic Analysis or PK/PD Modeling .....88
9.5.1.5. Statistical Analysis of Biomarker Endpoints ............................88
9.6. Safety Analysis........................................................................................................88
9.6.1. Analysis of Primary Safety Endpoint .........................................................88
9.6.2. Analysis of Secondary Safety Endpoints....................................................89
9.6.2.1. Adverse Events..........................................................................89
9.6.2.2. Laboratory Tests Abnormalities................................................89
9.6.2.3. ECG...........................................................................................89
9.6.3. Concomitant Medications/Follow-up Systemic Therapy...........................89
9.7. Data Monitoring Committee ...................................................................................89
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................90
11. DATA HANDLING AND RECORD KEEPING .............................................................90
11.1. Case Report Forms/Electronic Data Record .........................................................90
11.2. Record Retention...................................................................................................91
12. ETHICS..............................................................................................................................92
12.1. Institutional Review Board/Ethics Committee......................................................92
12.2. Ethical Conduct of the Study ................................................................................92
12.3. Patient Information and Consent...........................................................................92
12.4. Patient Recruitment...............................................................................................93
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................93
13. DEFINITION OF END OF TRIAL...................................................................................93
13.1. End of Trial in a Member State.............................................................................93


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13.2. End of Trial in all other Participating Countries...................................................94
14. SPONSOR DISCONTINUATION CRITERIA ................................................................94
15. PUBLICATION OF STUDY RESULTS..........................................................................94
15.1. Communication of Results by Pfizer ....................................................................94
15.2. Publications by Investigators ................................................................................95
16. REFERENCES ..................................................................................................................96
LIST OF TABLES
Table 1.
Dose Levels in the Dose Finding Phase ...............................................................33
Table 2.
Possible Dose Finding Sequences ........................................................................34
Table 3.
Detailed Dose Escalation/De-Escalation Scheme ................................................34
Table 4.
Axitinib Dose Levels ............................................................................................49
Table 5.
Axitinib Dose Modifications for Drug-Related Toxicity .....................................50
Table 6.
Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab........................................53
Table 7.
MK-3475 Infusion Reaction Treatment Guidelines .............................................61
Table 8.
Required Laboratory Tests ...................................................................................66
LIST OF FIGURES
Figure 1.
Study Schema .......................................................................................................30
APPENDICES
Appendix 1. ECOG Performance Status................................................................................100
Appendix 2. RECIST Version 1.1 .........................................................................................101
Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................104
Appendix 4. Abbreviations and Definitions of Term ............................................................105
Appendix 5. KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS 
RATING (%) CRITERIA...................................................................................108
Appendix 6. Revised Schedule of Activities Following Collection of Data for Primary 
Study Objective ..................................................................................................109


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1. INTRODUCTION
1.1. Indication
Advanced RCC tumors in the first-line setting. 
1.2. Background and Rationale
1.2.1. Renal Cell Cancer
An estimated 65,150 new cases of kidney cancer are expected to be diagnosed in the United 
States (US) in 2013.  This includes 93% RCC, 6% renal pelvis cancer and 1% Wilms tumor.  
An estimated 13,680 patients will die from kidney cancer in 2013.12
RCC arises from the renal epithelium and 5 major subtypes are currently recognized.  
Approximately 70-80% of these are clear cell RCC tumors while other less common cell 
types include papillary (Type I and II), chromophobe, collecting duct and unclassified 
RCC.13  Four RCC predisposing genes have been identified – MET protooncogene, von 
Hippel-Lindau tumor suppressor gene (VHL), fumarate hydratase tumor suppressor gene 
(FH), and Birt-Hogg-Dubé tumor suppressor gene (BHD).
Patients with von Hippel-Lindau disease have a >70% risk of developing clear cell RCC.  
This hereditary form of RCC is caused by germline mutations in the VHL tumor suppressor 
gene on chromosome 3p.  More than 90% of sporadic clear cell RCC involves somatic VHL
gene mutations or methylation.  VHL gene mutations lead to loss of function of the VHL 
protein, accumulation of hypoxia-inducible transcription factors (eg, HIF-1alpha and HIF-2 
alpha) which translocate to the nucleus and increase transcription of angiogenesis factors 
(such as VEGF and platelet derived growth factor [PDGF]) which induce tumorigenesis.  
Clear cell RCC is a highly vascular tumor with high expression of VEGF, VEGFRs and 
PDGF receptor.14  
About one-third of patients with clear cell RCC present with Stage IV disease.  Systemic 
therapy is given to patients with advanced disease (relapsed or Stage IV) that is not amenable 
to complete resection.  However, it is recommended that these patients undergo a 
cytoreductive nephrectomy where possible, prior to beginning systemic therapy, as per 
treatment guidelines.15  
There are 7 molecularly targeted agents approved in the US as systemic therapy for advanced 
RCC that is predominantly clear cell.  First line systemic therapy is usually one of the 
VEGFR TKIs (sunitinib, pazopanib, or sorafenib), the monoclonal anti-VEGF antibody 
bevacizumab (given in combination with IFN alpha) or the mTOR inhibitor, temsirolimus.  
The same targeted agents or the VEGFR TKI axitinib, or the mTOR inhibitor everolimus are 
used individually in subsequent lines of therapy for advanced clear cell RCC.15,16,17,18


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1.2.2. Pharmaceutical and Therapeutic Background 
1.2.2.1. Axitinib (INLYTA, AG-013736)
Axitinib (INLYTA, AG-013736) is an oral, small molecule, TKI selective for VEGFRs 1, 2 
and 3 and is approved multinationally for the treatment of advanced RCC after failure of one 
prior systemic therapy (actual indication varies according to region/country). 
Axitinib is an adenosine triphosphate (ATP)-competitive inhibitor that binds to the 
unphosphorylated (non-activated) “DFG-out” conformation of the catalytic domain of a 
receptor tyrosine kinase.  In enzymatic assays, axitinib was found to be highly potent 
(Ki = 28 picomolar) against the kinase activity of juxta-membrane (JM) domain containing 
human VEGFR 2 recombinant protein.19  In additional kinase assays, axitinib showed potent 
and ATP-competitive inhibition of the VEGFRs 1, 2, and 3 and PDGFR-, but not other 
closely-related family kinases.  Receptor binding studies and cell-based assays, confirmed 
that axitinib is a potent and selective inhibitor of VEGFRs 1, 2, and 3.  Axitinib was shown 
to have antiangiogenic activity in a number of models including spontaneous pancreatic 
islet-cell tumors of RIP-TAG-2 transgenic mice model and demonstrated antitumor efficacy 
including marked cytoreductive antitumor activity, in multiple tumor models implanted in 
athymic mice. 
1.2.2.2. Clinical Safety and Efficacy of Axitinib
The safety and efficacy of axitinib were evaluated in a randomized, open-label, multicenter 
Phase 3 study.  Patients with advanced RCC (99% clear cell) whose disease had progressed 
on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, 
temsirolimus-, or cytokine-containing regimens were randomized to receive axitinib (N=361) 
or sorafenib (N=362).  There was a statistically significant advantage for axitinib over 
sorafenib for the primary PFS endpoint, 6.7 (95% CI: 6.3, 8.6) vs 4.7 (95% CI: 4.6, 5.6) 
months, respectively (p <0.0001).  There was no statistically significant difference between 
the treatment arms in the secondary overall survival (OS) endpoint, 20.1 (95% CI: 16.7, 23.4) 
vs 19.2 (95% CI: 17.5, 22.3) for axitinib and sorfenib, respectively.  The objective response 
rate (ORR) was 19.4% (95% CI: 15.4, 23.9) for axitinib and 9.4% (95% CI: 6.6, 12.9) for 
sorafenib.  The most common (20%) adverse reactions observed in this study following 
treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, 
dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, 
vomiting, asthenia, and constipation.9
In a randomized, open-label, Phase 3 trial, treatment-naïve clear cell RCC patients were 
randomized (2:1) to receive axitinib (N=192) or sorafenib (N=96).  There was no significant 
difference in median PFS between patients treated with axitinib or sorafenib 10.1 months 
(95% CI 7.2,12.1) vs 6.5 months (95% CI 4.7, 8.3), respectively, with stratified hazard ratio 
0.77, (95% CI 0.56, 1.05).  The axitinib ORR assessed by an Independent Review Committee 
was 32%, risk ratio 2.21, (95% CI 1.31, 3.75, stratified one sided p=0.0006).  The most 
common adverse events (20%) observed with axitinib were diarrhea, hypertension, weight 
decrease, fatigue, decreased appetite, palmar-plantar erythrodysesthesia (hand-foot) 
syndrome, dysphonia, asthenia, hypothyroidism and nausea.8


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Overall, the adverse events reported for axitinib in clinical studies were considered 
manageable and generally reversible.  For single-agent axitinib, the most common adverse 
events (>20% of patients) reported from 699 cancer patients regardless of causality included 
diarrhea, fatigue, hypertension, decrease appetite, nausea, dysphonia, palmar-plantar 
erythrodysaesthesia syndrome, weight decreased, vomiting, constipation, headache, cough, 
arthralgia, dyspnea, and hemorrhagic events (including epistaxis, hematuria, hemoptysis, 
rectal hemorrhage, cerebral hemorrhage, gastric hemorrhage, and lower gastrointestinal 
hemorrhage).  In addition, hypothyroidism and proteinuria were reported in 17.5% and 
16.7% of the patients, respectively.
Additional information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the axitinib Investigator Brochure.19  
1.2.2.3. Pembrolizumab(MK-3475)
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.25  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.26,27,28,29,30 In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
The Programmed Death-1 (PD-1) receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).31,32  The structure of murine PD-1 has been resolved.33  PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.31,34,35,36  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.37,38  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.39,40  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.41  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.42,43,44,37  Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 


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triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues.37  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in patients with melanoma (MEL).45  This suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
MK-3475 is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. Pembrolizumab [Keytruda(US); previously known as lambrolizumab, 
MK-3475 and SCH 9000475] is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab was recently approved in the US 
for the treatment of advanced, unresectable or metastatic malignant melanoma, and for use in 
melanoma patients with disease progression after prior treatment with (a) ipilimumab or (b) a 
BRAF inhibitor, in the case of BRAF V600-mutant disease.50
1.2.2.4. Clinical Safety and Efficacy of MK-3475
The safety of MK-3475 is being assessed in six ongoing clinical trials, PN001, PN002, 
PN006, PN010, PN011 and PN012.  Safety data of single-agent MK-3475 are only available 
from Study PN001 at this time.  Protocol 001 (PN001) is an open-label Phase 1 study, which 
includes a dose-escalation component in patients with solid tumors (Part A) and with 
subsequent expansion cohorts in patients with melanoma (Parts B and D) and NSCLC (Parts 
C and F).  PN001 Part A evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered Q2W.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  Based on PK data showing a half-life of 21 days, the protocol was amended 
to include a dosing frequency of Q3W in the expansion cohorts (Parts B through F).
Preliminary data (as of 26 July 2013) are available from 479 patients enrolled in PN001: 
Part A (n=30) 1 mg/kg, 3 mg/kg, and 10 mg/kg MK-3475 dosed Q2W to Q3W, Part B 
(n=308) 2 mg/kg or 10 mg/kg MK-3475 dosed Q2W to Q3W, Part C (n=38) 10 mg/kg 
MK-3475 dosed Q3W, and Part D (n=103) 2 or 10 mg/kg MK-3475 dosed Q3W.  Of the 
479 patients who have received MK-3475 in Protocol 001, 466 (97.3%) experienced 
treatment emergent adverse events (AEs) of which 368 (76.8%) were considered 
drug-related.  Serious adverse events (SAEs) were reported in 30.1% of patients, but SAEs 
that were attributed as potentially (possibly, probably, or definitely) drug-related by 
Investigators were reported in 6.7% of patients overall.  Potentially immune-related AEs 
have been observed, including pneumonitis (Grade 1-2) in both melanoma and NSCLC 
cohorts.  The most commonly reported treatment emergent AEs experienced are fatigue, 
nausea, cough, pruritus, diarrhea and rash. Most patients continued treatment in spite of 
adverse events, and only 4.2% of patients discontinued study treatment due to an AE that was 
considered related to study treatment by Investigators.


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Of the 162 patients who received 2 mg/kg MK-3475 dosed Q3W (Parts B1, B2 and D) in 
PN001, 160 (98.8%) experienced treatment emergent AEs of which 128 (79.0%) were 
considered to be drug-related.  SAEs were reported in 27.2% of patients, but SAEs that were 
attributed as potentially (possibly, probably, or definitely) drug-related by Investigators were 
reported in 9.3% of this subset of patients.  The most commonly reported treatment emergent 
AEs experienced in this subset up patients are fatigue, nausea, cough, pruritus, rash and 
diarrhea.
Thus, the overall AE summary suggests that MK-3475 is generally tolerable and AEs are 
generally manageable in patients. 
The SRSD for combination agent MK-3475 is the MK-3475 Investigator Brochure.20
1.2.3. Rationale for Studying Axitinib in Combination with MK-3475 in Patients with 
Advanced Renal Cell Carcinoma
Tumor angiogenesis is a complex dynamic process necessary for the continued growth of 
solid tumors.  VEGF is one of the most important angiogenic factors secreted by the tumor 
and other cells.  Its production is enhanced by several stimuli, including hypoxia.  VEGF and 
VEGFRs are critical components of the processes leading to the branching, extension, and 
survival of endothelial cells which form new blood vessels during angiogenesis, and which is 
an absolute necessity for tumor growth beyond microscopic size.  Inhibitors of angiogenesis 
are now widely used in the treatment of cancer and most of these agents inhibit the VEGF 
pathway.  VEGF pathway inhibitors include the VEGFR TKIs axitinib, sunitinib, pazopanib, 
and sorafenib, and the monoclonal anti-VEGF antibody bevacizumab.  VEGF inhibitors have 
been approved in a number of indications, including the treatment of aRCC.10,11
There is a strong rationale for considering immunotherapy in RCC patients.  Cytokine based 
immunotherapy, especially high dose of IL-2, exhibited durable response in some aRCC 
patients. There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration of tumor tissues.2  These evidences have 
generated considerable interests in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune-check point inhibitors such as anti-PD1 and anti 
PD L1 antibodies in recent years.  Upregulations of programmed death-1 (PD-1) receptor on 
tumor-infiltrating lymphocytes, and its ligand PD-L1 on tumors are associated with more 
aggressive disease and poor prognosis.3,4  
Blocking the PD-1/PD-L1 interaction in aRCC is a novel immunotherapeutic approach, 
which has shown single agent efficacy in patients whose disease have progressed following 
VEGF pathway inhibitor therapy.6,7  BMS-936558, also named nivolumab, is a fully 
humanized anti-PD-1 antibody (Bristol-Myers Squibb) that has shown anti-tumor activity in 
296 patients with solid cancers.5  Among these 296 patients, 33 patients had aRCC and were 
heavily pretreated before nivolumab therapy. Nivolumab was given at a starting dose of 
1 mg/kg and then expanded to 10 mg/kg.  The objective response rate (ORR) was 27% (9/33) 
and another 9 patients (27%) had stable disease at the 24-week follow-up. Five patients had 
durable response longer than 1 year.5  It is therefore proposed that combining a PD-1 


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inhibitor with a VEGF pathway inhibitor may provide clinical benefit compared to treatment 
with a VEGF pathway directed therapy alone.5  
Antitumor activity of single agent axitinib in treatment-naïve patients with clear cell RCC 
was assessed against sorafenib in a randomized, open-label, phase 3 trial.  Although the study 
did not demonstrate statistically significant difference in median PFS between patients 
treated with axitinib or sorafenib, axitinib was associated with a longer mPFS value {median 
PFS of 10.1 months (95% CI 7.2,12.1) with axitinib vs. 6.5 months (95% CI 4.7, 8.3) with 
sorafenib, stratified hazard ratio 0.77, (95% CI 0.56, 1.05)}.  The median PFS observed with 
axitinib in this study was similar to those demonstrated earlier in phase 3 clinical trials with 
other approved VEGF TKIs in treatment-naïve aRCC patients.8  Toxicities in this clinical 
trial were manageable and similar to the clinical trials with axitinib done in pre-treated aRCC 
patients.9
It is therefore proposed that combining MK-3475 with axitinib may provide clinical benefit 
in treatment-naïve aRCC patients compared to treatment with a VEGF pathway directed 
therapy alone.
After the collection of data to verify the primary study objective and most of the secondary 
objectives of the study has been completed, this study (A4061079) will remain open to give 
patients an opportunity to continue to receive study treatment as described in Section 3 of 
this protocol. Guidance on the management of patients who continue on study (ie, patients 
who are still clinically benefiting from study treatment without unacceptable toxicity or 
disease progression and who have not withdrawn consent) is provided to investigators in 
Appendix 6. Clinical assessments will be reduced in scope and the required schedule of 
activities will be revised to maintain only those assessments that protect the well-being of the 
patient.
1.2.4. Rationale for Axitinib and MK-3475 Starting Doses in This Trial
1.2.4.1. Axitinib Starting Dose
In this trial, the axitinib starting dose will be 5 mg BID with or without food.  This dose has 
proven to be safe and efficacious in RCC and has been approved by regulatory authorities 
worldwide.
1.2.4.2. MK-3475 Starting Dose and Regimen
In this trial, the MK-3475 starting dose will be 2 mg/kg to be administered every 3 weeks 
(Q3W), based on the following observations: 

The MK-3475 Phase 1 dose escalation study in patients with solid tumors showed 
that MK-3475 was safe at the tested dose levels (1 mg/kg, 2 mg/kg and 10 mg/kg, 
administered every 2 weeks) without reaching a maximum tolerated dose.  In 
addition, clinical responses were observed at all the dose levels.21


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
The dose of 2 mg/kg dosed Q3W was well tolerated based on published21 single agent 
safety and tolerability data from the Phase 1 first-in-human study (PN001). In this 
study, MK-3475 showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  PK 
data analysis of MK-3475 administered in Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life, typical for therapeutic 
antibodies (refer to MK-3475 IB).  Pharmacodynamic data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing either Q2W or Q3W 
dosing schedules.

In the ongoing PN001 protocol, patients with ipilimumab-naïve or 
ipilimumab-pretreated advanced melanoma were treated on three different dosing 
regimens of MK-3475: 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  An 
interim analysis has suggested that there are no major differences in the safety profile 
or overall objective response rate for the doses of 2 mg/kg or 10 mg/kg given Q3W. 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To assess the safety and tolerability of axitinib in combination with MK-3475 in 
patients with previously untreated advanced RCC in order to estimate the maximum 
tolerated dose (MTD) and select the recommended Phase 2 dose (RP2D).
Secondary Objectives

To evaluate the overall safety profile of axitinib in combination with MK-3475.

To assess the anti-tumor activity of axitinib in combination with MK-3475 in patients 
with advanced RCC in the first-line treatment setting.

To characterize the pharmacokinetics (PK) of axitinib and axitinib plus MK-3475 
when administered in combination and to assess the effect of MK-3475 on the PK of 
axitinib.

To characterize, using translational approaches, genes and proteins such as PD-L1, 
VEGF-A and IL-8 relevant to angiogenesis drug target pathway, renal cell carcinoma 
biology, and sensitivity/resistance mechanisms to axitinib in combination with 
MK-3475 in tumor and/or blood.

To explore the pharmacodynamic effect of axitinib in combination with MK-3475 in 
blood and tumor by assessment of gene, RNAs and proteins including but not limited 
to VEGF-A, IL-8, VEGFR2 and T-cell receptors.

To assess the immunogenicity of MK-3475.


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2.2. Endpoints
Primary Endpoint

First 2 cycles (6 weeks) DLTs.
Secondary Endpoints

Adverse events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE
v.4.03]), timing, seriousness and relationship to study therapy.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing.

Vital signs (blood pressure, pulse rate, weight, ECOG Performance Status [PS]).

Objective tumor response, as assessed by Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1.

Time-to-event endpoints (Dose Expansion Phase): Duration of Response (DR) and 
Progression-Free Survival (PFS) and Overall Survival (OS). 

PK parameters of axitinib and MK-3475: Cmax, Tmax, AUC0-12, CL/F and V/F as data 
permit for axitinib and population-based PK parameters for MK-3475.

Immunogenicity (anti-drug antibodies; ADA) of MK-3475.

Biomarkers including but not limited to PD-L1 and VEGF-A in tumor biospecimens.

Pre- and post-dose serum biomarkers (including but not limited to VEGF-A, 
VEGFR2 and IL-8) and whole blood biomarkers (including but not limited to T cell 
receptor status).
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and pharmacodynamic 
study of axitinib in combination with MK-3475 in adult patients with previously untreated 
advanced RCC.  This clinical study will be composed of a Dose Finding Phase and a Dose 
Expansion Phase.  The Dose Finding Phase will estimate the MTD in patients with advanced 
RCC patients with clear cell histology who did not receive any prior systemic therapy for 
their advanced disease, using the modified toxicity probability interval (mTPI) method.


