A Phase II Study of Perioperative Pembrolizumab-Based Therapy in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Prior to Cytoreductive Nephrectomy or Metastasectomy
Phase: PHASE2
Conditions: Metastatic Clear Cell Renal Cell Carcinoma, Recurrent Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Clear Cell Renal Cell Carcinoma
Sponsor: University of California, San Francisco

Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Proprietary
A Phase II Study of Perioperative Pembrolizumab-Based 
Therapy in Patients with Locally Advanced or Metastatic 
Renal Cell Carcinoma Prior to Cytoreductive Nephrectomy 
or Metastasectomy
Protocol Number:  CC #197017
Merck Protocol Number:  3475-800
Study Drugs:  Pembrolizumab, Axitinib, TBD
Version Number:  1.9
Version Date:   01/30/2024
IND Number:  144040
Principal Investigator (Sponsor-Investigator)
David Oh, MD, PhD
University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Statistician
Li Zhang, PhD
Revision History
Version 1.9
Version 1.8
Version 1.7
Version 1.6
Version 1.5
Version 1.4
Dated 01/30/2024
Dated 02/23/2023
Dated 06/08/2022
Dated 01/13/2022
Dated 03/18/2021
Dated 12/07/2020
Version 1.3
Dated 07/15/2020
Version 1.2
Dated 01/02/2020
Version 1.1
Dated 07/03/2019
Version 1.0
Dated 03/14/2017

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Protocol CC#: 197017
Phase II – Pembrolizumab + Axitinib
Page 1 of 104
Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC).
2.
I will conduct the study per applicable IRB requirements, Federal regulations, and state and 
local laws to maintain the protection of the rights and welfare of study subjects.
3.
I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol.
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol per Good 
Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator 
(Form FDA 1572), and with local regulatory requirements. Per the FDA Modernization Act, I 
will ensure the registration of the trial on the www.clinicaltrials.gov website.
5.
I agree to keep adequate and accurate records per IRB policies, Federal, state, and local laws 
and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date

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Phase II – Pembrolizumab + Axitinib
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Abstract
Title
A Phase II Study of Perioperative Pembrolizumab-Based Combination 
Therapy in Patients with Locally Advanced or Metastatic Renal Cell 
Carcinoma Prior to Cytoreductive Nephrectomy or Metastasectomy 
Patient 
population

Treatment-naïve

Locally advanced or metastatic renal cell carcinoma (RCC; clear cell 
component)

Planned cytoreductive nephrectomy (CN) and/or metastasectomy (MET)
Rationale for 
Study
Recent studies show that combining anti-programmed cell death 1 (PD-1) with 
other targeted therapies increase response rates compared to checkpoint 
inhibitor monotherapy. However, the mechanisms of response and resistance 
to PD-1/programmed cell death ligand 1 (PD-L1)-based combination therapies 
remain unclear.
Primary 
Objective

To determine the impact of pembrolizumab-based combination therapy 
on the composition, phenotype, and function of tumor-infiltrating immune 
cells (TIICs) in subjects with advanced RCC undergoing CN/MET.
Secondary 
and 
Correlative 
Objectives
Secondary

To determine the clinical efficacy of preoperative pembrolizumab-based 
combination therapy in subjects with advanced RCC undergoing CN/MET

To explore the clinical efficacy of continued pembrolizumab-based 
therapy following CN/MET in subjects with advanced RCC
o
Subjects who achieve a complete response (CR) prior to or following 
CN/MET, a partial response (PR), or stable disease (SD) will receive 
continued pembrolizumab-based combination therapy up to 1-2 years 
(9-18 cycles) depending on their resection status

To determine the safety and tolerability of pembrolizumab-based 
combination therapy in subjects with advanced RCC undergoing CN/MET
Correlative

To explore the relationship between changes in TIICs and clinical efficacy 
in subjects with advanced RCC treated with pembrolizumab-based 
combination therapy

To characterize changes in the frequency and number of circulating 
T cells induced by pembrolizumab-based combination therapy in subjects 
with advanced RCC

To determine the impact of pembrolizumab-based combination therapy 
on the composition and phenotype of the tumor microenvironment 

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(including tumor and stromal cells) in subjects with advanced RCC

To determine whether locally advanced versus metastatic RCC exhibit 
differences in immune composition or phenotype at baseline and in 
response to pembrolizumab-based therapy

To determine the change in T cell repertoire within the tumor and blood 
induced by pembrolizumab-based combination therapy in subjects with 
advanced RCC

To explore molecular profiles to identify potentially predictive biomarkers 
for subjects with advanced RCC treated with immunotherapy
Study Design

Prospective, phase II

Single center

Open label

Multi-cohort study, with concurrent enrollment (nonrandomized)
o
Cohort A: Pembrolizumab monotherapy
o
Cohort B: Pembrolizumab + axitinib
o
Cohort C: Pembrolizumab + TBD (agent to be determined)