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The Dose Finding Phase will lead to the identification of an Expansion Test Dose for axitinib 
in combination with MK-3475 in patients with advanced RCC who did not receive prior 
systemic therapy.  The Expansion Test Dose will be either the MTD (ie, the highest dose of 
axitinib and MK-3475 associated with the occurrence of DLTs in <33% of patients) or the 
RP2D, ie, the highest tested dose that is declared safe and tolerable by the Investigators and 
Sponsor.  Once the Expansion Test Dose is identified, the Dose Expansion Phase will be 
opened and axitinib in combination with MK-3475 will be tested in patients with previously 
untreated advanced RCC. 
Approximately 60 patients (including Dose Finding Phase and Dose Expansion Phase) are 
expected to be enrolled in the study.
Figure 1.
Study Schema
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10Cycle 11
EOT or PD
Axitinib PO BID Continuous Dosing
Screening
MK-3475 IV q3wk
Lead-in D1
Lead-in D7
C1D1
C2D1
C3D1
C5D1
C7D1
C9D1
C11D1
Banked Biospecimen, Archival Tumor Tissue and De Novo  Tumor Biospecimens
Baseline 
Assessments
DLT Observation 
in Dose Escalation
Dosing
Pharmacokinetics
Anti-MK-3475 Antibodies
Serum and Whole Blood Biomarkers
Study Treatment: Axitinib will be given orally (PO) twice daily (BID), with or without food, 
on a continuous dosing schedule.  MK-3475 will be given as 30-minute intravenous infusion 
every 3-weeks.  In all patients, treatment with study drugs will continue until confirmed 
disease progression, patient refusal, patient lost to follow up, unacceptable toxicity, 
whichever occurs first, or the study is terminated by the Sponsor (see Section 6.4 Study 
Withdrawal). 
Patients will be monitored closely for toxicity and in the event of significant toxicity dosing 
may be delayed and/or reduced (Section 5.2.7).  Axitinib and MK-3475 dose modifications 
for drug-related toxicities are described in the Table 5 and Table 6.  Based on the known 
safety profile of axitinib, blood pressure as well as thyroid function will be monitored 
throughout the treatment period.  Axitinib treatment may be adjusted by dosing interruption 
with or without dose reduction (Section 5.2.7.2).  Based on data emerging from trials of 
VEGF tyrosine kinase inhibitors given in combination with PD-1 inhibitors, liver function 
tests will be monitored closely for the first 3 cycles.49  MK-3475 dose modification and 


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supportive care for drug related toxicities, including immune-related adverse events (irAEs 
are described in Section 5.2.7.4.
Intra-patient dose escalation for axitinib is permitted only after completing 12 weeks of 
treatment if the starting dose of axitinib is 5 mg BID (DL1), and after 6 weeks if axitinib 
starting dose is 3 mg BID (DL-1) (Section 5.2.7).
The treatment duration with MK-3475 is 24 months calculated from the date of the first dose 
of MK-3475.  Continuation of treatment with MK-3475 beyond 24 months should be 
discussed with the sponsor and not go beyond 36 months.  After completing treatment with 
MK-3475, patients experiencing objective response or stable disease may continue on 
treatment with axitinib single agent until disease progression, patient refusal, unacceptable 
toxicity or the study is prematurely terminated by the Sponsor; whichever comes first (please 
see Section 6.4, Patient Withdrawal).
Discontinuation from MK-3475 may be considered at the investigator’s discretion for 
patients who have attained a confirmed CR, have received at least 24 weeks of treatment with 
MK-3475, and have received at least two MK-3475 infusions beyond the date the CR was 
initially declared.  Axitinib may be continued in those patients.  Patients who then experience 
radiologic disease progression will be eligible for re-treatment with MK-3475 at the 
discretion of the investigator if no other cancer treatment was administered other than 
axitinib since the last dose of MK-3475, the patient still meets the safety parameters listed in 
the Inclusion/Exclusion criteria, and the trial is still open.  Patients will resume MK-3475 
therapy at the same dose and schedule in place at the time of discontinuation.  MK-3475 
treatment will be administered for up to one additional year.
Patients with unacceptable toxicity attributed to one of the two drugs may be eligible for 
continued treatment with the other drug (after discussion between the Investigator and the 
Sponsor). 
Tumor assessment: Anti-tumor activity will be assessed by radiological tumor assessments 
conducted at baseline, then at 12 weeks and every 6 weeks thereafter, using RECIST 
version 1.1.  In addition, radiological tumor assessments will also be conducted whenever 
disease progression is suspected (eg, symptomatic deterioration), and at the time of End of 
Treatment/Withdrawal (if not done in the previous 6 weeks).  In determining whether or not 
the tumor burden has increased or decreased, Investigators should consider all target lesions 
as well as non-target lesions according to RECIST v 1.1 (see Study Reference Manual).
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD.  Assigned study treatment may be continued at the investigator’s 
discretion while awaiting radiologic confirmation of progression.  If repeat imaging does not 
confirm PD, study treatment may be continued/resumed.  Patients that are deemed clinically 
unstable are not required to have repeat imaging for confirmation of PD and can discontinue 
treatment immediately.


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If the repeat imaging confirms PD (Section 5.2.4.1) patients may be discontinued from 
treatment.  However, according to the investigator’s clinical judgment and after discussion 
between the investigator and the Sponsor, if a patient with evidence of disease progression is 
still experiencing clinical benefit, he/she will be eligible for continued treatment with single 
agent axitinib, MK-3475 or axitinib combined with MK-3475 as long as the following 
criteria are met: 

Absence of clinical signs and symptoms of disease progression. 

No decline in performance status. 

Absence of rapid progression of disease by radiographic imaging. 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
Brain CT or MRI scans are required at baseline and when there is a suspected brain 
metastasis.  Bone scans: Bone scan (bone scintigraphy) or 18F-FDG-PET/CT is required at 
baseline then every 12 weeks only if bone metastases are present at baseline.  Otherwise bone 
imaging is required only if new bone metastases are suspected.  Bone imaging is also 
required at the time of confirmation of response for patients who have bone metastases. 
Retrospective central review of all imaging time points may be performed for this study, 
therefore all imaging source data should be retained at the site and be available for future 
inspection or further analysis.  Additional information is included in the Study Reference 
Manual.
Pharmacokinetic assessment: MK-3475 and axitinib do not have competing 
elimination/metabolism pathways, hence an overt PK interaction between the two drugs is 
not anticipated.  However, pharmacokinetic assessments will be conducted in this study to 
confirm the absence of drug-drug interactions.  To understand the PK effects of MK-3475 on 
axitinib, a 7-day lead-in period of single-agent axitinib will be included prior to Cycle 1 in all 
patients in the Dose Finding Phase and in at least 8 patients in the Dose Expansion Phase of 
the study.  Axitinib has a plasma half life of 2.5-4.1 hours and is expected to reach 
steady-state within 2 to 3 days of dosing.  MK-3475 has a long plasma half-life (21-28 days) 
and trough concentrations increase with successive doses until steady state, which is 
expected within 5 months of MK-3475 dosing.  The administration of single agent MK-3475 
to this patient population is not considered in this trial.  Therefore, the effect of axitinib on 
MK-3475 will be evaluated by comparing MK-3475 pharmacokinetics at steady-state in the 
presence of axitinib with those reported for MK-3475 alone in prior studies.  At least 
8 patients (target is 8 PK evaluable patients) from the Dose Expansion Phase will participate 
in PK assessments, therefore these patients will undergo the 7-day lead-in period for axitinib.  
There will be no lead-in period for the remaining patients in the Dose Expansion Phase. 


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Tumor biopsy assessment and translational studies: Archived (all patients) and baseline 
de novo tumor biospecimens from metastatic lesions (Dose Expansion Phase only) will be 
collected for retrospective assessment. For all patients in the Dose Expansion Phase, a 
second tumor biopsy is strongly encouraged at the time of first tumor assessment 
(ie, 12 weeks) to assess the effects of the combination on the relevant pathways.  Biomarker 
studies on tumor biospecimens including but not limited to tumor PD-L1 expression and 
blood levels of VEGF-A, IL-8 and VEGFR-2, will be carried out to help understand the 
mechanism of action of the axitinib plus MK-3475 combination, pharmacodynamic effects, 
as well as potential mechanisms of sensitivity and resistance.  Such results may help in the 
future development of this combination.  Analyses using translational approaches may also 
result in the identification of potential biomarkers of response to the axitinib plus MK-3475 
combination, ultimately leading to development of a patient selection strategy for further 
clinical investigation.  As such collection of tumor tissue and blood specimens at baseline 
and on study will be of paramount importance.
3.1.1. Dose Finding Phase
3.1.1.1. Starting Doses for Axitinib and MK-3475 (Dose Level 1)
The starting doses (Dose Level 1) are axitinib 5 mg BID and MK-3475 2 mg/Kg IV Q3W in 
three-week cycles. 
3.1.1.2. Criteria for Dose Finding 
Dose finding will follow an “Up-and-Down” design, using doses of MK-3475 and axitinib as 
shown in Table 1.
Table 1.
Dose Levels in the Dose Finding Phase
Dose Level
MK-3475
Axitinib
1 (Starting Dose Level)
2 mg /kg IV q3wk
5 mg BID
-1
2 mg /kg IV q3wk
3 mg BID
BID: twice daily; q3wk: every 3 weeks
Possible dose finding scenarios based on the starting (1) dose level tolerability are illustrated 
in Table 2.  DL-1 will be explored only if the MTD is exceeded already at DL1. 
In this dosing algorithm there are up to 2 potential dose levels (DL): (DL-1) MK-3475 
2 mg/kg q3wk + axitinib 3 mg BID and (DL1) MK-3475 2 mg/kg q3wk + axitinib 5 mg BID. 
Alternative doses, schedule(s) and PK time points may be reconsidered during the study 
based on the emerging safety and PK data.
There are several potential dosing finding sequences for MK-3475 + axitinib.  The specific 
sequence to be followed depends upon the number of patients enrolled in the study and the 
number of DLTs observed at each specific dose combination.  The sequences are mutually 
exclusive, meaning only one of the sequences will be followed through the course of the 
study.  Some possible sequences are listed below in Table 2. 


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Table 2.
Possible Dose Finding Sequences
Possible sequences starting at Dose Level 1 
DL1 
DL1 DL-1
DL1 DL-1DL1
Dosing will begin at DL1 and possibly de-escalated to DL -1 according to Table 3.  Dose 
escalation from DL -1 back to DL 1 will be allowed as long as DL 1 has not been determined 
to have exceeded the MTD.  The escalation/de-escalation rules will follow the mTPI 
method23 (see Section 9.2).  Briefly, the mTPI method relies upon a statistical probability 
algorithm, calculated using all patients treated in prior and current cohorts at the same dose 
level to determine where future cohorts should involve dose escalation, no change in dose, or 
dose de-escalation.  The detailed dose-finding rules based on the mTPI are illustrated in 
Table 3.
Table 3.
Detailed Dose Escalation/De-Escalation Scheme
Number of patients treated at current dose
1
2
3
4
5
6
7
8
9
10
Number of toxicities
0
NA
NA
E
E
E
E
E
E
E
E
1
NA
NA
S
S
S
E
E
E
E
E
2
NA
D
S
S
S
S
S
S
S
3
DU
DU
D
D
S
S
S
S
4
DU
DU
DU
DU
DU
DU
DU
5
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
NA = Not Applicable.  The first three patients will have to be evaluable for DLT before assigning DL for the 
next patient
MTD = 30%
As an example, if the total number of patients treated at DL1 is 3 the following dosing rules 
are applied:

0 - 1 DLT remain at the same dose (DL1);

2 DLTs de-escalate to DL-1 and allow for possible escalation back to DL1;


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
3 DLTs de-escalate to DL-1 and consider DL1 as intolerable.
If the dose is de-escalated to DL-1 and the total number of patients then treated at DL-1 is 3
the following dosing rules are applied:

0 DLTs escalate back to DL1; 

1 DLT remain at the same dose (DL-1);

2-3 DLTs de-escalation not possible consider DL-1 as intolerable.
Rules for dose-finding, using the mTPI method, include the following:

The target enrollment cohort size is 3 patients.  The first 3 patients treated at each 
dose level will initiate dosing sequentially, at least 2 days apart from each other to 
allow for the initial evaluation of toxicities and tolerability.  If the first 2 patients 
experience a DLT prior to enrollment of the third one, the dose level will be deemed 
intolerable and the dose level will be de-escalated.  If there are no safety concerns, 
any additional patients enrolled to this dose cohort will not be required to initiate 
dosing sequentially.

The next cohort can be enrolled when all patients at the current dose cohort have been 
evaluated for 6 weeks (ie, the first 2 treatment cycles), or experience a DLT, 
whichever comes first.

If a patient withdraws from study treatment before receiving at least 75% of the 
planned first two cycles dose of axitinib or two infusions of MK-3475 within the DLT 
observation period for reasons other than study drug-related toxicity, another patient 
will be enrolled to replace that patient at the current dose level.

The dose-finding component of the trial is completed when 10 DLT-evaluable 
patients have been treated at the highest dose associated with DLT rate <0.33.  It is 
estimated that approximately 20 DLT-evaluable patients will need to be enrolled to 
reach 10 DLT-evaluable patients at the estimated MTD.

The proposed doses, schedule, and PK timepoints may be reconsidered and amended 
during the study based on the emerging safety and pharmacokinetic data.

The RP2D will be confirmed in the Dose Expansion Phase, taking into account the 
MTD determination from the Dose Finding Phase, and other factors related to safety, 
efficacy, and PK/PD involving all available data from test cohorts.
No intrapatient dose escalation will be permitted in the Dose Finding Phase.


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3.1.2. DLT Definition
Severity of adverse events will be graded according to NCI CTCAE version 4.03 
(see Appendix 3).  For the purpose of Dose Finding, any of the following adverse events 
occurring during the DLT observation period (6 weeks) that are attributable to one or both 
study drugs will be classified as DLTs:

Hematologic:
Grade 4 neutropenia;
Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of 
38 degrees C (100.4 degrees F) for more than one hour; 
Grade 3 neutropenic infection;
Grade 3 thrombocytopenia with bleeding;
Grade 4 thrombocytopenia.

Non-hematologic:
Grade 3 non-laboratory toxicities despite maximum supportive therapy. 
Grade 3 hypertension despite maximal medical therapy.

Non-hematologic Grade 3 laboratory value if:
Medical intervention is required to treat the patient, or
The abnormality leads to hospitalization. 

Inability to complete at least 75% of axitinib dosing or two infusions of MK-3475 within 
the 6-weeks DLT observation period due to treatment-related toxicity. 
3.2. Maximum Tolerated Dose Definition
The MTD estimate is the highest dose of axitinib and MK-3475 associated with the 
occurrence of DLTs in <33% of patients.
3.3. Dose Expansion Phase Test Dose Definition
The Expansion Test Dose will be the MTD identified in the Dose Escalation Phase.  Further 
experience in the Dose Expansion Phase cohort may result in the need to explore a lower 
Expansion Test Dose.


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3.3.1. Dose Expansion Phase
All patients in the Dose Expansion Phase may be enrolled simultaneously.
3.4. Recommended Phase 2 Dose Definition
The RP2D is the dose of axitinib and MK-3475 in combination chosen for further clinical 
development.  If the MTD proves to be clinically feasible for long term administration in a 
reasonable number of patients, this dose usually becomes the RP2D.  Further experience in 
the Dose Expansion Cohort may result in a RP2D dose lower than the MTD.
For axitinib, intra-patient dose escalation to higher doses may be permitted after 12 weeks of 
treatment if the starting dose of axitinib is 5 mg BID (DL1), and after 6 weeks if axitinib 
starting dose is 3 mg BID (DL-1) (see Section 5.2.7.1).
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient. 
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the Investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis

Histologically or cytologically confirmed advanced RCC with predominantly clear 
cell subtype.

Primary tumor resected.

Mandatory archival tumor biospecimen (all patients) and baseline de novo biopsy 
from a metastatic lesion (Expansion Cohort only).  Formalin fixed, paraffin 
embedded [FFPE] tissue block(s) or at least 12 unbaked, unstained slides are 
required.  Tissue samples taken from a metastatic lesion prior to the start of screening 
are acceptable.

At least one measureable lesion as defined by RECIST version 1.1.
2. Age 18 years. 
3. ECOG performance status 0 or 1 (see Appendix 1).


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4. Adequate bone marrow function, including:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL.
5. Adequate renal function, including:
a.
Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 60 mL/min as calculated using the method standard for the institution; and 
b. Urinary protein <2+ by urine dipstick.  If dipstick is 2+, then a 24-hour urinary
protein <2 g per 24 hours.
6. Adequate liver function, including:
a.
Total serum bilirubin 1.5 x ULN; 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 x ULN 
(5.0 x ULN if there is tumor involvement in the liver); 
c.
Alkaline phosphatase 2.5 x ULN (5 x ULN in case of bone metastasis).
7. INR or prothrombin time (PT) <1.5 x ULN.
8. No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline 
blood pressure (BP) readings taken at least 1 hour apart.  The baseline systolic BP 
readings must be 150 mm Hg, and the baseline diastolic BP readings must be 
90 mm Hg. 
9. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legal representative) has been informed of all pertinent aspects of the study.
10. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
11. Serum/urine pregnancy test (for females of childbearing potential) negative at screening 
and at the baseline visit (before the patient may receive the investigational product).
12. Male and female patients of childbearing potential must agree to use two highly effective 
methods of contraception throughout the study and for at least 120 days after the last dose 
of assigned treatment.  A patient is of childbearing potential if, in the opinion of the 
Investigator, he/she is biologically capable of having children and is sexually active. 


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4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Prior systemic therapy directed at advanced RCC.
2. Prior adjuvant or neoadjuvant therapy if disease progression or relapse has occurred 
during or within 12 months after the last dose of treatment.
3. Prior therapy with axitinib (AG-013736).
4. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
5. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to study entry.
6. Active autoimmune disease or a documented history of autoimmune disease or syndrome 
that requires systemic steroids or immunosuppressive agents.  Patients with vitiligo or 
resolved childhood asthma/atopy would be an exception.  Patients that require 
intermittent use of bronchodilators or local steroid injections and patients with 
hypothyroidism stable with hormone replacement will not be excluded from study. 
7. Major surgery <4 weeks or radiation therapy <2 weeks of study entry.  Prior palliative 
radiotherapy (10 fractions) to metastatic lesion(s) is permitted, provided it has been 
completed at least 48 hours prior to the initiation of study medication and there is at least 
one measurable lesion that has not been irradiated. 
8. Gastrointestinal abnormalities including:

Inability to take oral medication;

Requirement for intravenous alimentation;

Prior surgical procedures affecting absorption including total gastric resection;

Treatment for active peptic ulcer disease in the past 6 months;

Active gastrointestinal bleeding as evidenced by hematemesis, hematochezia or 
melena in the past 3 months without evidence of resolution documented by 
endoscopy or colonoscopy;

Malabsorption syndromes.


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9. Requirement of anticoagulant therapy with oral vitamin K antagonists.  Low-dose 
anticoagulants for maintenance of patency of central venous access device or prevention 
of deep venous thrombosis is allowed.  Therapeutic use of low molecular weight heparin 
is allowed.
10. Evidence of inadequate wound healing.
11. Active bleeding disorder or other history of significant bleeding episodes within 30 days 
before study entry.
12. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations.
13. History or known active seizure disorder or new evidence of brain metastases, spinal cord 
compression, or carcinomatous meningitis. 
14. Any of the following within the 12 months prior to study drug administration: myocardial 
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack.
15. Deep vein thrombosis or pulmonary embolism within 6 months prior to study drugs 
administration.
16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness. 
17. Active infection requiring systemic therapy.
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected). 
19. Administration of a live vaccine within 30 days prior to the first dose of trial treatment. 
20. History of or known presence of extensive, disseminated/bilateral or Grade 3 or 4 
interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative 
bronchiolitis, or pulmonary fibrosis, but not including a history of prior radiation 
pneumonitis.
21. Current use or anticipated need for treatment with drugs or foods that are known strong 
CYP3A4/5 inhibitors including but not limited to atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin, voriconazole, and grapefruit or grapefruit juice.  The topical use of these 
medications (if applicable), such as 2% ketoconazole cream, is allowed.


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22. Current use of anticipated need for treatment with drugs that are known strong 
CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort.
23. Diagnosis of any other malignancy within 2 years prior to registration, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix or low grade (Gleason 6 or below) prostate cancer on surveillance 
with no plans for treatment intervention (eg, surgery, radiation or castration).
24. Patients who are investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of the 
trial. 
25. Participation in other studies within 4 weeks before the current study begins and/or 
during study participation.
26. Pregnant females; breastfeeding females; males and females of childbearing potential 
who are unwilling or unable to use a highly effective method of contraception as outlined 
in this protocol for the duration of the study and for at least 120 days after last dose of 
study drugs.
27. Other severe acute or chronic medical (including severe gastrointestinal conditions such 
as diarrhea or ulcer) or psychiatric condition, including recent (within the past year) or 
active suicidal ideation or behavior, or end-stage renal disease on hemodialysis, or 
laboratory abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the Investigator, would make the patient inappropriate for 
entry into this study.
4.3. Life Style Guidelines 
4.3.1. Contraception
In this study, fertile male patients and female patients who are of childbearing potential will 
receive axitinib, which has been associated with teratogenic risk, in combination with 
MK-3475.  Patients who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s) must agree to use 2 methods of highly effective contraception 
throughout the study and continued for at least 120 days after the last dose.  The Investigator 
or his or her designee, in consultation with the patient, will confirm that the patient has
selected 2 appropriate methods of contraception for the individual patient and his or her 
partner(s) from the permitted list of contraception methods (see below) and will confirm that 
the patient has been instructed in their consistent and correct use.  At time points indicated in 
the Schedule of Activities, the investigator or designee will inform the patient of the need to 
use 2 highly effective methods of contraception consistently and correctly and document the 
conversation, and the patient’s affirmation, in the patient’s chart.  In addition, the 
Investigator or designee will instruct the patient to call immediately if 1 or both of the 


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selected contraception methods is discontinued or if pregnancy is known or suspected in the 
patient or partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:

Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal),  provided the patient 
or male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.

Correctly placed copper containing intrauterine device (IUD).

Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.

Male sterilization with absence of sperm in the post-vasectomy ejaculate.

Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the Study Reference Manual.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the patients 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the patient directly and if a patient calls that number they 
will be directed back to the investigational site.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are axitinib and MK-3475.
5.1. Allocation to Treatment
Dose level allocation will be performed by the Sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments.
The site staff will fax or e-mail a complete Registration Form to the designated Sponsor 
study team member(s) requesting approval for patient enrollment.
After review of patient’s eligibility and concomitant medications, the Sponsor will approve 
patient’s enrollment, if appropriate, and assign a patient identification number, which will be 
used on all Case Report Form (CRF) pages and other trial-related documentation or 
correspondence referencing that patient.
The Sponsor will fax or email the approved Registration Form reporting the patient 
identification number to the site.
No patient shall receive study drug until the Investigator or designee has received the 
following information in writing from the Sponsor:

Confirmation of the patient’s enrollment.

Specification of the dose level for that patient.

Permission to proceed with dosing the patient.
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Drug Supplies
Axitinib (AG-013736) and MK-3475 will be supplied for the study by Pfizer Global Clinical 
Supply, Worldwide Research and Development.  Drug supplies will be shipped to the study 
sites with a Drug Shipment & Proof of Receipt form.  This form will be completed, filed, and 
the shipment confirmed as directed on the bottom of the Drug Shipment & Proof of Receipt 
form.  The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage 
of investigational product in accordance with the protocol and any applicable laws and 
regulations.


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5.2.1. Formulation and Packaging
5.2.1.1. Axitinib
Axitinib will be supplied as 1 mg, and 5 mg film-coated tablets for oral administration in 
High Density Polyethylene (HDPE) bottles with desiccant.
5.2.1.2. MK-3475
MK-3475 will be supplied in single-use vials containing 100 mg/4mL sterile solution for 
intravenous administration.  Each vial is sealed with a coated stopper and oversealed and 
labeled according to local regulatory requirements. 
5.2.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
Axitinib will be dispensed in opaque plastic bottles to protect the compounds from light.  
Axitinib is a hazardous drug (due to possible reproductive toxicity), and should be handled 
according to the recommended procedures described in the current edition of the American 
Society of Hospital Pharmacists (ASHP), Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs, American Hospital Formulary Service (AHFS) Drug 
Information (1999) and its references.  Procedures described in each institution’s pharmacy 
or hospital standard operating procedure manual should be followed when handling 
hazardous drugs.
Axitinib will be provided in quantities appropriate for the study visit schedule.  A qualified 
staff member will provide the study medication via a unique container number using the drug 
management system.
Axitinib will be dispensed every 3 weeks or as otherwise indicated.  Patients should be 
instructed to keep their medication in the bottles provided and not transfer it to any other 
container.  In the event of dose modification, a request should be made of the patient to 
return all previously dispensed medication to the clinic.
MK-3475 will be dosed at the investigational site as indicated in Section 5.2.4.1.
Specific preparation and dispensing instructions are provided in the Dosage Administration 
Instruction located in the Study Manual.
5.2.3. Administration
All trial treatment will be administered on an outpatient basis.


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5.2.3.1. Axitinib
Axitinib will be administered orally BID at approximately the same time in the morning and 
evening on a continuous daily dosing schedule, ie, without a break in dosing in the absence 
of drug-related toxicity (see Section 5.2.7.2).  Axitinib tablets are to be taken approximately 
12 hours apart and may be administered without regard to meals.  Tablets must not be 
crushed, split or dissolved and patients should be instructed to swallow the study medication 
whole without manipulation or chewing of the medication prior to swallowing. 
A dosing card will be provided to the patients to provide guidance for the correct use of the 
two drugs. 
Patients must be instructed that if they miss a dose or vomit anytime after taking a dose, they 
must not “make it up” with an extra dose, but instead resume subsequent doses as prescribed.  
Any missed dose may be taken late up to 3 hours for axitinib dose before the next scheduled 
dose, otherwise, it should be skipped and dosing resumed with subsequent doses as 
prescribed.  Patient must be instructed to record all doses (missed or vomited doses) in a 
dosing diary supplied by the site.  If doses are missed or vomited, this must be indicated in 
the source documents and CRFs.
If a patient inadvertently takes 1 extra dose during a day, the patient should not take the next 
dose.
Treatment with axitinib will continue until confirmed disease progression, patient refusal, 
patient lost to follow up, unacceptable toxicity, whichever occurs first, or the study is 
terminated by the Sponsor (see Section 6.4, Patient Withdrawal).
5.2.4. MK-3475
5.2.4.1. MK-3475 Timing of Dose Administration
MK-3475 will be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed in the Schedule of Activities table.  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.
MK-3475 will be administered as a 30 minute IV infusion every 3-weeks, next cycle 
administration may be delayed due to persisting toxicity as described in Section 5.2.7. 
See the Dosage and Administration Instructions (DAI), for instructions on how to prepare the 
investigational product for administration.  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as allowed by local, 
state, and institutional guidance.


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Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of 
-5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min).  
The exact duration of infusion should be recorded in both sources document and CRFs.
The dose amount required to prepare the MK-3475 infusion solution will be based on the 
patient’s weight in kilograms (kg).
For purposes of this trial, an overdose will be defined as any dose 20% over the prescribed 
dose for the standard treatments.  No specific information is available on the treatment of 
overdose of MK-3475.  In the event of overdose, the patient should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If a dose of MK-3475 meeting the protocol definition of overdose is administered without 
inducing any associated clinical symptoms or abnormal laboratory results, then the overdose 
is reported in CRF as a non-serious adverse event, using the terminology “accidental or 
intentional overdose without adverse effect.” Also see Section 5.2.5 Medication Errors. 
The Study Reference Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
5.2.4.2. MK-3475 Treatment Duration
The treatment duration with MK-3475 is 24 months calculated from the date of the first dose 
of MK-3475.  Continuation of treatment with MK-3475 beyond 24 months should be 
discussed with the sponsor and should not go beyond 36 months. Patients who stop 
MK-3475 for reasons other than confirmed disease progression may continue on treatment 
with axitinib single agent until disease progression (RECIST v. 1.1), patient refusal, and 
unacceptable toxicity occurs; or the study is prematurely terminated by the Sponsor; 
whichever comes first (see Section 6.4 Patient Withdrawal).
Discontinuation from MK-3475 treatment may be considered at the investigator’s discretion 
for patients who have attained a confirmed CR, that have been treated for at least 24 weeks 
with MK-3475 and have at least two treatments with MK-3475 beyond the date the initial CR 
was declared.  Axitinib treatment may continue in these patients.  Patients who then 
experience radiologic disease progression will be eligible for treatment (see 
Section 5.2.4.2.1) with MK-3475 at the discretion of the investigator if no cancer treatment 
was administered other than study drugs since the last dose of MK-3475, the patient meets 
the safety parameters listed in the Inclusion/Exclusion criteria and the trial is open.  Patients 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  
MK-3475 treatment will be administered for up to one additional year.


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5.2.4.2.1. Treatment after Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD.  Study treatment may continue according to the investigator’s discretion 
while awaiting radiologic confirmation of progression.  If repeat imaging shows a reduction 
in the tumor burden demonstrating CR, PR or SD compared to the initial scan, treatment may 
be continued/resumed.  In determining whether or not the tumor burden has increased or 
decreased, Investigators should consider all target lesions as well as non-target lesions 
(please refer to the Study Reference Manual). 
If the repeat imaging demonstrates confirmed evidence of PD, progressive disease, patients 
may be discontinued from the study.  However, according to the investigator’s clinical 
judgment and after discussion between the investigator and the Sponsor, if a patient with 
evidence of disease progression is still experiencing clinical benefit, the patient will be 
eligible for continued treatment with single agent axitinib, MK-3475 or axitinib combined 
with MK-3475.  The investigator’s judgment should be based on the overall benefit-risk 
assessment and the patient’s clinical condition, including performance status, clinical 
symptoms, adverse events and laboratory data.  Patients may receive study treatment while 
waiting for confirmation of PD if they are clinically stable as defined by the following 
criteria: 

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression. 

No decline in ECOG performance status. 

Absence of rapid progression of disease by radiographic imaging. 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
5.2.5. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page (refer to ADVERSE 
EVENT REPORTING section for further details).
5.2.6. Food Requirements
Axitinib can be taken with or without food.  MK-3475 is administered as a 30-minute 
intravenous infusion without regard to food.
5.2.7. Recommended Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule.
In the event of significant toxicity dosing may be delayed and/or reduced as described below.  
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed.  Patients are to be instructed to notify Investigators at the first occurrence of any 
adverse symptom.
Dose modifications may occur in three ways:

Within a cycle (for axitinib only): dosing interruption until adequate recovery, if 
required, during a given treatment cycle.

Between cycles (for MK-3475 only): next cycle administration may be delayed due to 
persisting toxicity when a new cycle is due to start 

In the next cycle (for axitinib only): dose reduction may be required in a subsequent 
cycle based on toxicity experienced in the previous cycle.
Investigators are encouraged to employ best supportive care according to local institutional 
clinical practices and according to the guidance for selected adverse events provided below.
Dose modifications will be reported in the CRF.
Axitinib dose levels for intrapatient dose modification are listed in Table 4.


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5.2.7.1. Axitinib Intra-Patient Dose Increase
Axitinib intra-patient dose increase is permitted only after completing 12 weeks of axitinib 
treatment if the starting dose of axitinib is 5 mg BID (DL1), and after 6 weeks if axitinib 
starting dose is 3 mg BID (DL-1) Table 1. 
Patients who tolerate the current axitinib dose with no grade 2 drug-related adverse events 
for 2 consecutive weeks have the option to have their axitinib dose increased by one dose 
level in subsequent cycles as indicated in Table 4, up to a maximum dose of 10 mg BID 
(unless the patient’s BP is >150/90 mm Hg or the patient is receiving antihypertensive 
medication).  Particular attention should be provided to a patient’s overall safety profile prior 
to implementing intra-patient dose increase for axitinib.
Table 4.
Axitinib Dose Levels
Dose Level
Dose
+2
10 mg BID
+1
7 mg BID
Starting dose
5 mg BID
-1
3 mg BID
-2
2 mg BID
5.2.7.2. Axitinib Dose Modifications in Case of Drug-Related Toxicity
Patients will be monitored closely for toxicity, and axitinib treatment may be adjusted by 
dosing interruption with or without dose reduction as indicated below.  Dose modification 
can occur independently for the 2 drugs used in this study.  Dosing interruption and/or dose 
reduction by 1, and if needed, 2 doses will be allowed depending on the type and severity of 
toxicity encountered.  If the patient is already at the lowest dose level (2 mg BID), axitinib 
should be permanently discontinued.  Management of patients requiring more than 2 dose 
reductions should be discussed with the Sponsor.
5.2.7.3. Management of Axitinib-Related Hypertension
Patients will be issued BP cuffs (provided by the Sponsor) for home monitoring and 
instructed to measure their BP twice daily, prior to taking each axitinib dose.  All BP 
measurements will be recorded in a diary and brought to the nurse or study coordinator at 
each clinic visit.  Patients should contact the site for guidance if their systolic BP rises above 
150 mm Hg, diastolic BP rises above 100 mm Hg, or if they develop symptoms perceived to 
be related to elevated BP (eg, headache, visual disturbance).
To treat an increase in BP, standard antihypertensives can be used (for example, thiazide or 
thiazide-like diuretics, angiotensin II receptor blockers, angiotensin converting-enzyme 
inhibitors, and dihydropyridine (DHP) calcium channel blockers) although bradycardic 
agents (such as beta adrenergic blockers with or without alpha-blocking properties, and 
non-DHP calcium channel blockers, clonidine, digoxin) should be avoided to the extent 
possible (see Section 5.4).47,48
Recommended axitinib dose modifications in case of drug-related toxicity are shown in 
Table 5.


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Table 5.
Axitinib Dose Modifications for Drug-Related Toxicity
Toxicity
NCI CTCAE Severity 
Grade
Axitinib
Dose Modification
Hematologic Laboratory 
Abnormalities
Grade 1, 2 or 3
Continue at the same dose level.
Grade 4
Withhold until recovery to Grade 2.
Then, reduce by 1 dose level and resume treatment.
Grade 4 lymphopenia not associated with clinical events, 
eg, opportunistic infection: study treatment may 
continue without interruption.
AST, ALT with total 
bilirubin <2xULN and 
PT/INR <1.5xULN 
Grade 1
Continue at the same dose level
Grade 2
Withhold until resolution to <2xULN or baseline.  
Restart at same dose level or one lower dose level.
Grade 3 and 4
Withhold until resolution to <2xULN or baseline.  
Restart at one lower dose level.
AST/ALT Elevation with 
clinically significant 
hepatic dysfunction 
(ie, total bilirubin 
2xULN excluding 
biliary obstruction or 
PT/INR 1.5xULN)
Permanently discontinue and follow-up per protocol.
Non-hematologic
Toxicities, Laboratory 
Abnormalities and/or 
Other Drug Related 
Toxicitiesb
Grade 1 
Continue at the same dose level.
Grade 2
Continue at the same dose level. 
Grade 3
Reduce by 1 dose level.
Grade 3 toxicities controlled with symptomatic 
medications, or Grade 3 asymptomatic biochemistry 
(other than LFTs) laboratory abnormalities may continue 
at the same dose level per Investigator judgment. 
Grade 4
Other non-hematologic/laboratory and non-laboratory 
abnormalities, hold treatment until recovery to Grade <2
then, reduce by 1 dose level and resume treatment.
Grade 4 asymptomatic biochemistry laboratory (other 
than LFTs) abnormality: study treatment may continue 
without interruption per Investigator’s judgment.  
Proteinuria
Dipstick negative or 
shows 1+ (Grade 1)
Continue at the same dose level.
If dipstick shows >1+, perform 24 hour urine collection.  Dosing may continue 
while waiting for test results
<2 g proteinuria/
24 hour
Continue at the same dose level.


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Toxicity
NCI CTCAE Severity 
Grade
Axitinib
Dose Modification
2 g proteinuria/
24 hours
Withhold until proteinuria is <2 g/24 hours.
Repeat 24-hour urine collection for proteinuria and 
creatinine clearance (interval at Investigator discretion) 
until proteinuria is <2 g/24 hours. 
Then, resume at the same dose level or reduce by 1 dose 
level as per Investigator judgment.
Hypertension
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure 150 mm Hg 
(one or both readings) 
And
2 diastolic BP readings 
separated by at least 1 
hour show diastolic 
pressure 100 mm Hg 
(one or both readings)
Continue at the same dose level
See Section 5.2.7.3 for monitoring/management of 
axitinib-related hypertension
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >150 mm Hg
OR
2 diastolic BP readings 
separated by at least 1 
hour show diastolic 
pressure >100 mm Hg
If not on maximal antihypertensive treatment, institute 
new or additional antihypertensive medication and 
continue at the same dose level. 
If on maximal antihypertensive treatment, reduce by 
1 dose level.
See Section 5.2.7.3 for monitoring/management of 
axitinib-related hypertension.
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >160 mm Hg 
OR
2 diastolic BP readings 
separated by at least 1 
hour show diastolic 
pressure >105 mm Hg
Withhold until BP is less than 150/100 mm Hg 1 and 
adjust antihypertensive medication.
Then, reduce by 1 dose level and resume treatment. 
1 If axitinib dosing is temporarily discontinued, patients 
receiving antihypertensive medications should monitor 
closely for hypotension.  The plasma half-life of axitinib
is 2-4 hours and BP usually decreases within 1-2 days 
following dose interruption.
See Section 5.2.7.3 for monitoring/management of 
axitinib-related hypertension
Recurrent hypertension 
following previous dose 
reduction (2 systolic BP 
readings separated by at 
least 1 hour show 
systolic pressure 
>150 mm Hg)
OR
Recurrent diastolic BP 
>100 mm Hg (2 BP 
readings separated by at 
least 1 hour) following 
previous dose reduction
Repeat dose reduction by one lower dose level.
See Section 5.2.7.3 for monitoring/management of 
axitinib-related hypertension.
Hypophysitis
Grade 1
Continue at the same dose level.
Grade 2-4
Continue at the same dose level.


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Toxicity
NCI CTCAE Severity 
Grade
Axitinib
Dose Modification
Type 1 diabetes mellitus 
(if new onset) or 
hyperglycemia
Grade 1-2
Continue at the same dose level.
Grade 3-4
Continue at the same dose level or follow guidelines in 
non-hematologic toxicities.
Diarrhea/Colitis
Grade 1
Continue at the same does level.
Grade 2
Continue at the same dose level.
Grade 3
Reduce by 1 dose level.
Follow the guidelines as in non-hematologic toxicities in 
Table 5.
Grade 4
Follow the guidelines as in non-hematologic toxicities in 
Table 5.
Pneumonitis
Grade 1
Continue at the same dose level.
Grade 2
Continue at the same dose level or follow the guidelines 
in non-hematologic toxicities.
Grade 3-4
Follow the guidelines in non-hematologic toxicities.
Hyperthyroidism
Grades 1-2
Continue at the same dose level.
Grade 3
Grade 3 toxicities controlled with symptomatic 
medications, or Grade 3 asymptomatic biochemistry 
(other than LFTs) laboratory abnormalities: may 
continue at the same dose level or reduce by one dose 
level per Investigator judgment.
Grade 4
Interrupt until recovery to Grade <2 then reduce by one 
lower dose level
Renal Failure or 
Nephritis
Grade 1
Continue at the same dose level
Grade 2
Continue at the Same dose level
Grade 3 and 4
Hold treatment until recovery to Grade 2.  Then, reduce 
by 1 dose level and resume treatment.
5.2.7.4. MK-3475 Immune-Related Adverse Events
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation.  Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 6.  Additional guidance can be found in the Pembrolizumab Events of 
Clinical Interest Guidance Document.


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Table 6.
Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered.  Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid.  Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and 
follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants 
for signs and 
symptoms of 
pneumonitis
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment
Add prophylactic 
antibiotics for 
opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants 
for signs and 
symptoms of 
enterocolitis 
(ie, diarrhea, 
abdominal pain, blood 
or mucus in stool with 
or without fever) and
of bowel perforation 
(ie, peritoneal signs 
and ileus).
Participants with 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
Grade 4
Permanently 
discontinue


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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and 
follow-up 
to rule out colitis. 
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline or 
is stable
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold
Initiate insulin replacement 
therapy for participants with 
T1DM 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia 
Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism Grade 2
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate 
Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyroinine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of 
renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes
Grade 3 or 4
Permanently 
discontinue


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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and 
follow-up 
All other 
immune-related 
AEs
Intolerable/ 
persistent 
Grade 2
Withhold
Based on type and severity 
of AE administer 
corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes
Grade 3
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
5.2.8. Compliance
An Investigational Product (IP) manual will be provided to the sites and will contain 
information about the drug supplies.  A patient diary will be provided to the patients to aid in 
axitinib compliance.  The diary will be maintained by the patient to include missed or 
changed axitinib doses.
Patients will be required to return all bottles of axitinib after every cycle (every 21 days).  
The number of axitinib tablets remaining will be documented and recorded at each clinic 
visit.  The patient diary may also be used to support this part of the axitinib accountability 
process.
The site is to follow up (for example, via a telephone call) with each patient at Cycle 1 Day 5 
(+2 days) to confirm that the patient understands and is in compliance with axitinib dosing 
instructions.  If needed, the patient will be re-trained.  The same follow up process will be 
applied in case the dose of axitinib is modified during the treatment period.
5.3. Drug Storage and Drug Accountability 
The Investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 


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Investigational products should be stored in their original containers and in accordance with 
the labels.

Axitinib must be stored at controlled room temperature (between 15-30C) or as 
specified on the label.

MK-3475 must be stored under storage conditions specified on the label. 
Any storage conditions stated in the SRSD (ie, Investigator Brochure) will be superseded by 
the storage conditions stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Pfizer provides permission to use the investigational product.  It will not be 
considered a protocol deviation if Pfizer approves the use of the investigational product after 
the temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site.  Receipt of materials, door opening and closing, and other routine 
handling operations where the products are briefly out of the temperature range described in 
the labeling are not considered excursions.  Site staff will instruct patients on the proper 
storage requirements for take home investigational products.
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  Pfizer may supply drug 
accountability forms that must be used or may approve use of standard institution forms.  In 
either case, the forms must identify the investigational product, including batch or code 
numbers, and account for its disposition on a patient-by-patient basis, including specific dates 
and quantities. 


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The prescribed dose should be recorded in the patient’s medical records.  Drug dispensing 
needs to be verified and documented by a second individual and the forms must be signed by 
both the individual who dispensed the drug and the second individual who verified the 
dispensing.  Copies must be provided to Pfizer. 
All bottles of study drug must be returned to the Investigator by the patient.  The sponsor or 
designee will provide guidance on the destruction of unused investigational product (eg, at 
the site).  If destruction is authorized to take place at the investigator site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer, and all 
destruction must be adequately documented.
5.4. Concomitant Medication(s)
Concomitant treatment considered necessary for the patient’s well being may be given at 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment and up to 28 days post the last dose of study 
treatment.  All concomitant medications should be recorded in the CRF including supportive 
care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat adverse 
events or chronic diseases, and non drug supportive interventions (eg, transfusions).
Concurrent anticancer therapy with agents other than axitinib and MK-3475 is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed. 
5.4.1. Inhibitors and Inducers of CYP Enzymes (Axitinib)
In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19 and UGT1A1. 
The concomitant use of strong CYP3A4/5 inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole) should be avoided.  Selection of an alternate concomitant 
medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although 
axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 
inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of 
axitinib by approximately half is recommended, as this dose reduction is predicted to adjust 
the axitinib area under the plasma concentration vs time curve (AUC) to the range observed 
without inhibitors.  The subsequent doses can be modified based on individual safety and 
tolerability.  If co-administration of the strong inhibitor is discontinued, the axitinib dose 
should be returned (after 3 – 5 half-lives of the inhibitor) to that used prior to initiation of the 
strong CYP3A4/5 inhibitor. 