Additional cohorts may be added after discussion with Study Steering 
Committee and mutual agreement between the Principal Investigator 
(PI)/Sponsor and Merck; see schema below.
Number of 
subjects
Up to 84 subjects in total will be enrolled.
Up to twelve subjects will be enrolled into the pembrolizumab monotherapy 
cohort (Cohort A).  The first 6 subjects accrued to Cohort A will be evaluated 
in a safety lead-in for the safety of pembrolizumab prior to planned CN/MET.
Once 6 subjects are enrolled in Cohort A, the pembrolizumab-based 
combination cohorts will open to concurrent enrollment. A minimum of 4 and a 
maximum of 36 subjects may be enrolled into each pembrolizumab-based 
combination cohort. 
Duration of 
Therapy
PREoperative therapy: 3 cycles (9 weeks; see study schema below)
CN/MET:

Surgery will occur 2 weeks following completion of the preoperative 
treatment period

Subjects with locally advanced disease who achieve radiographic CR 
during the preoperative treatment period will proceed with CN followed by 
postoperative therapy as described below.
POST-operative therapy:

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
Subjects will begin postoperative therapy no sooner than 3 weeks and no 
later than 6 weeks following CN/MET, to allow for postoperative recovery 
(adequate wound healing and recovery from any postoperative 
complications, as determined by the treating surgeon).

Subjects who achieve R0 resection (NED, negative margins) or R1 
resection (microscopic disease, positive margins) after preoperative 
treatment will receive continued pembrolizumab-based combination 
therapy for up to 9 cycles following CN/MET, or until disease progression, 
death, unacceptable toxicity, or withdrawal from study, whichever occurs 
first.

Subjects who achieve R2 resection (macroscopic disease after surgery) 
after preoperative treatment, or who do not undergo nephrectomy after 
achieving pre-operative radiographic CR, will receive continued 
pembrolizumab-based combination therapy for up to 18 cycles following 
CN/MET, or until disease progression, death, unacceptable toxicity, or 
withdrawal from study, whichever occurs first.
Subjects with progressive disease (PD) during preoperative therapy: Subjects 
may still undergo CN/MET under study if the study investigator and treating 
physician determine that the subject will benefit from cytoreductive surgery. 
Subjects unlikely to benefit from CN/MET, or in whom CN/MET is not feasible 
due to PD or safety reasons, will be required to provide a tumor biopsy, unless 
deemed unsafe or delays appropriate standard of care. These subjects will 
discontinue study participation after CN/MET or tumor biopsy. Subjects in 
whom cytoreductive surgery or tumor biopsy is not feasible or safe, or will lead 
to delay in standard of care, will discontinue study participation immediately.
Subjects with PR/SD who cannot undergo CN/MET for any reason following 
therapy: In rare cases, subjects who were deemed eligible for CN/MET prior 
to study participation and have PR/SD after preoperative therapy may not be 
able to undergo CN/MET (for example, due to adverse events). These subjects 
will be required to provide a tumor biopsy, unless deemed unsafe or delays 
appropriate standard of care. Subjects may continue study treatment until 
disease progression, death, unacceptable toxicity, or withdrawal from study. 
Subjects in whom tumor biopsy is not collected will not be evaluable for the 
primary endpoint.

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Duration of 
Follow up
Subjects with R0 or R1 resection who complete 9 cycles of either 
pembrolizumab monotherapy or pembrolizumab combination therapy, or 
subjects with R2 resection who complete 18 cycles of either pembrolizumab 
monotherapy or pembrolizumab combination therapy, will be followed for up 
to 1 year, or until disease progression, death, or withdrawal from study, 
whichever occurs first.
Subjects who discontinue study participation due to PD will return for the 
mandatory Safety Follow-up visit 30 days (+7 days) after the final study 
treatment.  All adverse events (AEs) that occur prior to the Safety Follow-Up 
Visit should be recorded. Subjects with an AE of Grade >1 will be followed until 
the resolution of the AE to Grade 0-1 or until the beginning of a new anticancer 
therapy, whichever occurs first. Serious AEs that occur within 90 days of the 
end of treatment should also be followed and recorded.
Duration of 
study
Each cohort is expected to reach primary completion 36 months after opening 
to accrual.
Study Drugs
Pembrolizumab (Investigational, intravenous [IV]; all cohorts)
Axitinib (Standard of care, by mouth [PO]; Cohort B)
Additional study drugs for Cohort C and each subsequent cohort may be 
added at a later time.
Safety 
Assessments
Safety assessments will include AEs (including AEs related to surgery) and 
clinical laboratory evaluations.
Efficacy 
Assessments
Clinical efficacy assessments:

Objective response rate

Rate of R0 resection

Disease/Progression-free survival (DFS/PFS; rate at 1-year and 2-years, 
and median)
Unique 
Aspects of 
this Study
The perioperative approach proposed in this study provides a unique 
opportunity to evaluate the in vivo immunologic impact of pembrolizumab-
based therapy in subjects with advanced RCC. Paired tissue collection (pre- 
and post-treatment) enables rich scientific correlatives. 

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Study Schema

Patient population: Treatment-naïve, advanced (locally advanced or metastatic) RCC 
subjects, with clear cell component on histology, who have planned CN and/or MET 
surgery.

Preoperative treatment: 3 cycles (9 weeks); each cycle is 21 days in duration.
o
Cohort A: Each cycle consists of pembrolizumab monotherapy (200 mg Q3W) given 
on Day 1 of each cycle. Total duration of therapy: 9 weeks.
o
Cohort B: Each cycle consists of pembrolizumab (200 mg Q3W) given on Day 1 of 
each cycle, and axitinib (5 mg PO twice daily [BID]) taken on days 1-21.  Axitinib dose 
may be titrated per standard of care (SOC) after first 3 weeks. Total duration of 
therapy: 9 weeks.
o
Cohort C: To be decided later after consideration by the Study Steering Committee, 
Sponsor, and Merck.

There will be a 2-week break after preoperative therapy, prior to CN and/or MET.

For subjects experiencing unequivocal disease progression during the preoperative 
treatment period in whom CN/MET is unlikely to provide clinical benefit, core biopsies may 
be performed prior to the subject discontinuing study participation, if in the judgment of the 
treating physician, the biopsy would not delay appropriate standard of care and is safe 
and feasible.

Subjects will begin postoperative therapy no sooner than 3 weeks and no later than 6 
weeks following CN/MET.

Subjects who achieve R0 resection (NED, negative margins) or R1 resection (microscopic 
disease, positive margins) after preoperative treatment will receive continued 
pembrolizumab-based combination therapy (42-day cycles) for up to 9 cycles following 
CN/MET.

Subjects who achieve R2 resection (macroscopic disease after surgery) after preoperative 
treatment, or who do not undergo nephrectomy after achieving pre-operative radiographic 

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CR, will receive continued pembrolizumab-based combination therapy (42-day cycles) for 
up to 18 cycles following CN/MET.

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List of Abbreviations
AE
adverse event
ACE
angiotensin-converting-enzyme
ADL
activities of daily living
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All Patients as Treated
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
BID
Twice daily
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CD
Cluster of differentiation
CN
Cytoreductive nephrectomy
CR
complete response
CRF
case report form
CT
computed tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
DFS
disease-free survival
DILI
drug induced liver injury
DLT
Dose-limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
ERC
Ethics Review Committee 
FACS
fluorescence-activated cell sorting
FDA
United States Food and Drug Administration

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List of Abbreviations
FNA
Fine needle aspirate
FSH
Follicle stimulating hormone
FT4
Free thyroxine
GCP
Good Clinical Practice
GEP
Gene expression profile
GI
Gastrointestinal 
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
Ig
immunoglobulin
IHC
immunohistochemistry
IND
investigational new drug application
IRB
Institutional Review Board
IV
Intravenous(ly)
KN
KEYNOTE
LD
Longest diameter
LDH
lactate dehydrogenase
mAb
Monoclonal antibody
MET
metastasectomy
mRCC
Metastatic renal cell carcinoma
MRI
magnetic resonance imaging
MSI
microsatellite instability
mTOR
Mammalian target of rapamycin
NCI
National Cancer Institute

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List of Abbreviations
NSAE
Non-serious adverse event
NSCLC
Non-small cell lung cancer
ORR
objective response rate
OS
Overall survival
PBMC
peripheral blood mononuclear cell
PBPK
Physiologically based pharmacokinetics
PD
disease progression
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetic(s)
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
PTT
partial thromboplastin time
q3 months Every 3 months
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q6W
Every 6 weeks
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors 
RTK(I)
receptor tyrosine kinase (inhibitor)
SAE
Serious adverse event
SD
Stable disease
T3
triiodothyronine

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List of Abbreviations
TCR
T-cell receptor
TIICs
Tumor-infiltrating immune cells
TKI
Tyrosine kinase inhibitor
TSH
Thyroid stimulating hormone
ULN
upper limit of normal
VEGF
Vascular endothelial growth factor
VEGFR
Vascular endothelial growth factor receptor
WBC
white blood cell
WES
whole genome sequencing

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Table of Contents
Protocol Signature Page ...............................................................................................................1
Abstract
2
List of Abbreviations ......................................................................................................................8
Table of Contents ........................................................................................................................12
List of Tables
17
1
Introduction...........................................................................................................................18
1.1
Background on Indication...................................................................................18
1.2
Background on the Compounds.........................................................................19
1.2.1
Pembrolizumab...............................................................................................19
1.2.2
Axitinib ............................................................................................................20
1.3
Rationale for the Proposed Study.......................................................................21
1.3.1
Rationale for a Perioperative Study in Subjects Eligible for CN/MET.............21
1.3.2
Overarching Objective ....................................................................................22
1.4
Correlative Studies .............................................................................................23
1.4.1
Correlative Studies Background .....................................................................23
1.4.2
Biomarker Research.......................................