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Co-administration of axitinib with strong CYP3A4/5 inducers (eg, rifampin, dexamethasone, 
phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be 
avoided.  Selection of concomitant medication with no or minimal CYP3A4/5 induction 
potential is recommended.  Moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, 
etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and 
should be avoided if possible.
5.4.2. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first 6 weeks of treatment but they may be used to treat treatment emergent neutropenia 
as indicated by the current American Society of Clinical Oncology (ASCO) guidelines.45
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Patients who enter the study on stable doses 
of erythropoietin or darbepoietin may continue this treatment, and patients may start either 
drug during the study at the discretion of the treating physician.
5.4.3. Concomitant Surgery 
5.4.3.1. Axitinib
No formal studies of the effect of axitinib on wound healing have been conducted, however 
caution is advised based on the mechanism of action.  If a major surgery or an interventional 
procedure (eg, endoscopy) is required, treatment with axitinib must be interrupted at least 
24 hours before the procedure and the patient BP should be monitored closely for 
hypotension.  Patients may resume axitinib seven days after minor surgery and 2-3 weeks 
after major surgery, provided that wound has completely healed and there are no wound 
healing complications (eg, delayed healing, wound infection or fistula).
5.4.3.2. MK-3475
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy such as elective surgery, unrelated medical events, patient 
vacation and holidays.  Patients should be placed back on study therapy within 3 weeks of 
the scheduled interruption, unless otherwise discussed with the sponsor.  The reason for the 
interruption should be documented.
5.4.4. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain the sites of bone disease should be present at baseline, otherwise, it will be 
considered disease progression. 


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5.4.5. Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor Clinical Director.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on trial therapy or vaccination schedule requires the mutual 
agreement of the Investigator, the Sponsor, and the patient. 
5.4.6. Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol. 

Chemotherapy not specified in this protocol. 

Investigational agents other than axitinib and MK-3475. 

Radiation therapy. 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.  
However, intranasal influenza vaccines (eg, Flu - Mist) are live attenuated vaccines, and are 
not allowed.
Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of therapeutic doses of corticosteroids 
may be approved for symptomatic treatment after consultation with the Sponsor. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5. Rescue Medications & Supportive Care 
5.5.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 


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
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 

Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a MAXIMUM total daily dose of 2 g is permitted.  
Daily intake over 2 g is prohibited.

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low dose heparin cannot be administered, the 
administration of coumadin or other coumarin derivatives or other anti-coagulants 
may be allowed; however appropriate monitoring of prothrombin time/International 
normalized ratio (PT/INR) should be performed.
5.5.2. Management of MK-3475 Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Table 7 below shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of MK-3475.


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Table 7.
MK-3475 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAID, narcotics, IV fluids); 
prophylactic medications indicated 
for < = 24 hours
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluid
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the patients is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the infusion rate (eg, from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Patients may be premedicated 
1.5 hour (30 minutes) prior to 
infusion of MK-3475 with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3;
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor of 
ventilatory support indicated
Stop infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine**
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Patient is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration.


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6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see Schedule of Activities (SOA) and ASSESSMENTS section 
(Section 7). 
6.1.1. Tumor Biospecimens
Provision of archival tumor biospecimens (all patients) and baseline de novo biospecimens 
from metastatic lesions (expansion cohort) is mandatory for all patients.  Although baseline 
de novo biopsies taken from metastatic lesions prior to the date of screening are acceptable, 
sponsor provided neutral buffered formalin in kits for preferred collection on the date of 
screening to optimize tissue fixation for subsequent analysis.  A second de novo biopsy is 
strongly encouraged and collected at the time of first tumor assessment at after 4 Cycles of 
treatment (12 weeks).  It is recommended, if possible, that the 12 week biopsy be taken from 
a lesion in the same anatomical location and also fixed in sponsor provided neutral buffered 
formalin. 
For archival tumor biospecimens,  formalin fixed, paraffin embedded (FFPE) tissue block(s) 
from initial diagnosis that contain sufficient tissue to generate at least 12 slides, each with 
tissue sections (4 microns thickness preferred, 5 microns thick acceptable), will be collected.  
If no FFPE block is available, then at least 12 unbaked and unstained slides containing FFPE 
tissue sections, 5 microns thick acceptable).  However FFPE blocks are strongly encouraged 
over slides.  See Section 7.3.1.  Additional information on tumor biospecimen collection, 
processing and immediate shipping procedures is included in the study laboratory manual.
6.2. Study Period
For treatment period procedures, see Schedule of Activities (SOA) and ASSESSMENTS
section (Section 7).
6.3. End of Treatment/Withdrawal and Follow-up Visits
For follow-up procedures see Schedule of Activities (SOA) and ASSESSMENTS section 
(Section 7).  All patients should be followed for survival at least every 3 months after 
discontinuing study treatment.  Survival monitoring will continue until 3 years after Cycle 1 
Day 1 of the last patient enrolled in the study.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events and the Patient Withdrawal section) or 
behavioral reasons, or the inability of the patient to comply with the protocol required 
schedule of study visits or procedures at a given study investigator site. 


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Reasons for discontinuation of study treatment may include:

Confirmed objective disease progression according to RECIST version 1.1.  
However, patients with disease progression who are continuing to derive clinical 
benefit from the study treatment will be eligible to continue with single agent axitinib, 
MK-3475 or axitinib plus MK-3475 provided that the treating physician has 
determined that the benefit/risk for doing so is favorable;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
study drugs, the Investigator (in discussion with the Sponsor) can continue the study 
treatment with the other study drug;

Pregnancy;

Significant protocol violation (post study start; includes patient noncompliance);

Lost to follow-up;

Patient refused further treatment (follow-up permitted by patient);

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;

Lost to follow-up;

Refused further follow-up for survival;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request the patient return all unused investigational 
product(s), request the patient return for a final visit, if applicable, and follow up with the 
patient regarding any unresolved AEs.


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If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
If the patient refuses further treatment visits, the patient should continue to be followed for 
survival unless the patient withdraws consent for disclosure of future information or for 
further contact.  In this case, no further study specific evaluations should be performed, and 
no additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases the Investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol required test cannot be performed the 
Investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, ECG (12-lead), laboratory assessments, including pregnancy tests and 
verification of concurrent medications.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on two occasions prior to starting study 
therapy - once at the start of screening and once at the baseline visit, immediately before 
starting the investigational products.  Following a negative pregnancy result at screening, 
appropriate contraception must be commenced and a further negative pregnancy result will 
then be required at the baseline visit before the patient may receive the investigational 
products.  Pregnancy tests will be repeated at every treatment cycle during the active 
treatment period, at the end of study treatment and additionally whenever 1 menstrual cycle 
is missed or when potential pregnancy is otherwise suspected.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from administration of investigational 
product but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board/Independent Ethics Committees (IRB/IECs) or if required by local regulations.


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7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CAE] 
version 4.03), timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the adverse events CRF page.
7.1.2.1. MK-3475 Adverse Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms and reported 
within 24 hours to the Sponsor.  Sponsor Contact information can be found in the Study 
Reference Manual.
ECIs for this trial include:
1. An overdose of Sponsor's product, as defined in Section 5.2.4.1. MK-3475 Timing of 
Dose Administration that is not associated with clinical symptoms or abnormal laboratory 
results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents.  The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Study Reference Manual. 
3. Additional adverse events
A separate guidance document has been provided entitled “Event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document can be found in the 
Study Reference Manual and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.  Additional ECIs are identified in this guidance document 
and also need to be reported to the SPONSOR within 24 hours of the event.
Patients should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and patients should be asked for signs and symptoms suggestive of an 
immunerelated event.  Patients who develop an ECI thought to be immune-related should 
have additional testing to rule out other etiologic causes.  If lab results or symptoms indicate 
a possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.


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ECIs that occur to any patient from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Sponsor's product, must be reported within 24 hours to the Sponsor either 
by electronic media or paper.  Sponsor Contact information can be found in the Study 
Reference Manual.
7.1.3. Laboratory Safety Assessment
Haematology, blood chemistry and urinalysis will be drawn at the time points described in 
the Schedule of Activities (SOA) and analyzed at local laboratories.  They may also 
performed when clinically indicated.  The required laboratory tests are listed in Table 8.
Table 8.
Required Laboratory Tests
Hematology
Chemistry
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT
Protein, glucose and 
blood.
Urine dipstick for 
urine protein: If 
positive collect 
24-hour and 
microscopic (Reflex 
Testing)
Urine dipstick for 
urine blood: If positive 
collect a microscopic 
(Reflex Testing)
PT
For female 
patients of 
childbearing 
potential, serum 
or urine 
Platelets
AST
INR
WBC
Alk Phos
PTT
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Absolute Eosinophils
Chloride
Absolute Basophils
Calcium
Total Bilirubin***
BUN or Urea
Creatinine
Uric Acid
Glucose (non-fasted)
Albumin
Total Protein
Phosphorus or Phosphate
Thyroid Function Tests: 
TSH, free T3, free T4 (as 
indicated)
*** For potential Hy's law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR, alkaline phosphatase, total bile acids and acetaminophen drug and/or 
protein adduct levels.


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7.1.4. Vital Signs and Physical Examination
Patients will have a physical exam to include examination of major body systems, weight, 
blood pressure, pulse rate, assessment of ECOG performance status and height; (height will 
be measured at screening only) at the time points described in the Schedule of Activities
(SOA).  Blood pressure and pulse rate should be taken with the patient in the seated position 
after the patient has been sitting quietly for at least 5 minutes.  Two blood pressure readings 
will be taken at least 1 hour apart at each clinic visit.
7.1.5. ECG Measurements
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs at 
screening, Cycle 1 Day 1 and End of Treatment/Withdrawal.  Clinically significant abnormal 
findings in baseline ECGs will be recorded as medical history.  Additional ECGs will be 
performed as clinically indicated.  Clinically significant findings seen on the follow-up ECGs 
should be recorded as adverse events.
7.2. Pharmacokinetics Assessments
Plasma/serum samples will be obtained from patients for PK analysis of axitinib, MK-3475 
and anti-MK-3475-antibodies depending on the treatment cohort that they belong to.  
Samples for MK-3475 PK and anti-MK-3475-antibodies (ADA) will be collected from all 
patients in the study.  Axitinib PK samples will be collected from all patients in the Dose 
Finding Phase and at least 8 patients in the Dose Expansion Phase. 
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis 
Where noted in the Schedule of Activities (SOA), blood samples will be collected at 
approximately the same time as other assessments wherever possible. 
The PK table indicates PK blood sampling time points for axitinib alone and axitinib in 
combination with MK-3475.  On the days of axitinib PK sample collection, patients should 
be instructed to hold morning axitinib dosing until the pre dose sample has been drawn.  
Patients should have been taking axitinib uninterrupted for at least 3 days prior to each of the 
axitinib pharmacokinetic sample collection visits.  For all collections, the actual time of 
axitinib and MK-3475 dosing, as well as actual times of pharmacokinetic collections will be 
recorded in the source documents and CRF. 
Blood samples for axitinib PK, MK-3475 PK and anti-MK-3475 antibodies (ADA) will be 
collected as outlined in the Schedule for Pharmacokinetic Sample Collections table.
Pharmacokinetic samples for MK-3475 and anti-MK-3475 antibodies will also be collected 
at 1 month, 3 months and 6 months after end of MK-3475 treatment. 
In addition to samples collected at the scheduled times, additional blood samples for axitinib 
and MK-3475 should be collected from patients experiencing unexpected and/or SAE’s and 
the date and time documented in the CRF.


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All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) will be considered protocol complaint, and the exact time 
of the sample collection noted on the CRF.  If a scheduled blood sample collection cannot be 
completed for any reason, the missed sample collection may be rescheduled with agreement 
of clinical Investigators, patient and Sponsor.
PK samples will be assayed for axitinib, MK-3475 and those for anti-MK-3475 antibodies 
using validated analytical methods.  Additional details regarding the collection, processing, 
storage and shipping of the blood samples will be provided in the study manual.  As part of 
the understanding of the pharmacokinetics of the study drug, samples may be used for 
potential qualitative and/or quantitative metabolite analyses and/or evaluation of the 
bioanalytical methods for axitinib, MK-3475 and anti-MK-3475 antibodies (ADA).  The 
results of such analyses may be included in the clinical report. 
7.2.2. Collection of Axitinib PK Samples
At each time point for axitinib, a 3 mL whole blood sample will be collected into an 
appropriately labeled K3EDTA tube to provide a minimum of 1 mL plasma for 
pharmacokinetic analysis.
7.2.3. Processing, Storage and Shipment of Axitinib PK Samples
The following special precautions should be taken to minimize the rapid degradation of 
axitinib in plasma when exposed to visible light:

Following collection of blood samples, samples should be processed as soon as 
possible.  Preferably, harvested plasma should be frozen within 1 hour of collection.

The blood collection tube should be gently inverted (8-10 times) to thoroughly mix 
the blood with the anti-coagulant. 

Vacutainer tubes should be protected from light (covered completely in aluminum 
foil or in black protection tubes) and placed in an ice-bath while samples are waiting 
to be centrifuged to harvest plasma.

Following centrifugation (for at least 10 minutes at 1700 g at 4C or lower), plasma 
should be transferred rapidly to labeled amber cryovials and stored at -20C or lower. 

All samples should be transferred to an opaque box to protect from light exposure 
during storage and shipment.  If a sample is inadvertently exposed to light (for 
5 minutes or more), the sponsor should be notified so that the sample can be flagged 
for possibly spurious results.

Once frozen, samples should not be allowed to thaw, including during shipment.


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Samples will be shipped with the completed sample inventory form and sufficient dry ice to 
last for at least two days.  Detailed instructions on sample collection, preparation, storage, 
and shipping will also be provided in the Study Manual.
Axitinib and MK-3475 pharmacokinetic samples will be analyzed using separate validated 
analytical methods for each drug in compliance with Pfizer Standard Operating Procedures to 
determine plasma concentrations for axitinib, and MK-3475.
7.2.4. Collection and processing of MK-3475 PK Samples
At each time point 3-mL of blood will be collected into a 3.5 mL Serum Separator Tube 
(SST) at the designated times.  The tube should be inverted 5-6 times without shaking.  After 
collection, sample should be left standing upright at room temperature for 30 minutes but no 
more than 60 minutes to coagulate.  Centrifuge at 1100 to 1300 x g at room temperature for 
15 minutes until clot and serum are separated.  Serum should be aliquoted into 2 new tubes: 
Corning 2-mL polypropylene cryovials.  Serum samples must be frozen within 30 minutes of 
collection at –70C or colder (alternatively –20C is acceptable for up to 1 month) and 
maintained in the frozen state until assayed.
7.2.5. Collection and Processing of Anti-MK-3475 Antibody Samples
At each time point 6-mL of blood will be collected into a Serum Separator Tube (SST) at the 
designated times.  Allow blood to remain upright at room temp for at least 30 min but not to 
exceed 60 min.  Centrifuge for 10 to 15 min at 1100 to 1300 x g at room temperature.  
Collect serum and dispense evenly into two aliquots in polypropylene cryovials.  Serum 
samples must be frozen within 30 min of collection at -70C or colder (alternatively -20C is 
acceptable for up to 1 month) and maintained in the frozen state until assayed.
7.3. Translational and Pharmacodynamic Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may have predictive value in identifying those patients 
who may benefit from treatment with MK-3475 when used in combination with a VEGF 
inhibitor.  In addition, analyses of sequentially obtained tissue and blood biomarkers will 
provide an opportunity to investigate pharmacodynamic effects.  Samples collected at the 
End of Treatment visit will also help understand potential mechanisms of resistance to the 
drug combination.
7.3.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Tumor biospecimens from archived tissue samples and metastatic lesions (see Section 6.1.1) 
will be used to analyze candidate DNA, RNA or protein markers, or relevant signature of 
markers for their ability to predict or identify those patients who are most likely to benefit 
from treatment with the study drugs.  Markers that may be analyzed include, but may not be 
limited to drug targets such as PD-L1.  Studies will investigate whether potential predictive 
markers represent intrinsic or acquired mechanisms of resistance.  Only core biopsies are 
suitable.  Fine needle aspirates are not acceptable.  Additional information on tissue 
collection procedures are included in the study laboratory manual.


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7.3.2. Peripheral Blood
Blood biospecimens (10 mL) for serum and whole blood will be obtained from all enrolled 
patients to measure DNA, RNA, or proteins known or suspected to be of relevance to the 
mechanism of action, the development of resistance, or the identification of those patients 
who might benefit from treatment with axitinib and MK-3475 combination.  Markers that 
may be analyzed include, but may not be limited to VEGF-A, VEGFR2, IL8 and T-cell 
receptors.  Biospecimens should be obtained pre-dose (see Schedule of Activities).
7.4. Banked Biospecimens
7.4.1. Markers of Drug Response
Banked biospecimens will be collected from patients for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.
They will be handled in a manner that protects each patient’s privacy and confidentiality.  
Banked biospecimens will be assigned the patient’s study identification code (ID) at the site.  
The data generated from these banked biospecimens will also be indexed by this ID.  
Biospecimens will be kept until destruction in facilities with access limited to authorized 
personnel, and biospecimen-derived data will be stored on password-protected computer 
systems.  The key between the patient’s ID and the patient’s direct personally identifying 
information (eg, name, address) will be held at the study site.  Biospecimens will be used 
only for the purposes described in the protocol and the informed consent document/patient 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored for many years (no time limit) to allow for research in the future, including research 
conducted during the lengthy drug development process and also post-marketing research.  
Patients may withdraw their consent for the use of their banked biospecimens at any time by 
making a request to the Investigator; in this case, any remaining biospecimen will be 
destroyed, but data already generated from the biospecimens will continue to be available to 
protect the integrity of existing analyses.  Unless prohibited by local regulations or ethics 
committee decision, a 4 mL blood genomic banked biospecimen Prep D1
(dipotassium edetic acid [ethylenediaminetetraacetic acid] [K2 EDTA] whole blood 
collection optimized for DNA analysis) will be collected at the time specified in the Schedule 
of Activities section of the protocol to be retained for potential pharmacogenomic/biomarker 
analyses related to drug responseand disease under study.  For example, putative safety 
biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes thought 
to be related to the mechanism of drug action may be examined.  The primary purpose is to 
examine DNA; however, the biospecimen may also be used to study other molecules 
(eg, RNA, proteins, and metabolites).
The Banked Biospecimens will be collected from all patients unless prohibited by local 
regulations or IRB/EC decision. 


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It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.4.2. Additional Research
Unless prohibited by local regulations or IRB/EC decision, patients will be asked to indicate 
on the consent form whether they will allow the Banked Biospecimens to also be used to 
design and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in Markers of Drug Response Section will be used.  Patients may still 
participate in the clinical trial if they elect not to allow their Banked Biospecimens to be used 
for the additional purposes described in this section.
7.5. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or magnetic resonance imaging (MRI) scans; brain CT or MRI 
scan at baseline and when suspected brain metastases.  The CT scans should be performed 
with contrast agents unless contraindicated for medical reasons. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline (screening), at 12 weeks, and every 6 weeks thereafter. In addition, radiological 
tumor assessments will also be conducted whenever disease progression is suspected 
(eg, symptomatic deterioration) and at the time of withdrawal from the treatment (if not done 
in the previous 6 weeks).  See Schedule of Activities (SOA) and Section 5.2.4.2.1 for 
treatment after initial evidence of disease progression.
Bone scan (bone scintigraphy) or 18F-FDG-PET/CT is required at baseline then every 
12 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is 
required only if new bone metastases are suspected.  Bone imaging is also required at the 
time of confirmation of response for patients who have bone metastases. 
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy.
Assessment of response will be made using RECIST version 1.1 (Appendix 2).
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure.
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during 
pregnancy, exposure via 
breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the Investigator must pursue and obtain adequate information both to 
determine the outcome of the AE and to assess whether it meets the criteria for classification 
as an SAE (see the Serious Adverse Events section below) requiring immediate notification 
to Pfizer or its designated representative.  In addition, the investigator may be requested by 
Pfizer Safety to obtain specific follow-up information in an expedited fashion.  This 
information is more detailed than that recorded on the CRF.  In general, this will include a 


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description of the event in sufficient detail to allow for a complete medical assessment of the 
case and independent determination of possible causality.  Any information relevant to the 
event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the Investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/ legally acceptable representative.  In addition, each study 
patient/ legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of a SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
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For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.

If a patient begins a new anticancer therapy, SAEs occurring during the above 
indicated active collection period must still be reported to Pfizer Safety irrespective of 
any intervening treatment.
Pregnancy or breast feeding that occur during the trial, within 120 days of discontinuing 
treatment with MK-3475, or within 28 days after the cessation of study treatment if the 
patient begins a new anticancer therapy, whichever is earlier, should be reported as in 
Section 8.4 (Exposure During Pregnancy).
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non serious AEs and SAEs are recorded on the 
CRF.
Follow up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non 
serious); the investigator must record the causal relationship on the CRF, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 


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defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Event
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;


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
Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with CTCAE Grade 5 (see the section on Severity Assessment).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute an 
hospitalization; however, the event leading to the emergency room visit should be assessed 
for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);


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
Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.


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8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over the counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product or the female becomes, or is found to be pregnant after discontinuation and/or 
being exposed to the investigational product. 


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
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male patient has been exposed (eg, due to treatment or environmental exposure) to 
the investigational product prior to or around the time of conception or is exposed 
during his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the study patient’s 
treatment with the investigational product, the Investigator must submit this information to 
the Pfizer Safety on a CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy outcome and its
information for all EDP reports with an unknown outcome.  The Investigator will follow the 
pregnancy until completion (or until pregnancy termination) and notify Pfizer Safety of the 
outcome as a follow-up to the initial EDP supplemental form.  In the case of a live birth, the 
structural integrity of the neonate can be assessed at the time of birth.  In the event of a 
termination, the reason(s) for termination should be specified and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection 
(unless pre-procedure test findings are conclusive for a congenital anomaly and the findings 
are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product. 


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Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the EDP Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences a SAE associated with such a 
drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the Pfizer Safety unit within 24 hours of the 
Investigator’s awareness, using the CT SAE Report Form, regardless of whether there is an 
associated SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not reported on a CRF, however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors. 
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with 
an SAE
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 


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Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Analysis Sets 
The following patient sets will be assessed.

Safety analysis set.
The safety analysis set includes all enrolled patients who receive at least one dose of axitinib 
or MK-3475.

Per protocol analysis set (evaluable for DLT).
All enrolled patients who are eligible, receive at least one dose of axitinib and MK-3475, and 
who either experience DLT during the first two cycles, or complete the observation period 
for the first two cycles of treatment (6 weeks).  Patients who withdraw from study treatment 
before receiving at least 75% of the planned first two cycles doses of axitinib or two 
infusions of MK-3475 within the DLT observation period due to reasons other than treatment 
related adverse events are not evaluable for DLT. A patient who is unable to start at the 
assigned Cycle 1 Day 1 dose level after the lead-in period will not be evaluable for DLTs but 
will be evaluated for safety and efficacy.


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
Response evaluable analysis set. 
All patients who receive study treatment with an adequate baseline tumor assessment will be 
considered evaluable for anti-tumor efficacy using standard RECIST 1.1 criteria. 

PK analysis set.
The PK concentration population is defined as all treated patients who have at least 
1 concentration of either of the study drugs. 
The PK parameter analysis population is defined as all treated patients who have at least 1 of 
the PK parameters of interest of any of the study drugs. 

Biomarker analysis set.
The biomarker analysis set is defined as all treated patients who have at least one screening 
biomarker assessment, and have received at least one dose of any study drug.  Analysis sets 
will be defined separately for blood-based and tumor tissue-based biomarkers.
If mutational profiling is performed on samples derived from the biomarker analysis set, the 
analysis may be limited to screening samples only.
9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation/De-Escalation: mTPI
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation trials that improve accuracy, efficiency and statistical validity. 
The modified toxicity probability interval (mTPI) design23 uses a Bayesian statistics 
framework and a beta/binomial hierarchical model to compute the posterior probability of 
three dosing intervals that reflect the relative difference between the toxicity rate of each 
dose level to the target rate (pT = 0.30).  If the toxicity rate of the currently used dose level is 
far smaller than pT, the mTPI will recommend escalating the dose level; if it is close to pT, 
the mTPI will recommend continuing at the current dose; if it is far greater than pT, the mTPI 
will recommend de-escalating the dose level.  These rules are conceptually similar to those 
used by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different trials with different toxicity parameters.  More 
importantly, all the dose-escalation/ de-escalation decisions for a given trial can be 
pre-calculated under the mTPI design and presented in a two-way table (Table 2).  Thus, 
compared to other advanced model-based designs published in the literature, the mTPI 
design is logistically less complicated and easier to implement.  Recently, a Phase I trial 
based on the mTPI design has been published.23


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Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of axitinib and MK-3475, e1 is selected as 0.05, and e2 is selected as 0.03.  
Therefore, the target dosing interval for the DLT rate is (0.25, 0.33).
The three dosing intervals are associated with three different dose-escalation decisions.  The 
under-dosing interval corresponds to a dose escalation (E), over-dosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to staying at the current dose (S).  Given a 
dosing interval and a probability distribution, the unit probability mass (UPM) of that dosing 
interval is defined as the probability of a patient belonging to that dosing interval divided by 
the length of the dosing interval.  The mTPI design calculates the UPMs for the three dosing 
intervals, and the one with the largest UPM informs the corresponding dose-escalation 
decision, which is the dose level to be used for future patients.  For example, if the 
under-dosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Ji and collaborators23 have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision). 
The dose-finding component of the trial is completed when at least 10 DLT-evaluable 
patients have been treated at the highest dose associated with a DLT rate <0.33.  It is 
estimated that approximately 20 DLT-evaluable patients will need to be enrolled to reach 
10 DLT-evaluable patients at the estimated MTD. 
9.2.2. Statistical Method for Estimating the MTD
As described in Section 3.2, the estimated MTD will be the highest tested dose level with a 
DLT rate <0.33 in 10 DLT evaluable patients.  We assume that higher doses of MK-3475 
result in higher toxicity rates.  But, due to the relatively low number of patients that may be 
potentially allocated to any dose combination, this assumption may be violated.  For 
example, at the end of the study, the dose combination (MK-3475 2 mg /kg q3wks, axitinib 
5 mg BID) may have a higher proportion of observed toxicities than, say, (MK-3475 1 mg 
/kg q3wks, axitinib 5 mg BID), and this variability may be simply related to small cohort size 
alone.  To overcome this potential problem, we use a bivariate isotonic regression to smooth 
the resulting toxicity surface to a monotonically increasing one.  The determination of the 
MTD contour is accomplished using the Dykstra-Roberston algorithm.24  Once a 
monotonically increasing toxicity surface is obtained (either observed or smoothed according 
to the bivariate isotonic regression algorithm), the MTD combinations closest to the targeted 
DLT rate of 0.3 but still <0.33 are calculated. 
9.3. Sample Size Determination
The sample sizes planned for the study arise from logistic feasibility and past experience with 
Phase 1b studies in oncology and are not entirely driven by statistical considerations.  It is 
expected that approximately 60 patients will be required to achieve all study objectives. 


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Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
Up-and-Down design using the mTPI approach cannot be determined in advance.  It is 
estimated 20 DLT evaluable patients will be enrolled in the dose finding stage in order to 
have a reliable and accurate estimate of the MTD.  In addition, there will be a Dose 
Expansion Phase cohort to characterize safety, biomarkers, and efficacy in terms of 
probability (p) of achieving an event of interest including, but not limited to, objective 
response (OR).  The goal will be to estimate proportions of such patients with the standard 
error (SE) of not greater than 0.08, ie, by definition,
n
n
p
p
SE
2
1
)
1(



Therefore, a sample of forty patients (n=40) in the Dose Expansion Phase cohort will allow 
estimation of the probability of achieving an event of interest with the standard error 0.08.  
The sample size estimate for the expansion cohort also takes into consideration the key tumor 
biomarker PD-L1 endpoints.  If the observed rate of PD-L1 positives is 20% then 
approximately 40 patients would be required to enroll 8 PD-L1 positive patients.
9.4. Efficacy Analysis 
In this study, anti-tumor activity is a secondary objective.  Efficacy analyses will be 
presented in the form of statistical summaries and data listings for the Dose Expansion Phase 
cohort.  For the Dose Finding cohorts only data listings for BOR will be presented.
9.4.1. Analysis of Efficacy Endpoints (Dose Expansion Phase Cohort)
Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1 
definitions, relative to the response evaluable population.  Confirmed responses are those that 
persist on repeat tumor assessments for at least 4 weeks after initial documentation or 
response.  Otherwise, the patient will be counted as a non-responder in the assessment of 
ORR.
Time to Response (TTR) is defined as the time from first dose of study treatment to the first 
documentation of objective tumor response (CR or PR) that is subsequently confirmed.
Duration of Response (DR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) that is subsequently confirmed to the first documentation of 
objective tumor progression or to death due to any cause, whichever occurs first. 
Progression Free Survival (PFS) is defined as the time from the first dose of study treatment 
to the first progression of disease (PD) or death for any reason in the absence of documented 
PD.  PFS will be summarized in the response evaluable population.  PFS data will be 
censored on the date of the last tumor assessment on study for patients who do not have 
objective tumor progression and who do not die within 28 days of last dose.  Patients lacking 
an evaluation of tumor response after enrollment will have their PFS time censored on the 
date of first dose with a duration of 1 day.  Patients who are treated and removed from study 


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prior to on-study tumor assessment because of disease progression will be considered 
evaluable for efficacy and counted as an event at the time of progression.  Additionally, 
patients who start a new anti-cancer therapy prior to documented PD will be censored at the 
date of the last tumor assessment prior to the start of the new therapy.
Overall Survival (OS) is defined as the time from the first dose of study treatment to the date 
of death due to any cause.  OS will be summarized in the response evaluable population.  For 
patients still alive at the time of the analysis, the OS time will be censored on the last date 
they were known to be alive.  Patients lacking data beyond the day of first dose of study 
treatment will have their survival times censored at 1 day.
Summaries will include: ORR, TTR, DR, PFS and OS.  Time-to event endpoints (TTR, DR 
PFS and OS) will be analysed with Kaplan-Meier method.  Point estimates will be presented 
with their 95% confidence intervals.  In addition, progression date, death date, date of first 
response and last tumor assessment date will be listed, together with best overall response 
(BOR), TTR, DR, PFS and OS.
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Pharmacokinetic Analysis of MK-3475 and Axitinib
All patients who complete at least one day of PK blood sampling will be included in the PK 
analyses.  Standard plasma PK parameters for axitinib will be estimated using 
non-compartmental analysis.  For axitinib, standard PK parameters will include Cmax, Tmax, 
AUC0-12, oral plasma clearance (CL/F), and apparent volume of distribution (Vz/F) 
Descriptive statistics for the PK parameters for axitinib will be provided by dose, cycle and 
day of assessment in tabular form.  For MK-3475, pharmacokinetics will be evaluated using 
population pharmacokinetic modeling.
All plasma/serum concentrations will be summarized descriptively (n, mean, SD, CV, 
median, minimum, maximum, geometric mean, its associated CV, and 95% confidence 
interval) by dose, cycle, day and nominal time.  Individual patient and median profiles of the 
concentration-time data will be plotted by dose, cycle and day (single dose and steady-state) 
using nominal times.  Median profiles will be presented on both linear-linear and log-linear 
scales.
Trough concentrations for MK-3475 will be plotted for each dose using a box-whisker plot 
by cycle and day in order to assess the attainment of steady-state.
In addition, Non-linear Mixed Effects Modeling (NONMEM) approaches will be explored to 
further describe the pharmacokinetic profile and assess potential drug interaction for 
MK-3475.


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9.5.1.2. Effect of MK-3475 on Axitinib Pharmacokinetics 
The effect of repeated MK-3475 dosing on axitinib PK will be evaluated based on changes in 
AUC0-12 of axitinib on Lead-in Day 7 and Cycle 7 Day 1, respectively, as the primary 
pharmacokinetic parameter.  The associated 90% confidence interval will also be computed 
to assess the magnitude of the effect.
9.5.1.3. Immunogenecity Assessment
Results for the anti-MK-3475 antibody (ADA) assessment will be provided.  The effect of 
ADA on MK-3475 concentration will be evaluated.
9.5.1.4. Population Pharmacokinetic Analysis or PK/PD Modeling
MK-3475 disposition will be evaluated using a population PK model for the drug.  The 
results of this analysis, if performed, will be reported separately.
9.5.1.5. Statistical Analysis of Biomarker Endpoints
Biomarkers will be assessed separately for blood and tumor tissue biospecimens.  In each 
case, summaries of baseline levels and changes from baseline will be reported.  Summary 
statistics may include the mean and standard deviation, median, and minimum/maximum 
levels of biomarker measures or frequency statistics, as appropriate. 
Data from biomarker assays will be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach may examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
Due to the exploratory nature of the proposed biomarkers, the data analysis will be conducted 
with the goal of identifying biomarkers with the strongest concordance to clinical outcome, 
encompassing both safety and efficacy.  Candidate biomarkers will be validated in 
subsequent trials.
9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the per protocol 
analysis set.  All other summaries and analyses of safety parameters will include all patients 
in the Safety Analysis Set.  Safety data will be summarized by each cohort for all treated 
patients using appropriate tabulations and descriptive statistics.  Safety data collected during 
the lead-in PK period will be reported separately.  The analysis of safety will extend through 
90 days after the last administration of study drug.
9.6.1. Analysis of Primary Safety Endpoint
Dose Limiting Toxicity (DLTs) is the primary endpoint of the Dose Finding Phase of the 
study.  The occurrence of DLTs observed in the Dose Finding Phase is used to estimate the 
MTD (if reached) as described in Section 3.2.  Adverse Events constituting DLTs will be 
listed per cohort.


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9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Adverse Events
Adverse Events (AEs) will be graded by the Investigator according to the Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of study medication.  The number and percentage of patients who 
experienced any AE, serious AE (SAE), treatment related AE, and treatment related SAE
will be summarized according to worst toxicity grades.  The summaries will present AEs 
both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). 
9.6.2.2. Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay.  The analyses will 
summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and 
Cycles beyond 1).  Shift tables will be provided to examine the distribution of laboratory 
toxicities.
For laboratory tests without NCI CTCAE grade definitions, results will be categorized as 
normal, abnormal or not done. 
9.6.2.3. ECG
All ECGs obtained during the study will be evaluated for safety.  Single ECG measurement 
will be obtained at screening and on Cycle 1 Day 1 and End of Treatment/Withdrawal.  
Additionally, ECGs should be performed when clinically indicated. 
9.6.3. Concomitant Medications/Follow-up Systemic Therapy 
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary.  Patients who received 
concomitant medications will be listed.  Follow-up systemic therapy for the primary 
diagnosis will be summarized by categories of follow-up therapy and will be listed for each 
patient as appropriate.
9.7. Data Monitoring Committee
This study will not use a data monitoring committee (DMC).  For the purpose of this 
protocol, Pfizer procedures for periodic safety review will be applied by an internal safety 
review team with medical and statistical capabilities to review individual and summary data 
collected in the safety and clinical databases.  Procedures include:

Surveillance for SAEs according to regulatory guidelines.


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
Discussions between the Investigators and the Sponsor of AEs, laboratory tests 
abnormalities, vital signs and ECGs escalations observed at each dose level in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety 
profile and make risk/benefit assessment and decide if further enrollment is 
appropriate.  During the Dose Finding Phase, in particular, monitoring and safety 
findings satisfying the DLT criteria will be discussed in an on-going manner. 

Findings having immediate implication for the management of patients on study will 
be communicated to all Principal Investigators in the timeframe associated with 
unexpected and drug-related SAEs.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to
review by the IRB/ EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.


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A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the Investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
Investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the Investigator according to ICH guidelines, according to local regulations, or as 
specified in the Clinical Study Agreement (CSA), whichever is longer.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
Investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The Investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the Investigator File.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the Investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, address, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify the study patients.  The 
investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patient’s personal data 
consistent with applicable privacy laws.
The informed consent document(s) and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent document(s) used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/IEC 
before use, and available for inspection. 


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The Investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he or she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents.
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific 
activity is performed.  The Investigator will retain the original of each patient's signed 
consent document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and Investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.


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13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
axitinib or MK-3475 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
Investigator.  After notification, the Investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date (PCD) for 
studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the pre-specified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.


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www.pfizer.com
Pfizer posts Public Disclosure Synopses (CSR synopses in which any data that could be used 
to identify individual patients has been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of Confidential Information or unprotected 
Inventions, Investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, Investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
Information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multi-centre study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
Study at all participating sites, Investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Hutson E., Lesovoy V., Al-shukri S., Axitinib versus sorafenib as first-line therapy in 
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Rini BI, Escudier B, Tomczak p, et al, comperative effectiveness of axitinib versus 
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Ferrar N. Kerbel R. S. 2005 Angogenesis as a therapeutic target. Nature 438:967.  
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Choueiri T.K., Vaishampayan U., Rosenberg J.E., et al 2013 Phase II and Biomarker 
Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients with Papillary Renal 
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Finley D.S., Pantuck A.J., Belldegrun A.S. 2011 Tumor Biology and Prognostic Factors 
in Renal Cell Carcinoma. The Oncologist, 16:4. 
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NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 1.2013.
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Gross-Goupil M., Massard C., Ravaud A. 2012 Targeted Therapies in Metastatic Renal 
Cell Carcinoma: Overview of the Past Year Curr. Urol. Rep. 13:16-23.
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Mihaly Z., Sztupinszki Z., Surowiak P., and Gyorffy B. 2012 A Comprehensive 
Overview of Targeted Therapy in Metastatic Renal Cell Carcinoma Current Cancer 
Drug Targets 12:857-872.
18.
Escudier B., Albiges L., and Sonpavde G. 2013 Optimal Management of Metastatic 
Renal Cell Carcinoma: Current Status Drugs 73:427-38.
19.
Investigator’s Brochure of AG-013736, dated November 2013.
20.
Investigator’s Brochure of MK-3475, dated 10 January 2014.
21.
Hamid O.et al Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in 
Melanoma, N Engl J Med (2 June 2013), doi:10.1056/nejmoa1305133 
Key:citeulike:12397700.
22.
United States Package Insert for Inlyta, dated January 2012.
23.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials 2010; 7:653 663.
24.
Dykstra R, Robertson T. An algorithm for isotonic regression for two or more 
independent variables. Ann Stat. 1982;10:708-716.
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Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28 (29):4531-8. 
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Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8 (8):793-800. 
27.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
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Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66. 


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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
30.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61. 
31.
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
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Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81. 
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Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7. 
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Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 
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Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94. 
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Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4. 
37.
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 
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Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30. 
39.
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53. 
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Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
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41.
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106. 
42.
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11. 
43.
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59. 
44.
Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7. 
45.
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6. 
46.
2006.  Update of Recommendations for the Use of White Blood Cell Growth Factors: 
An Evidence-Based Clinical Practice Guideline.  J. Cin Oncol Jul 1:3187-3205.  
47.
Larochelle P., Kollmannsberger C., Feldman R.D., et al. 2012 Hypertension 
management in patients with renal cell cancer treated with anti-angiogenic agents. Curr. 
Oncol 19:202-208.
48.
Brian I. Rini, David I. Quinn, Michael Baum, Laura S. Wood, Jamal Tarazi, Brad 
Rosbrook, Lillian Shahied Arruda, Laura Cisar, W. Gregory Roberts, Sinil Kim, Robert 
J.  Motzer.  Hypertension among patients with renal cell carcinoma receiving axitinib or 
sorafenib: analysis from the randomized phase III AXIS trial.  Targ Oncol DOI 
10.1007/s11523-014.
49.
A.Amin, E.R. Plimack, J.R. Infante, et al.  Nivolumab (anti-OD1; BMS-936558; ONO-
45380 in combination with sunitinib or pazopanib in patients with metastatic renal cell 
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Poole, R.M., Pembrolizumab: First Global Approval. Drugs, 2014.


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Appendix 1. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead


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Appendix 2. RECIST Version 1.1
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation. 
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable:
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable: All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques. 
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 
diameter to be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters.


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All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent.”
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Definitions of Tumor Response
Target Lesions
Complete response (CR) is defined as the disappearance of all target lesions.  Any
pathological lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
Partial response (PR) is defined as a 30% decrease in the sum of the longest dimensions of 
the target lesions taking as a reference the baseline sum longest dimensions.
Progressive disease (PD) is defined as a 20% increase in the sum of the longest dimensions 
of the target lesions taking as a reference the smallest sum of the longest dimensions 
recorded since the treatment started, or the appearance of one or more new lesions.  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the smallest sum of the longest dimensions 
since the treatment started. 
Non-Target Lesions
Complete response (CR) is defined as the disappearance of all non-target lesions.  All
lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.
Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of 1 new lesion.
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease.


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Confirmation of Tumor Response
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 12 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.
Response Evaluation Criteria in Solid Tumors
Target Lesions1
Non-Target Lesions2
New Lesions3
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
1 Measurable lesions only.
2 May include measurable lesions not followed as target lesions or non-measurable lesions.
3 Measurable or non-measurable lesions.
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  For CR and PR, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 12 weeks.
NOTE: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.  It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation to 
document whether or not objective tumor progression has occurred. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy before 
confirming the complete response status. 


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Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:
http://ctep.cancer.gov/reporting/ctc.html


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Appendix 4. Abbreviations and Definitions of Term
AE
Adverse Event
AHFS
American Hospital Formulary Service
AIDS 
Acquired Immune Deficiency Syndrome
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine aminotransferase
ANC
Absolute Neutrophil Count
ATP
Adenosine TriPhosphate
ASHP
American Society of Hospital Pharmacists
AST 
Aspartate aminotransferase
AUC
Area Under the Curve
BCG
Bacillus Calmette–Guérin
BID
Twice/day
BOR
Best Oveall Response
BP
Blood Pressure
BUN 
Blood Urea Nitrogen
CDS
Core Data Sheet
CHF
Congestive Heart Failure
CI
Confidence Interval
CK
Creatinine kinase
CL
Clearance
Cmax
Maximum plasma Concentration 
Cmin
Minimum plasma Concentration
CR
Complete Response
CRF
Case Report Form
CT
Computerized Tomography
CTCAE 
Common Terminology Criteria for Adverse Events (US-NCI)
CTM
Clinical Trial Material
CYP1A2
Cytochrome P450 enzyme-1A2
CYP3A4/5
Cytochrome P450 enzyme-3A4/5
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DR
Duration of Response
EC 
Ethics Committee
ECG 
Electrocardiogram
ECOG
Easter Cooperative Oncology Group
ECI
Event of Clinical Interest
EIU
Exposure in Utero
EU
Europe
FDA
Food and Drug Administration
FFPE
Formalin Fixed, Paraffin Embedded
FH
Fumarate Hydratase
GCP 
Good Clinical Practice


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GGT
Gamma-Glutamyl Transferase
GI
Gastro-intestinal
HCV
Hepatitis C Virus
HCV
Hepatitis C Virus
HDPE
High Density PolyEthylene
HGF
Hepatocyte Growth Factor
HIF
Hypoxia-Inducable transcription Factor
HIV 
Human Immunodeficiency Virus
ICH
International Committee Harmonization
ID
Identification 
IEC 
Independent Ethics Committee
IFN
Interferon alpha
IL-2
Interleukin-2
IHC
ImmunoHistoChemistry
IND 
Investigational New Drug
INR 
International Normalized Ratio
irAE
Immune-related adverse event
IRB 
Institutional Review Board
IUD
Intra Uterine Device
IV
Intravenous
LFT
Liver Function Test
MedDRA
Medical Dictionary for Regulatory Activities
MET
Mesenchymal Epithelial Transition factor
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target Of Rapamycin
mTPI
Modified Toxicity Probability Interval
NCI 
National Cancer Institute
NONMEM
Non linear Mixed Effects Modeling
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS 
Overall Survival
PD
Pharmacodynamic
PD
Progressive Disease 
PD1
Programmed Death 1
PDGF 
Platelet-Derived Growth Factor
PDGFR
Platelet-Derived Growth Factor Receptor
PD-L1
Programmed Death Ligand 1
PFS
Progression Free Survival
PK
Pharmacokinetics
PO
Per Os (by mouth)
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
QD
Every Day
QTc
Corrected Q-T interval


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RCC
Renal Cell Cancer 
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
SD
Standard Deviation
SRSD
Single Reference Safety Document
t½
Plasma elimination half life
TBili
Total Bilirubin
TIL
Tumor Infiltrating Lymphocytes 
TIDM
Type 1 Diabetes Mellitus
TKI
Tyrosine Kinase Inhibitor
Tmax
Time to maximum plasma concentration
TSH
Thyroid Stimulating Hormone
TTR
Time To Response
ULN 
Upper Limit of Normal
US
United States
USPI
United States Package Insert
VEGF 
Vascular Endothelial Growth Factor
VEGFR 
Vascular Endothelial Growth Factor Receptor
VHL
Hippel Lindau tumor suppressor gene
WBC 
White Blood Cell
WHO
World Health Organization


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Appendix 5. KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING 
(%) CRITERIA
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) 
CRITERIA 
Able to carry on normal 
activity and to work; no 
special care needed. 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity or do 
active work. 
60 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
50 
Requires considerable assistance and frequent medical 
care. 
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly.
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund: fatal processes progressing rapidly 
0 
Dead 
Reference: 
http://www.npcrc.org/usr_doc/adhoc/functionalstatus/Karnofsky%20Performance%20Scale.pd
f 


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Appendix 6. Revised Schedule of Activities Following Collection of Data for Primary 
Study Objective
After the collection of data for the primary study objective and most of the secondary 
objectives has been completed, patients who are still clinically benefiting from study 
treatment as judged by the investigator may be candidates for continuation of study 
treatment.  Discussion with sponsor is required. 
The following protocol sections should be disregarded: Schedule of Activities the original 
protocol and the trial procedures in Section 6.2 Study Period, 7.2 Pharmacokinetics 
Assessments, 7.2.1 Blood Sample Collection for Pharmacokinetic Analysis, 7.2.2 Collection 
of Axitinib PK Samples, 7.2.3 Processing, Storage and Shipment of Axitinib PK Samples, 
7.2.4 Collection and Processing of MK-3475 PK Samples, 7.2.5 Collection and processing of 
anti-MK3475 Antibody Samples, and 7.3 Translational and Pharmacodynamic Assessments.  
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table in order to conduct evaluations or assessments required to 
protect the well-being of the patient.
The following schedule of activities will be implemented for patients still on active treatment 
and long-term survival follow-up.  Patients on axitinib monotherapy have the opportunity to 
continue axitinib treatment on a Pfizer-sponsored patient access program at the time of the
discontinuation of survival status follow-up.
Study Treatment[1]
Post-Treatment 
Protocol Activities
and Forms to be Completed
Cycles 24
End of Tx or 
Withdrawal[2]
–3/+3 
28 Days Post-
Treatment 
–7/+7 
Survival 
Follow-Up
–7/+7
Day 1
–3/+3
Physical Examination [3]
X
X
In Clinic Blood Pressure, Pulse 
Rate [4]
X
X
Home Blood Pressure Monitoring[5]
X
X
Hematology [6]
Local Standard of Care
X
Blood Chemistry [6]
Local Standard of Care
X
Coagulation [6]
Local Standard of Care
Urinalysis [7]
X
12-lead ECG [8]
X
X
Thyroid Function Tests [9]
X
X
Pregnancy Test [10]
X
X
Tumor Assessments [11]
Local Standard of Care and at End of Treatment
Adverse Events [12]
X
X
X
Concomitant 
Medications/Treatments(13)
X
X
X
Study Treatment (14)
X
Post Study Survival Status (15)
X
X


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Footnotes for Schedule of Activities
1.
During Treatment: All assessments should be performed prior to dosing with study treatment unless otherwise 
indicated.  Acceptable time windows for performing each assessment are described in the column headings.  
Patients who permanently discontinue pembrolizumab and continue on axitinib treatment, it is at the discretion of 
the investigator to follow patients on axitinib monotherapy every 3 weeks + or – 3 days (ie, cycle=21 days) or 
6 weeks + or – 3 days (ie, cycle=42 days). All tests and assessments outlined in the schedule of activities must be 
conducted at that visit. 
2.
End of Study Treatment/Withdrawal: Obtain these assessments if not completed during the previous two weeks 
on study.
3.
Physical Examination: Includes an examination of major body systems and weight.  
4.
In Clinic Blood pressure, pulse rate: Blood pressure, and pulse rate should be taken with the patient in the seated 
position after the patient has been sitting quietly for at least 5 minutes.  Two blood pressure readings will be taken 
at least 1 hour apart at each clinic visit.
5.
Home blood pressure monitoring: All patients will receive home blood pressure monitoring devices and blood 
pressure will be monitored at home.  While on axitinib (as single agent or combined with MK 3475) patients will 
monitor their blood pressure at least twice daily (before taking each dose of axitinib) and blood pressure should 
be recorded in a patient diary.  Patients should be instructed to contact the site immediately for guidance if their 
systolic blood pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or if they 
develop symptoms perceived to be related to elevated blood pressure (eg, headache, visual disturbance) although 
a different blood pressure threshold for contacting the site may be used according to the Investigator’s clinical 
judgment (see Section 5.2.7.3).
6.
Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 8.  All laboratory tests may be 
performed per standard of care and when clinically indicated.  Dose adjustment may be required (see 
Section 5.2.7).
7.
If protein 2+ by semiquantitative method (eg, urine dipstick), protein will have to be quantified by 24 hour urine 
collection.  Dose adjustment may be required (see Section 5.2.7.2).  May be performed also when clinically 
indicated.
8.
Single ECG measurement will be obtained at End of Treatment/Withdrawal. Additionally, ECGs should be 
performed when clinically indicated.  Clinically significant findings seen on follow-up ECGs should be recorded 
as adverse events.
9.
Subsequently, TSH should be assessed every 6 weeks thereafter starting from Cycle 24 Day 1.  Free T3 and free 
T4 should additionally be performed when clinically indicated.  Hypothyroidism should be treated per standard 
medical practice to maintain euthyroid state.  See Table 8.
10. For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least
25 mIU/mL, will be performed and routinely repeated at every cycle during the active treatment period, at the end 
of study treatment and additionally whenever one menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local 
regulations (see Section 7.1.1).  
11. Tumor assessments will include all known or suspected disease sites: frequency to be performed per local 
standard of care and again at treatment withdrawal if not performed within previous 6 weeks. Tumor imaging 
must be measured using RECIST version 1.1 tumor assessment criteria to determine disease progression.  
12. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE 
version 4.03.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time 
that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, 
ie, prior to undergoing any study related procedure and/or receiving investigational product, through and 
including 90 calendar days after the last administration of the investigational product and before initiation of a 
new anti-cancer treatment.  The prolonged follow up is due to the pharmacokinetic properties of the 
investigational product MK-3475.  SAEs experienced by a patient after the active reporting period (see 
Section 8.1.4) has ended should be reported to the Sponsor if the Investigator becomes aware of them; at a 
minimum, all SAEs that the Investigator believes have at least a reasonable possibility of being related to study 
drug are to be reported to the Sponsor.  AEs (serious and non serious) should be recorded on the Case Report 
Form (CRF) from the time the patient has taken at least one dose of study treatment through last patient visit 
(Day 28 after last dose).  If a patient begins a new anticancer therapy, the AE reporting period for non serious 
AEs ends at the time the new treatment is started.  Pregnancy or breast feeding that occur during the trial, within 
120 days of discontinuing treatment with MK-3475, or within 28 days after the cessation of axitinib if the patient 
begins a new anticancer therapy, whichever is earlier, should be reported as in Section 8.4.2.1 (Exposure During 


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Pregnancy).
13. Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 28 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF 
including supportive care drugs (eg, anti emetic treatment and prophylaxis), and the drugs used to treat adverse 
events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
14. Study treatment: will be administered as in Section 5.2.4.2.1 Axitinib will be given orally twice daily PO on a 
continuous schedule.  MK-3475 will be given as a 30 minute intravenous infusion every 3 weeks.  (one 
Cycle = 3 weeks) (see Section 5).  Patients with disease progression who are continuing to derive clinical benefits 
from the study treatment may continue treatment with axitinib provided that the treating physician has determined 
that the benefit/risk for doing so is favorable and after discussion with the sponsor.  Continuation of treatment 
with MK-3475 beyond 24 months should be discussed with the sponsor and not go beyond 36 months. Patients 
who permanently discontinue pembrolizumab and continue on axitinib treatment, it is at the discretion of the 
investigator to follow the patient on axitinib monotherapy every 3 weeks + or – 3 days (ie, cycle=21 days) or 
6 weeks + or– 3 days (ie, cycle=42 days).  All tests and assessments outlined in Appendix 6 Schedule of 
Activities must be conducted at that visit or when clinically indicated.  Patients on axitinib monotherapy have the 
opportunity to continue axitinib treatment on a Pfizer-sponsored program at the time of the discontinuation of 
survival status follow-up. 
15. Survival: All patients should be followed for survival at least every 3 months after discontinuing study treatment.
Survival monitoring will continue until approximately 3 years after last patient has been enrolled.  Information on 
antineoplastic treatments (ie, systemic, surgery, and radiotherapy) will be collected.

SAP_001.pdf: 
Protocol A4061079                                                                           Statistical Analysis Plan
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PROTOCOL A4061079
A PHASE 1B, OPEN LABEL, DOSE FINDING STUDY TO EVALUATE 
SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF 
AXITINIB (AG-013736) IN COMBINATION WITH PEMBROLIZUMAB
(MK-3475) IN PATIENTS WITH ADVANCED RENAL CELL CANCER
Statistical Analysis Plan
(SAP)
Version:  1.1 
Author:  
Date:  July 14, 2015
PPD


Protocol A4061079                                                                               Statistical Analysis Plan
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TABLE OF CONTENTS
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Design .............................................................................................................4
2.2. Study Objectives .......................................................................................................5
2.2.1. Primary Objective.........................................................................................5
2.2.2. Secondary Objectives ...................................................................................5
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING.................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS POPULATIONS ...............................................................................................6
5.1. Safety Analysis Set....................................................................................................6
5.2. Per Protocol Analysis Set (Evaluable for DLT)........................................................7
5.3. Response Evaluable Analysis Set .............................................................................7
5.4. PK Analysis Set.........................................................................................................7
5.5. Biomarker Analysis Set.............................................................................................7
5.6. Treatment Misallocations..........................................................................................7
5.7. Protocol Deviations...................................................................................................7
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoints ....................................................................................................8
6.2. Safety Endpoints .......................................................................................................9
6.2.1. Dose Limiting Toxicity (DLT) (Primary Endpoint for Dose Finding 
Cohorts)..............................................................................................................9
6.2.2. Adverse Events...........................................................................................10
6.2.3. Laboratory Abnormalities...........................................................................10
6.3. PK Endpoints...........................................................................................................10
6.4. Biomarker Endpoints...............................................................................................11
6.5. Covariates................................................................................................................11
7. HANDLING OF MISSING VALUES ................................................................................11
7.1. Missing Dates..........................................................................................................11
7.2. Missing Efficacy Endpoint Values..........................................................................11
7.3. Pharmacokinetics ....................................................................................................11


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7.4. Pharmacodynamic Biomarkers ...............................................................................13
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................13
8.1. Statistical Methods ..................................................................................................13
8.1.1. Statistical Methods for Dose Escalation: Up-and-Down Matrix 
Design with the mTPI Method.........................................................................13
8.1.2. Methods for Estimating the MTD...............................................................14
8.1.3. Sample Size Determination ........................................................................14
8.2. Statistical Methods for Different Types of Endpoints ............................................15
8.3. Statistical Analyses .................................................................................................15
8.3.1. Standard Analyses ......................................................................................15
8.3.2. Analysis of Efficacy Endpoints ..................................................................16
Error! Bookmark not defined.16
8.3.3. Analysis of Safety Endpoints......................................................................16
8.3.3.1. Analysis of Primary Endpoint...................................................17
8.3.3.2. Analysis of Secondary Safety Endpoint....................................17
8.3.4. Analysis of Pharmacokinetics.....................................................................20
8.3.4.1. Pharmacokinetic Analysis of MK-3475 and Axitinib...............21
8.3.4.2. Effect of MK-3475 on Axitinib Pharmacokinetics ...................22
8.3.4.3. Immunogenecity Assessment....................................................22
8.3.4.4. Population Pharmacokinetic Analysis or PK/PD Modeling .....22
8.3.5. Analysis of Biomarker Endpoints...............................................................22
8.4. Summary of Secondary Efficacy Analyses.............................................................24
9. REFERENCES ....................................................................................................................25
10. APPENDICES ...................................................................................................................26
Appendix 1. Programming Specifications for AE Analyses ...................................................26
Appendix 2. Study Specific Information for Efficacy.............................................................31
Appendix 3. RECIST 1.1.........................................................................................................32
Appendix 4. Detailed Dose Escalation/De-Escalation Scheme...............................................35


Protocol A4061079                                                                               Statistical Analysis Plan
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 

Specifies analyses of safety data (adverse events and laboratory tests) which includes 
the period from the start of treatment with the axitinib + MK-3475 combination 
(CD1).

Clarified language regarding analysis sets for efficacy endpoints.  Clarified that data 
from patients treated at the MTD in the dose escalation and dose expansion portions 
of the study will be pooled for the secondary safety and efficacy analyses.

Removed supportive efficacy analysis.
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol A4061079.  This 
analysis plan is meant to supplement the study protocol. In this document, any text taken
directly from the protocol is italicized. 
Any deviations from this main analysis plan will be described in the Clinical Study Report. 
2.1. Study Design
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, pharmacokinetics (PK)
and pharmacodynamic study of axitinib in combination with MK-3475 in adult patients with 
previously untreated advanced renal cell carcinoma (aRCC).  This clinical study will be 
composed of a Dose Finding Phase and a Dose Expansion Phase.  The Dose Finding Phase 
will estimate the maximum tolerated dose (MTD) in patients with aRCC with clear cell 
histology who did not receive prior systemic therapy for the advanced disease, using the 
modified toxicity probability interval (mTPI) method.
The Dose Finding Phase will lead to the identification of an Expansion Test Dose for axitinib 
in combination with MK-3475 in patients with aRCC who did not receive prior systemic 
therapy.  The Expansion Test Dose will be either the MTD (ie, the highest dose of axitinib 
and MK-3475 associated with the occurrence of dose limiting toxicities (DLTs) in <33% of 
patients) or the recommended phase II Dose (RP2D), ie, the highest tested dose that is 
declared safe and tolerable by the Investigators and Sponsor.  Once the Expansion Test Dose 
is identified, the Dose Expansion Phase will be opened and axitinib in combination with 
MK-3475 will be tested in patients with previously untreated aRCC. 
Anti-tumor activity will be assessed by radiological tumor assessments conducted at 
baseline, 12 weeks, and every 6 weeks thereafter, using response evaluation criteria in solid 
tumors (RECIST) version 1.1.  In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (e.g., symptomatic deterioration), and 
at the time of End of Treatment/Withdrawal (if not done in the previous 6 weeks).  Brain CT 
or MRI scans are required at baseline and when there is a suspected brain metastasis.  Bone 
scan (bone scintigraphy) or 18F-FDG-PET/CT is required at baseline then every 15 weeks 
only if bone metastases are present at baseline.  Otherwise bone imaging is required only if 


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new bone metastases are suspected.  Bone imaging is also required at the time of 
confirmation of response for patients who have bone metastases.
MK-3475 and axitinib do not have competing elimination/metabolism pathways, hence an 
overt PK interaction between the two drugs is not anticipated.  However, pharmacokinetic 
assessments will be conducted in this study to confirm the absence of drug-drug interactions. 
To understand the PK effects of MK-3475 on axitinib, a 7-day lead-in period with 
single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose Finding 
Phase and in at least 8 patients in the Dose Expansion Phases of the study.  On the contrary, 
the administration of single agent MK-3475 to this patient population is not considered in 
this trial.  The effect of axitinib on MK-3475 will be evaluated by comparing MK-3475 
trough concentrations at steady-state in the presence of axitinib with those reported for 
MK-3475 alone in prior studies.  MK-3475 has a long half-life (21-28 days) and an increase 
in trough concentration over time is expected.  
Archived tumor biospecimens, and baseline de novo biospecimens from metastatic lesions 
will be collected for all patients in the dose expansion cohort.  Every effort will be made to 
obtain a second biopsy at the time of first tumor assessment at 12 weeks.  Biomarker studies 
on tumor and blood biospecimens will be carried out to help understand the mechanism of 
action of the axitinib plus MK-3475 combination, as well as potential mechanisms of 
resistance.  Such results may help in the future development of this combination.  Analyses 
using translational approaches may also result in the identification of potential biomarkers 
of response to the axitinib plus MK-3475 combination, ultimately leading to the development 
of a patient selection strategy for further clinical investigation.  As such, collection of tumor 
and blood biospecimens at baseline and on study will be of paramount importance.
2.2. Study Objectives 
2.2.1. Primary Objective

To assess the safety and tolerability of axitinib in combination with MK-3475 in 
patients with previously untreated advanced RCC in order to estimate the MTD and 
select the RP2D.
2.2.2. Secondary Objectives

To evaluate the overall safety profile of axitinib in combination with MK-3475.

To assess the anti-tumor activity of axitinib in combination with MK-3475 in patients 
with advanced RCC in the first-line treatment setting.

To characterize the PK of axitinib and axitinib plus MK-3475 when administered in 
combination, and to assess the effect of MK-3475 on the PK of axitinib.

To characterize, using translational approaches, genes and proteins such as PD-L1, 
VEGF-A and IL-8 relevant to angiogenisis drug target pathway, renal cell carcinoma 
biology, and sensitivity/resistance mechanisms to axitinib in combination with 
MK-3475 in tumor and/or blood. 


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
To explore the pharmacodynamic effect of axitinib in combination with MK-3475 in 
blood and tumor by assessment of gene, RNAs and proteins including but not limited 
to VEGF-A, IL-8 and VEGFR2 and T-cell receptors.

To assess the immunogenicity of MK-3475.
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING
This is an open label, single-arm trial for which no formal interim analysis is planned.  The 
final analysis of efficacy will be performed approximately 18 months after enrollment of the
last subject; however, earlier analyses of the data may be performed for publication and 
regulatory reporting purposes.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The emphasis of the final analyses will be on estimation of key summary statistics rather than 
hypothesis testing.
4.2. Statistical Decision Rules
Up-and-Down Matrix Design with the mTPI Method
The dose escalation/de-escalation rules will follow the mTPI method (see Section 8 for a 
detailed description).  Briefly, the mTPI method relies upon a statistical probability 
algorithm, calculated using data from all patients treated at the same dose level (and not 
simply those in the current cohort) to determine whether future cohorts should involve dose 
escalation, no change in dose, or dose de-escalation.
Maximum Tolerated Dose Definition
The MTD estimate is the highest dose of axitinib and MK-3475 associated with the
occurrence of DLTs in <33% of patients.
Dose Expansion Phase Cohorts
Once the MTD (or the RP2D) for the combination has been defined, up to 40 response-
evaluable patients with advanced RCC will be enrolled and treated in the Expansion Phase.  
The expansion phase will confirm the safety and tolerability as well as explore the antitumor 
activity of axitinib in combination with MK-3475 in patients with previously untreated 
advanced RCC.
5. ANALYSIS POPULATIONS
5.1. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of axitinib 
or MK-3475. This is the primary population for all standard analyses.  


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5.2. Per Protocol Analysis Set (Evaluable for DLT)
All enrolled patients who are eligible, receive at least one dose of axitinib and MK-3475, and 
who either experience DLT during the first two cycles, or complete the observation period
for the first two cycles of treatment (6 weeks).  Patients who withdraw from study treatment
before receiving at least 75% of the planned first two cycles doses of axitinib or two 
infusions of MK-3475 within the DLT observation period due to reasons other than treatment 
related adverse events are not evaluable for DLT.
5.3. Response Evaluable Analysis Set
All patients who receive study treatment (at least one dose of axitinib and MK-3475) with an 
adequate baseline tumor assessment will be considered evaluable for anti-tumor efficacy 
using standard RECIST 1.1 criteria.  
5.4. PK Analysis Set
The PK concentration population is defined as all treated patients who have at least 
1 concentration of either of the study drugs. 
The PK parameter analysis population is defined as all treated patients who have at least 1 of 
the PK parameters of interest of any of the study drugs. 
5.5. Biomarker Analysis Set
The biomarker analysis population is defined separately for blood-based and tumor tissue-
based biomarkers. The biomarker analysis population includes all enrolled patients who 
receive at least one dose of any study drug, and have at least one biomarker parameter from 
the corresponding assay sample with at least one baseline biomarker measurement. The 
following are the biomarker analysis sets for the purpose of specific PD biomarker analysis:
Serum biomarker analysis set,
Whole blood biomarker analysis set, and 
Tumor biomarker analysis set.
5.6. Treatment Misallocations
Not applicable.
5.7. Protocol Deviations
All deviations will be described when they appear and relate to the statistical analyses or 
analyses populations.  


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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints 
Assessment of response will be made using RECIST version 1.1. All response statuses will 
be derived from lesion measurement data recorded on the electronic case report forms as 
provided by the investigator. .
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan for patients with known 
or suspected brain metastases; bone scan for patients with known or suspected bone 
metastases.
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline (screening), at 12 weeks, and every 6 weeks thereafter. In addition, radiological 
tumor assessments will also be conducted whenever disease progression is suspected 
(e.g. symptomatic deterioration) and at the time of withdrawal from the treatment (if not done 
in the previous 6 weeks).

Objective Response Rate (ORR) is defined as the percent of patients with confirmed 
complete response (CR) or confirmed partial response (PR) according to the RECIST 
1.1, relative to the response evaluable population. Confirmed responses are those that 
persist on repeat imaging study at least 4 weeks after initial documentation of 
response. Patients who do not have on-study radiographic tumor re-evaluation or who 
die, progress, or drop out for any reason prior to reaching a CR or PR will be counted 
as non-responders in the assessment of ORR.  A patient who initially meets the 
criteria for a PR and then subsequently becomes a confirmed CR will be assigned a 
best response of CR.

Progression Free Survival (PFS) is defined as the time from the date of first dose of 
MK-3475 (C1D1) to the date of the first documentation of objective tumor 
progression or death on-study due to any cause, whichever occurs first. If tumor 
progression data include more than 1 date, the first date will be used. PFS (in months) 
will be calculated as (first event date − first dose date +1)/30.44.
Patients lacking an evaluation of tumor response after the date of the first dose of
MK-3475 (C1D1) will have their event time censored on the date of the first dose 
unless death occurs prior to 18 weeks (in which case the death is an event).  
If patients have at least 1 on-study disease assessment, PFS data will be censored on 
the date of the last evaluable tumor assessment documenting absence of progressive 
disease for patients:

Who are alive and progression free at the time of the analysis (note: summaries 
will distinguish between subjects still in disease follow-up verses those who have 
discontinued);


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
Who have documentation of disease progression or death on study after ≥2, 
consecutive missed tumor assessments (i.e. >18 weeks for the first two 
assessments and then subsequently >12 weeks after last tumor assessment);

Who are given anti-tumor treatment other than the study medication prior to 
documented disease progression or death.  
PFS (months) = [progression/death date – date of first dose +1]/30.44

Six-month progression-free survival (6m-PFS) is summarized as a product limit 
estimator based on the Kaplan-Meier method to account for censored events.

Twelve-month progression-free survival (12m-PFS) is summarized as a product 
limit estimator based on the Kaplan-Meier method to account for censored events.

Time to Response (TTR) is defined as the time from first dose of MK-3475 (CID1)
to the first documentation of objective tumor response (CR or PR) that is 
subsequently confirmed.  TTR will only be calculated for the subgroup of patients 
with a confirmed objective tumor response.
TTR (months) = [first date of OR – date of first dose +1]/30.44

Duration of Response (DR) is defined as the time from first documentation of 
objective tumor response (CR or PR) until the first date that recurrent, progressive 
disease, or death due to any cause (whichever occurs first) is objectively documented. 
If tumor progression data include more than 1 date, the first date will be used.  
Censoring for DR is identical to the censoring rules presented for PFS. DR will only 
be calculated for the subgroup of patients with a confirmed objective tumor response.
DR (months) = [progression/death date – first date of OR +1]/30.44

Overall Survival (OS) is defined as the time from the first dose of MK-3475 (C1D1) 
to the date of death due to any cause. OS will be summarized in the response 
evaluable population.  For patients still alive at the time of the analysis, the OS time 
will be censored on the last date they were known to be alive.  Patients lacking data 
beyond the day of first dose of study treatment will have their survival times censored 
at 1 day.
OS (months) = [date of death – date of first dose +1]/30.44
6.2. Safety Endpoints
6.2.1. Dose Limiting Toxicity (DLT) (Primary Endpoint for Dose Finding Cohorts)
Severity of AEs will be graded according to NCI CTCAE v 4.03. AEs meeting one of the 
definition criteria in protocol Section 3.1.2 occurring in the DLT observation period (6 weeks
post C1D1) which are attributable to one or both study drugs will be classified as DLTs.


Protocol A4061079                                                                               Statistical Analysis Plan
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6.2.2. Adverse Events
AEs will be characterized by type, frequency, severity (as graded by NCI CTCAE version 
4.03), timing, seriousness and relationship to study treatment.  Adverse events occurring 
during the 7 day lead in phase for PK will be summarized separately from adverse events 
reporting after first dose of MK-3475 (C1D1).  Baseline signs and symptoms will be 
recorded at baseline and then reported as adverse events during the trial if they worsen in 
severity or increase in frequency.
Treatment Emergent Adverse Events
All deaths and serious AEs, regardless of cause, occurring from start of treatment until 28 
days after the last dose will be considered treatment-emergent.  All other non-serious AEs
occurring after treatment start regardless of cause, will be considered treatment-emergent up 
until 28 days after the last dose or until start of new anti-cancer treatment, whichever occurs
first.  Disease progression is not considered a treatment emergent AE unless the patient dies 
of disease prior to 28 days after the last dose.  Events that are continuations of baseline 
abnormalities are considered treatment emergent AEs only if there is an increase in grade 
over baseline, or if there is an increase following a decrease during the study.
For subjects with a 7 day lead-in phase for PK, adverse events reported during the lead-in 
phase will only be considered as treatment emergent for the combination if there is an 
increase in grade after the first dose of MK-3475 (C1D1) or if there is a decrease and then
subsequent increase during treatment with the combination.  
Treatment Related Adverse Events
Treatment emergent AEs with causality related to treatment, as judged by the investigator, 
will be considered treatment-related.  Events that are continuation of baseline abnormalities 
are not considered treatment- related unless there is an increase in grade, or if there is an 
increase following a decrease, and the increase is judged by the investigator to be due to 
treatment.
6.2.3. Laboratory Abnormalities
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v. 4.03) and timing.  Abnormalities occurring during the 7 day lead in phase for PK 
will be summarized separately from abnormalities occurring after first dose of MK-3475 
(C1D1).  
For summaries of the lead-in PK phase and the treatment period starting at C1D1, baseline 
will be defined as the last evaluation within 28 days prior to the first dose of axitinib and 
MK-3475, respectively.  For laboratory summaries of the entire treatment period (including 
by cycle), baseline will be defined as the last evaluation within 28 days prior to the first dose 
of either axitinib or MK-3475, whichever occurs first.  
6.3. PK Endpoints
Axitinib pharmacokinetic analysis will be conducted at Pfizer. The MK-3475 
pharmacokinetic analysis will be conducted at Merck and results will be shared with Pfizer. 


Protocol A4061079                                                                               Statistical Analysis Plan
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Pharmacokinetic parameters for axitinib:

Cmax, Tmax, AUC0-12, CL/F and Vz/F as data permit.
6.4. Biomarker Endpoints
Translational and pharmacodynamic biomarkers will be assessed separately for blood and 
tumor biopsy specimens. These will include measurements of DNA, RNA or protein markers 
known or suspected to be of relevance to the mechanism of action, the development of 
resistance, or the identification of those patients who might benefit from treatment with 
axitinib and MK-3475 combination.  The assessment will include pre- and post-baseline
blood level of circulating biomarkers; Circulating markers that may be analyzed include, 
but may not be limited to soluble proteins/cytokines  such as VEGF-A, VEGFR2, IL8 and T-
cell receptor expansion.  
Archival tumor biospecimens (all patients) and baseline de novo biospecimens
from metastatic lesions (expansion cohort) will be assessed.  Post-baseline assessment may 
be performed for expansion cohort.  Tumor biopsies assessment will include tumor tissue 
biomarkers (e,g, drug targets such as PD-L1; and other markers, such as CD68).
6.5. Covariates
None.
7. HANDLING OF MISSING VALUES
7.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (e.g., date of resolution cannot be prior to date
of onset; if replacing resolution date with the 1st of the month results in a negative duration, 
the resolution date will be set to the onset date.).  In this case, the date resulting in 0 time
duration will be used. Pfizer standards are also used if both month and day are missing (Jan 
1 unless negative time duration).  For PFS, TTR, DR and OS, if conventions result in a 
negative duration, durations will be reset to 1 day.
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date.
7.2. Missing Efficacy Endpoint Values
For all efficacy analyses no values will be imputed for missing data, except as specified in 
Section 6.1, where for ORR, patients with no post-baseline tumor evaluations will be counted 
as non-responders.  
7.3. Pharmacokinetics
Concentrations below the limit of quantification:


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In all data presentations (except listings), axitinib concentrations below the limit of 
quantification (BLQ) will be set to zero.  In listings, BLQ values will be reported as “<LLQ”, 
where LLQ will be replaced with the value for the lower limit of quantification for axitinib.
Deviations, missing concentrations and anomalous values:
For summary tables and plots of median profiles, appropriate summary statistics will be 
calculated.  Concentrations will be set to missing if one of the following cases is true:
1. A concentration has been reported as ND (i.e., not done) or NS (i.e., no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
as anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than
50% of the data are missing. For analysis of PK concentrations, no values will be imputed 
for missing data.  
Pharmacokinetic parameters:
Axitinib pharmacokinetic analysis will be conducted at Pfizer. The MK-3475 
pharmacokinetic analysis will be conducted at Merck and results will be shared with Pfizer. 
Actual PK sampling times (and where possible the actual dosing information) will be used in 
the derivation of axitinib PK parameters. If a PK parameter cannot be estimated from a 
subject’s concentration data, the parameter will be coded as NC (i.e., not calculated). (Note 
that NC values will not be generated beyond the day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will not be presented for a particular treatment if more than 50% of the data are NC. For 
statistical analyses (i.e., analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before allof the drug is absorbed in the body), this will 
be footnoted in summary tables and will not be included in the calculation of summary 
statistics or statistical analyses.
For PK analysis, patients will be required to have at least one quantifiable concentration of 
each drug to be included in the concentration summary.  For evaluation of changes in PK of
axitinibwhen administered alone vs in combination, only patients with matching pair of PK 
assessments under both conditions will be included in the PK summary.  Patients who have 
been treated with axitinib for whom drug plasma concentrations (from both PK visits, when 
administered alone and in combination) are available will be included in average 
concentration summary.


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7.4. Pharmacodynamic Biomarkers
For analysis of pharmacodynamic biomarkers, no values will be imputed for missing data.
Duplicate biomarker (i.e., more than one set of data for a particular visit) is not expected.   
For continuous data, if duplicate data is received, the results will be averaged and the average 
value will be used.  The average value will be added to the analysis dataset.  For non-
continuous data, the results will be reviewed by the study team and a representative sample 
will be selected.  The representative sample will be flagged in the analysis dataset. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Statistical Methods for Dose Escalation: Up-and-Down Matrix Design with the 
mTPI Method
The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of three dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target rate (pT = 0.30).  If the 
toxicity rate of the currently used dose level is far smaller than pT, the mTPI will recommend 
escalating the dose level; if it is close to pT, the mTPI will recommend continuing at the 
current dose; if it is far greater than pT, the mTPI will recommend de-escalating the dose 
level.  These rules are conceptually similar to those used by the 3+3 design, except the 
decisions of an mTPI design are based on posterior probabilities calculated under a coherent 
probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different trials with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given trial can be pre-calculated under the 
mTPI design and presented in a two-way table (Appendix 4).  Thus, compared to other 
advanced model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement.  Recently, a Phase 1 trial based on the mTPI design has 
been published.4
Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of axitinib and MK-3475, e1 is selected as 0.05, and e2 is selected as 0.03.  
Therefore, the target dosing interval for the DLT rate is (0.25, 0.33).
The three dosing intervals are associated with three different dose-escalation decisions.  The 
under-dosing interval corresponds to a dose escalation (E), over-dosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (R).  
Given a dosing interval and a probability distribution, the unit probability mass (UPM) of 
that dosing interval is defined as the probability of a subject belonging to that dosing interval 
divided by the length of the dosing interval.  The mTPI design calculates the UPMs for the 


Protocol A4061079                                                                               Statistical Analysis Plan
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three dosing intervals, and the one with the largest UPM informs the corresponding 
dose-finding decision, which is the dose level to be used for future patients.  For example, if 
the under-dosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Ji and collaborators have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision)5. 
The dose-finding component of the trial is completed when at least 10 evaluable patients 
have been treated at the highest dose with DLT rate < 0.33. It is estimated that approximately 
20 DLT evaluable patients have been enrolled to reach10-DLT evaluable patients at the 
estimated MTD.
8.1.2. Methods for Estimating the MTD
The estimated MTD will be the highest tested dose level with a DLT rate <0.33 in 10 DLT 
evaluable patients.  We assume that higher doses of MK-3475 result in higher toxicity rates.  
But, due to the relatively low number of patients that may be potentially allocated to any 
dose combination, this assumption may be violated.  For example, at the end of the study, the 
dose combination (MK-3475 2 mg /kg q3wks, axitinib 5 mg BID) may have a higher 
proportion of observed toxicities than, say, (MK-3475 1 mg /kg q3wks, axitinib 5 mg BID), 
and this variability may be simply related to small cohort size alone.  To overcome this 
potential problem, we use a bivariate isotonic regression to smooth the resulting toxicity 
surface to a monotonically increasing one.  The determination of the MTD contour is 
accomplished using the Dykstra-Roberston algorithm.6  Once a monotonically increasing 
toxicity surface is obtained (either observed or smoothed according to the bivariate isotonic 
regression algorithm), the MTD combinations closest to the targeted DLT rate of 0.3 but still 
<0.33 are calculated.  
8.1.3. Sample Size Determination
The sample sizes planned for the study arise from logistic feasibility and past experience with 
Phase 1b studies in oncology and are not entirely driven by statistical considerations.  It is 
expected that approximately 60 patients will be required to achieve all study objectives. 
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
Up-and-Down design using the mTPI approach cannot be determined in advance.  It is 
estimated 20 DLT evaluable patients will be enrolled in the dose finding stage in order to 
have a reliable and accurate estimate of the MTD.  In addition, there will be a Dose 
Expansion Phase cohort to characterize safety, biomarkers, and efficacy in terms of 
probability (p) of achieving an event of interest including, but not limited to, objective 
response (OR).  The goal will be to estimate proportions of such patients with the standard 
error (SE) of not greater than 0.08, ie, by definition,
n
n
p
p
SE
2
1
)
1(



Therefore, a sample of forty patients (n=40) in the Dose Expansion Phase cohort will allow 
estimation of the probability of achieving an event of interest with the standard error 0.08.  


Protocol A4061079                                                                               Statistical Analysis Plan
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The sample size estimate for the expansion cohort also takes into consideration the key tumor 
biomarker PD-L1 endpoints.  If the observed rate of PD-L1 positives is 20% then 
approximately 40 patients would be required to enroll 8 PD-L1 positive patients.
8.2. Statistical Methods for Different Types of Endpoints
Listings and standard summary statistics will be used to analyze the study.  
Analysis of Time-to-Event Endpoints
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate. Medians and two-sided 95% confidence intervals will be 
provided.
Analysis of Binary Endpoints
Binary endpoints will be summarized by percentage rates along with the 95% confidence 
intervals using an exact method.
Analysis of Continuous Endpoints
Continuous endpoints will be summarized by descriptive statistics, including the mean, 
standard deviation, median, minimum, and maximum values.
Analysis of Categorical Endpoints
The number and percentage of patients in each category will be provided for categorical 
variable.
8.3. Statistical Analyses
8.3.1. Standard Analyses

Study Conduct and Patient Disposition - an accounting of the study patients in the 
safety analysis (SA) population will be provided.  Patients not meeting the eligibility 
criteria will be listed.  Patients not completing the study will be listed along with the 
reason for their discontinuation.  Reasons for discontinuation will be summarized.

Baseline Characteristics – for patients in the SA population, characteristics such as 
age, height, weight, race, ethnicity, diagnosis, performance status, MSKCC risk group 
and medical history at study entry will be summarized in frequency tables, and 
descriptive statistics will be provided for quantitative variables.

Treatment Administration/Compliance – Administration of study medication will be 
presented for the SA population, by medication administered within each treatment 
group and will be described in terms of the duration of treatment in days (mean, median 
and range), number of cycles administered (mean, median and range), dose intensity, 


Protocol A4061079                                                                               Statistical Analysis Plan
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dose modifications, dose interruptions, dose delays. Summaries for axitinib will include 
drug that may have been received during the lead-in PK period.
8.3.2. Analysis of Efficacy Endpoints
PFS, DR, and OS will be summarized using the Kaplan-Meier method and displayed 
graphically.  The median event time and 2-sided 95% confidence interval (CI), calculated 
using the Brookmeyer-Crowley method, for the median will be provided for each endpoint.
Six-month and twelve-month progression-free survival (6m-PFS and 12m-PFS) will be 
summarized as a product limit estimator based on the Kaplan-Meier method to account for 
censored events, together with the corresponding 2-sided 95% CI.  The 2-sided 95% CI for 
the log[-log(6 and 12-month PFS probabilities)] will be calculated using normal 
approximation and then back transformed to give the CI for the 6 and 12-month PFS rates.  
Analysis results will be included in the table for the PFS analysis.
The ORR will be summarized along with the corresponding exact 2-sided 95% CI calculated 
using a method based on the F distribution. If a patient has not achieved an objective 
response, but remain stable for at least 12 weeks, then the best overall response for such a 
patient will be SD.
For TTR, descriptive statistics including the mean (95% CI), median, and range will be 
provided.
Tumor Response will be presented in the form of patient data listings that include, but are not 
limited to, lesion type (target/non-target), received (maximum) dose, overall tumor response 
at each visit, and best overall response.  In addition, progression date, death date, date of first 
response and last tumor assessment date, dates of first dose and last dose will be listed, 
together with DR, PFS and OS.  
Listings or/and tables (when applicable) will be sorted by treatment cohort.
Analysis Sets

Response-evaluable population for Tumor Response, PFS and OS (dose expansion 
cohort including the patients from the Dose Escalation Phase of the study treated at 
the MTD).

Patients with an overall objective response of CR or PR in the response-evaluable 
population for Duration of Tumor Response and Time to Response (dose expansion 
cohort including the patients from the Dose Escalation Phase of the study treated at 
the MTD).
8.3.3. Analysis of Safety Endpoints
Analysis Set 

Summaries and analyses of the primary safety endpoint will be based on the per 
protocol analysis set. Summaries and analyses of all other safety parameters will 
include all patients in the Safety Analysis Set.


Protocol A4061079                                                                               Statistical Analysis Plan
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
Secondary safety endpoint data will be summarized by dose level (pooling patients 
treated at the MTD from both phases of the study). 

Adverse events and laboratory tests will be summarized for the following study 
periods: entire study period and by cycle (Cycle 1, Cycle 2 and Cycles beyond 2) in 
the Safety Analysis Set; the PK lead-in period for those patients receiving at least one 
dose of axitinib during the 7 day PK lead-in period; and the treatment period starting 
at C1D1 for patients receiving the combination treatment.
8.3.3.1. Analysis of Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the study.  The occurrence of DLTs 
observed in the dosing cohorts is used to estimate the MTD as described in the protocol.  AEs
constituting DLTs will be listed per dose level.
DLT-related listings will be produced by dose

Patient ID.

Dose and Date at which DLT occurred.

Time from treatment start to onset of DLT.

Time to resolution of DLT to Grade 1 or baseline.

Dose interruption (yes, no).

Time to resumption of treatment.

DLT term.

Action(s) taken due to DLT (stopped temporarily, permanently discontinued, no 
action taken, etc).
8.3.3.2. Analysis of Secondary Safety Endpoint
Adverse Events
AEs will be graded by the Investigator according to the Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The focus of AE summaries will be on treatment-
emergent AEs.  The number and percentage of patients who experienced any AE, serious AE 
(SAE), treatment-related AE, and treatment-related SAE will be summarized according to 
worst toxicity grades.  The summaries will present AEs on the entire study period, separately 
for the lead-in PK period and by cycle (Cycle 1, Cycle 2 and Cycles beyond 2),  as well as 
for the entire treatment period starting at C1D1 (first dose of MK-3475).
For AE summaries of the treatment period starting at C1D1, treatment-emergent will be 
defined as an adverse event with an initial onset or increasing severity after the first dose of 


Protocol A4061079                                                                               Statistical Analysis Plan
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MK-3475.  For all other AE summaries, treatment-emergent will be defined as an adverse 
event with an initial onset or increasing severity after the first dose of any study medication 
(axitinib, in the case of the lead-in PK period).

An overall summary of AEs will be provided.  The number and percentage of   
patients who experienced any AE, who experienced any SAE, who experienced any 
treatment-related AE, who experienced any treatment-related SAE, and who 
discontinued because of an AE will be presented.  Treatment-related AEs are those 
judged by the investigator to be at least possibly related to the study drug (with a 
cause related to the study drug indicated on the CRF).  

All treatment-emergent AEs will be summarized by MedDRA SOC and preferred 
term. A summary of AEs by preferred term and maximum CTCAE grade will be 
presented.  A summary of AEs by preferred term and maximum CTCAE grade group 
(Grade 1-2, Grade 3-4, and Grade 5) will also be presented. Treatment-emergent AEs 
will also be summarized for each group and pooled across the groups.

Treatment-related AEs will be summarized by MedDRA SOC and preferred term
separately for axitinib, MK-3475 and both. A summary of treatment-related AEs by 
preferred term and maximum CTCAE grade will be presented.  A summary of 
treatment related AEs by preferred term and maximum CTCAE grade group (Grade 
1-2 vs. Grade 3-5) will also be presented. Treatment-related AEs will also be 
summarized for each group and pooled across the groups.

Deaths will be summarized by three time periods (on-treatment vs. within 90 days of 
end of treatment vs. > 90 days after end of treatment) and cause of death.  Deaths that 
occurred within 28 days after the last dose of study treatment are defined as on-
treatment deaths.  Death data will also be listed. 

Patients who withdraw from study treatment because of an AE will be listed
separately for axitinib and MK-3475.  Patient discontinuation will be determined 
from the end of treatment (EOT) evaluation (where reason for termination is 
“Adverse Event”) and the specific AE(s) will be determined from the AE CRF page 
(where action taken is “Withdrawn from Treatment”).

SAEs and treatment-related SAEs will be summarized by MedDRA SOC and 
preferred term.  Patients who experienced a SAE will be listed. 
The following analyses will be performed for AEs of special interest (including, but not 
limited to, hepatic disorders [ALT, AST and bilirubin], thyroid dysfunction [hypo-
/hyperthyroidism], diarrhea, colitis and pneumonitis).

Hy’s Law eDISH scatterplot of Maximum ALT vs. Maximum Total Bilirubin on 
treatment.


Protocol A4061079                                                                               Statistical Analysis Plan
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
Hy’s Law eDISH scatterplot of Maximum AST vs. Maximum Total Bilirubin on 
treatment.

The prevalence of AEs of special interest will be summarized by preferred term and 
maximum CTC severity grade.

Descriptive statistics will be presented for time to AE onset (days), time to grade 2 
and grade 3/4 AE onset.
For all safety analyses, only descriptive methods will be used without any formal statistical 
test.
Laboratory Tests
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay.  The analyses will 
summarize laboratory tests on the entire treatment period, separately for the lead-in PK 
period and by cycle (Cycle 1, Cycle 2 and Cycles beyond 2),  as well as for the entire 
treatment period starting at C1D1 (first dose of MK-3475) for patients receiving combination 
therapy. 
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done. 

Hematology – Descriptive statistics will be provided for each test result and for 
change from baseline by visit. Hematology results will be graded according to the 
NCI CTCAE Version 4.03. A summary of maximum CTCAE grade as well as shift 
summary of baseline grade by maximum CTCAE grade, cycle, and dose will be 
presented. Patients who developed a grade 3 or greater toxicity will also be listed.

Biochemistry - Descriptive statistics will be provided for each parameter result and 
for change from baseline by visit. Biochemistry results will be graded according to 
the NCI CTCAE version 4.03. A summary of maximum CTCAE grade as well as 
shift summary of baseline grade by maximum CTCAE grade, cycle, and dose will be 
presented. Patients who developed a grade 3 or greater toxicity will also be listed.

Urine - Descriptive statistics will be provided for urine protein and blood results and 
for change from baseline by visit. Urine protein and blood data will also be listed and 
patients with urine protein ≥2+ by semiquantitative method (e.g., dipstick) will have 
their 24 hour urine collection protein levels listed as well. A shift summary of 
baseline value by maximum value, cycle and dose will be presented for urine protein.

Other Laboratory Tests – Individual patient test results will be listed.
ECOG Performance Status 


Protocol A4061079                                                                               Statistical Analysis Plan
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ECOG performance status data will be summarized with a shift table of the baseline and the 
worst on study status.  Baseline will be defined as the last evaluation within 28 days prior to 
the first dose of either axitinib or MK-3475, whichever occurs first.
Vital Signs
Summaries and listings will be presented for blood pressure, body weight and pulse rate.
In addition, the baseline and the change from baseline in blood pressure and pulse rate will 
be summarized using descriptive statistics by visit.  Baseline will be defined as the last 
evaluation within 28 days prior to the first dose of either axitinib or MK-3475, whichever 
occurs first.  
ECG
All ECG measurements obtained during the study will be listed.  Single ECG measurements
will be obtained at screening and on Cycle 1 Day 1 and End of Treatment/Withdrawal as well 
as when clinically indicated.
Concomitant Medications and Non-drug Procedure/Treatments 
All drug medications will be coded by the World Health Organization (WHO) medical 
dictionary. Non-drug procedure/treatments will be coded by the MedDRA dictionary. All 
medications with a start date prior to lead-in D1 (for patients with a lead-in period) or prior to 
C1D1 (for patients with no lead-in period) are considered previous medication. All ongoing 
medications at the end of study or medications with a stop date on or after lead-in D1 (for 
patients with a lead-in period) or prior to C1D1 (for patients with no lead-in period) are 
considered concomitant medication. If a medication satisfies both the definition of previous 
and concomitant medication, it will be considered both previous and concomitant 
medication.
The number of subjects with any concomitant drug/non-drug treatment will be summarized. 
Listings of prior and concomitant drug/non-drug treatment will be provided separately.  If 
any prior or concurrent surgery or radiation therapy is given, these data will be listed for each 
patient. Furthermore, follow-up systemic therapy for the primary diagnosis will be 
summarized by categories of follow-up therapy and will be listed for each patient as 
appropriate.
Data Safety Monitoring Committee
A Data Safety Monitoring Committee will not be established for the study.
8.3.4. Analysis of Pharmacokinetics
Analysis Set: PK


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8.3.4.1. Pharmacokinetic Analysis of MK-3475 and Axitinib
Standard PK parameters for axitinib (Cmax, Tmax, AUC0-last, AUC0-12, AUC0-24, CL/F, Vz/F, 
and plasma elimination half life t1/2) will be estimated using non-compartmental methods.  
For MK-3475, pharmacokinetics will be evaluated at Merck using population 
pharmacokinetic modeling and results will be shared with pfizer.
Presentation of pharmacokinetic data will include:

Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of plasma 
concentrations for axitinib will be presented in tabular form by treatment cohort, dose 
level, cycle, day and nominal time. Additionally similar descriptive statistics will also 
be generated for dose-normalized axitinib pharmacokinetic parameters

Linear-linear and log-linear plots of mean and median plasma concentrations by 
nominal time for axitinib will be presented for PK sampling days by treatment cohort, 
cycle, and study day. Similar plots will be presented for axitinib for each individual 
patient concentrations. Only patients who have matched pairs of PK collections 
available on both planned treatments (when administered alone and in combination
with MK-3475) will be included in the axitinib plasma concentration descriptive 
summary and median concentration profiles. Patients who have undergone intra-
patient dose reduction or escalation will be excluded from the median plasma 
concentration-time plots.

Pharmacokinetic parameters for axitinib will be listed and summarized by treatment 
cohort/dose level, cycle and study day using descriptive statistics (n, mean, SD, 
%CV, median, minimum, maximum, geometric mean and its associated %CV, and 
95% confidence interval). For Tmax, the range (min, max) will be also be provided. 
Only patients who have a matched pair of estimated axitinib PK parameters available 
on both planned treatments (when administered alone and in combination) will be 
included in the axitinib PK parameter summary tables. PK parameters with zero 
values will be excluded from the calculation of geometric means and its associated 
%CV. If an intra patient dose escalation or reduction occurs, dose-dependent PK 
parameters (AUC and Cmax) for that patient may be dose-normalized when it is known
that the drug exhibits linear PK within the dose range and other PK parameters will 
be reported as estimated; or may only be included in descriptive statistics and 
summary plots up to the time of the dose change. In addition, dose-normalized 
axitinib Cmax and AUC parameters will be summarized (as described above) using 
data pooled across cohorts in which different axitinib doses were administered. 

Box plots for AUC and Cmax for axitinib (during treatments when given alone and in 
combination) will be generated.  Individual data points, the geometric mean and the 
median of the parameter in each treatment will be overlaid on the box plots.  If a 
cohort has limited evaluable PK data (n<4), matchstick plots showing changes in 
AUC and Cmax for each drug (during treatments when given alone and in 
combination) in individual patients will then be generated.  The geometric mean of 
the parameter in each treatment will be overlaid in the plots.  In addition, box plots 


Protocol A4061079                                                                               Statistical Analysis Plan
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for dose-normalized axitinib Cmax and AUC parameters will be created using data 
pooled across cohorts in which different axitinib doses were administered.  

Trough concentrations for MK-3475, if available, will be plotted for each treatment 
cohort using a box-whisker plot by cycle and day within cycle in order to assess the 
attainment of steady-state.
8.3.4.2. Effect of MK-3475 on Axitinib Pharmacokinetics
The effect of repeated MK-3475 dosing on steady-state axitinib PK will be evaluated using 
AUC0-12 (or AUC0-last, if AUC0-12 is not estimable) of axitinib on Lead-in Day 7 and Cycle 7
Day 1, respectively, as the primary PK parameter.  Ninety-percent confidence interval for the 
ratio of geometric means of AUC0-12 and Cmax (axitinib in presence of MK-3475/axitinib 
alone) will be computed to assess the magnitude of the effect.
8.3.4.3. Immunogenecity Assessment
Results for the anti-MK-3475 antibody (ADA) assessment will be provided by Merck.  
8.3.4.4. Population Pharmacokinetic Analysis or PK/PD Modeling
Mechanism-based or semi-mechanistic sequential pharmacokinetic-pharmacodynamic 
models may be developed using NONMEMto explore any relationships between plasma 
drug concentrations and selected safety, biomarker, and efficacy endpoints.
The results of these analyses, if performed, will be reported separately.
8.3.5. Analysis of Biomarker Endpoints
Translational and pharmacodynamic biomarkers will be summarized using the appropriate 
biomarker analysis set.  Summaries of baseline and ratio to baseline values at post-treatment
visits will be provided using N, mean, standard deviation, median, % CV (as appropriate) and 
minimum/maximum for circulating biomarkers serum and tumor RNA measurements for 
potential gene signature development.  Summary statistics will be provided for baseline 
values of circulating markers including VEGF-A, VEGFR2, IL8 and T-cell receptors, and 
archival tumor and baseline de novo biospecimens markers such as PD-L1 for all biomarker 
evaluable patients.  Post-baseline values will be summarized for biomarker evaluable patients 
in the dose expansion cohort, when available.   
Correlations of biomarker results with measures of anti-tumor efficacy will be examined for 
dose escalation and expansion cohorts separately.  Summary of level of biomarkers at 
baseline and/or ratio of values to baseline versus ORR category will be made by timepoint.   
Summary of PFS and DR will be provided for dose expansion cohort after stratification by a 
preset cutpoint of biomarker values at baseline and/or ratio of values to baseline by timepoint. 
Receiver Operating Characteristics（ROC）analysis may be conducted for significant test 
results (p<0.05) in correlations of PFS and/or ORR with PD-L1 expression level.  Receiver
Operating Characteristics (ROC) analysis may also be performed if significant test results 
(p<0.05) in correlations of ORR and/or PFS with tumor RNA measurements are observed.
Graphical display will be provided for level of biomarkers at baseline and/or ratio of values 


Protocol A4061079                                                                               Statistical Analysis Plan
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to baseline at each timepoint.  Box and Whisker plots will be produced for level of 
biomarkers at baseline and/or ratio of values to baseline versus ORR category by timepoint in 
dose escalation and expansion cohorts separately.   Kaplan-Meier plots will be produced for 
PFS and DR after stratification by < or >= median levels of biomarkers at baseline and/or
ratio of values to baseline at each timepoint in the dose expansion cohort.   
All biomarker data will be listed.


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8.4. Summary of Secondary Efficacy Analyses 
Endpoint
Analysis 
Population
Statistical Method
Missing Data
Analysis 
Type/Timing
ORR
Response 
Evaluable
Exact method based on 
F-distribution (95% CI)
(See 8.3.2)
See Section 6.1
Secondary 
analysis
DR
Subgroup of 
pts with OR 
from the 
Response 
Evaluable
K-M method (median 
and 95% CI) (See 8.3.2)
See Section 6.1
Secondary 
analysis
TTR
Response 
Evaluable
Univariate (median and 
95% CI) (See 8.3.2)
See Section 6.1
Secondary 
analysis
PFS
Response 
Evaluable 
K-M method (median, 6
and 12m-PFS and 95% 
CIs)
(See 8.3.2)
Censor patients on 
the day of the last 
evaluable tumor 
assessment 
documenting 
absence of disease 
progression for … 
(See Section 6.1)
Secondary 
analysis 
OS
Response 
Evaluable 
K-M method (median 
and 95% CIs)
(See 8.3.2)
See Section 6.1
Secondary 
analysis 
CI: Confidence intervals; DR: Duration of Response; K-M: Kaplan-Meier; OR: Objective Response; ORR: 
Objective Response Rate; PFS: Progression-free Survival; TTR: Time to Response; OS: Overall Survival


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9. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
3.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
4.
Fanale M et al. Phase I study of bortezomib plus ICE (BICE) for the treatment of 
relapsed/refractory Hodgkin lymphoma. British Journal of Haematology, 154:284 286, 
2011.
5.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials 2010; 7:653 663.
6.
Dykstra R, Robertson T. An algorithm for isotonic regression for two or more 
independent variables. Ann Stat. 1982;10:708-716.


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10. APPENDICES
Appendix 1. Programming Specifications for AE Analyses
a. Time to AE onset
1. Definition
Time to AE onset (days) will be calculated as first AE start date – first dose date +1.  
The definition and calculations are similar for time to Grade 3/4 AE onset.
AE start date
The Date of Onset for the first occurrence of the AE based on the Log AE CRF page.  
First dose date
For AE summaries of the lead-in PK period: The date of the first dose taken from the 
Axitinib Dosing CRF page. 
For AE summaries of the treatment period starting at C1D1: The date of the first dose 
taken from the MK-3475 Dosing CRF page. 
For AE summaries of the entire treatment period (including by cycle): The date of the 
first dose taken from either the Axitinib or MK-3475 Dosing CRF page, whichever 
occurs first.
b. Duration of AE
1. Definition
Duration of AE (days) is defined as the cumulative duration across episodes of the
specific AE (by preferred terms) where duration for each episode is calculated as AE 
end date – AE start date +1 excluding any overlap. Duration of AE is defined for 
subjects with the AE.
AE start date
The Date of Onset based on the Log AE CRF page.  
AE end date
The Date Resolved based on the Log AE CRF page.  
2. Censoring


Protocol A4061079                                                                               Statistical Analysis Plan
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AE resolution is considered an event (censoring variable=1).  If a subject has an AE 
that was ongoing (does not have to be the last AE) at the time of analysis, the time is 
censored (censoring variable=0) at the last available on treatment visit date.  Subjects 
who die prior to resolution of the AE will be censored at the date of death. If the date 
of death is the same as the date of the resolution of the AE, the subject will be 
censored at that date (i.e. resolution will not be considered an event) and only if the 
AE is the AE that resulted in death will it be counted as an event.
Date of death
Death date is based on the Notice of Death CRF page.
3. Clustered Events
For clustered events, a patient could have multiple events in the cluster which may 
overlap.  In this case, AE duration will be summed across all events in the cluster 
accounting for the overlap (i.e. overlapping periods between events in the same 
cluster are not double-counted).  Lags between events in the same cluster are not 
included in the duration.
The following scenarios provide examples of the calculation for 2 events in the same 
cluster.  The extension to 3 or more events of the same cluster is similar.

TWO EVENTS OF THE SAME CLUSTER WHERE ONE EVENT COMPLETELY 
CONTAINS THE OTHER EVENT
    event 1                  [------------------------------]
           
                 startdate1                     enddate1
    event 2                      [------------------------]
                                         startdate2            enddate2
   
duration = enddate1-startdate1+1

CERTAIN PORTIONS OF TWO EVENTS IN THE SAME CLUSTER OVERLAP
    event 1                  [------------------------------]
            
                 startdate1                     enddate1
    event 2                                          [------------------------]
            
                                              startdate2            enddate2
    duration = enddate2-startdate1+1

TWO EVENTS OF THE SAME CLUSTER ARE CONTIGUOUS TO EACH OTHER  
    event 1                 [------------------------------]
            
              startdate1                     enddate1
    event 2                                                           [------------------------]
            
                                                            startdate2            enddate2


Protocol A4061079                                                                               Statistical Analysis Plan
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duration = enddate2-startdate1+1

TWO EVENTS OF THE SAME CLUSTER ARE NON-OVERLAPPING 
    event 1                  [------------------------------]
            
                 startdate1                     enddate1
    event 2                                                                               [------------------------]
                                                                                                     startdate2         enddate2
    duration = (enddate1-startdate1+1) + (enddate2-startdate2+1)


Protocol A4061079                                                                               Statistical Analysis Plan
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c.
AE Prevalence
1. Definition
AE prevalence is defined as the number of patients with an AE in a particular time 
period (including both new cases with an onset date during the specified time period 
AND cases with an AE continued from a previous time period) divided by the 
number of patients at risk during the specified time period.  The number of patients at 
risk includes all subjects except those who either have discontinued or died prior to 
the specified time period.
AE prevalence will be presented for the entire study period, separately for the lead-in 
PK period and by cycle (Cycle 1, Cycle 2 and Cycles beyond 2),  as well as for the 
entire treatment period starting at C1D1.
2. Assumptions
For AE summaries of the study period starting at C1D1 the following apply:

A patient is counted in the numerator if the patient has an onset date of the AE 
during Cycle 1 OR for patients with a 7 day lead-in PK period there is an increase 
in grade of the AE after the first dose of MK-3475 (C1D1) or if there is a decrease 
and then subsequent increase during treatment with the combination.

The denominator will include subjects who have received at least one dose of 
MK-3475.  
For AE summaries of the entire study period including by cycle (Lead-in PK period, 
Cycle 1, Cycle 2 and Cycles beyond 2) the following apply:

Patients are counted for an AE in each cycle up until the cycle where the AE 
resolved.  Thus, the calculation conservatively assumes that if the AE resolved in 
a cycle, it resolved at the end of the cycle.

For Lead-in PK period, a patient is counted in the numerator if the patient has an 
onset date of the AE during the Lead-in period.

For Cycle 1, a patient is counted in the numerator if the patient has an onset date 
of the AE during Cycle 1 OR an onset date during the Lead-in PK phase that is 
still ongoing in Cycle 1 (did not have a resolution date in the Lead-in phase).

For Cycle 2, a patient is counted in the numerator if the patient has an onset date 
of the AE during Cycle 2 OR an onset date during the Lead-in PK phase or Cycle 
1 that is still ongoing in Cycle 2 (did not have a resolution date in the Lead-in 
phase or Cycle 1).


Protocol A4061079                                                                               Statistical Analysis Plan
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
For Cycles ≥2, a patient is counted in the numerator if the patient has an onset 
date in Cycles ≥2 OR an onset date in a previous cycle that is still ongoing (did 
not have a resolution date in Cycle 1 or earlier).

The denominator for a particular time period will include subjects who are at risk 
prior to the time period.  The number at risk includes all subjects except those 
who either have discontinued (based on the ‘Subject Summary’ CRF) or died
prior to the specified time period (i.e. Death Date based on ‘Notice of Death’ CRF 
is prior to start of time period). 


Protocol A4061079                                                                               Statistical Analysis Plan
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Appendix 2. Study Specific Information for Efficacy

Baseline:  is defined as the last observation within 28 days prior to the first dose of any 
study treatment (first dose of axitinib for patients receiving the lead-in PK dose or first 
dose of either drug for patients not receiving the lead-in PK dose).

Adequate Baseline: 

Baseline tumor evaluations must be performed within 4 weeks (28 days) prior to 
the first dose of any study treatment (first dose of axitinib for patients receiving 
the lead-in PK dose or first dose of either drug for patients not receiving the lead-
in PK dose);  

Presence of at least one measurable lesion per RECIST version 1.1;

All lesions recorded at baseline must have an associated status recorded on the 
CRF;

Baseline lesions must be assessed with an acceptable method that includes: 
Conventional CT Scan, Spiral CT Scan, X-ray, MRI, Physical Exam, Bone Scan 
and Other. Note: If based on data review “unacceptable” methods (e.g. 
ultrasound, etc) are noted under “Other”, then this category will not be considered 
acceptable (on a case by case basis).

“On-study” period for efficacy: is defined as the period from the date of the first dose
of MK-3475 until subject death, progression of disease, subject no longer willing to 
participate, start of other anti-cancer treatment,, whichever is earlier.

Subsequent anti-tumor treatment:  includes any systemic anticancer therapy (other 
than study medication), radiation to target lesions, and surgery for removal (resected or 
partially resected) of target lesions.


Protocol A4061079                                                                               Statistical Analysis Plan
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Appendix 3. RECIST 1.1
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation.  
Measurability of Tumor Lesions
At baseline, individual tumor lesions will be categorized by the Investigator as either 
measurable or non-measurable by the RECIST criteria as described below.
Measurable:
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-Measurable:  All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with >10 mm to <15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques. 
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 
diameter to be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters.


Protocol A4061079                                                                               Statistical Analysis Plan
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All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as “present” or “absent.”
Techniques for Assessing Measurable Disease
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up.  Imaging-based evaluation 
is preferred to evaluation by clinical (physical) examination when both methods have been 
used to assess the antitumor effect of a treatment.
Definitions of Tumor Response
Target Lesions
Complete response (CR) is defined as the disappearance of all target lesions. Any
pathological lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
Partial response (PR) is defined as a 30% decrease in the sum of the longest dimensions of 
the target lesions taking as a reference the baseline sum longest dimensions.
Progressive disease (PD) is defined as a 20% increase in the sum of the longest dimensions 
of the target lesions taking as a reference the smallest sum of the longest dimensions 
recorded since the treatment started, or the appearance of one or more new lesions. In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the smallest sum of the longest dimensions 
since the treatment started. 
Non-Target Lesions
Complete response (CR) is defined as the disappearance of all non-target lesions.  All
lymph nodes must be non-pathological in size (<10mm short axis).
Non-CR/Non-PD is defined as a persistence of 1 non-target lesions.
Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of 1 new lesion.
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease.
Confirmation of Tumor Response


Protocol A4061079                                                                               Statistical Analysis Plan
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To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 4 weeks 
after the criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 12 weeks.
Determination of Tumor Response by the RECIST Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the 
following table.
Response Evaluation Criteria in Solid Tumors
Target Lesions1
Non-Target Lesions2
New Lesions3
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
1 Measurable lesions only.
2 May include measurable lesions not followed as target lesions or non-measurable lesions.
3 Measurable or non-measurable lesions
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  For CR and PR, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria. In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 12 weeks.
NOTE:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.  It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation to 
document whether or not objective tumor progression has occurred. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy before 
confirming the complete response status.


Protocol A4061079                                                                               Statistical Analysis Plan
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Appendix 4. Detailed Dose Escalation/De-Escalation Scheme
Number of patients treated at current dose
1
2
3
4
5
6
7
8
9
10
Number of toxicities
0
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
2
DU
D
S
S
S
S
S
S
S
3
DU
DU
D
D
S
S
S
S
4
DU
DU
DU
DU
DU
DU
DU
5
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU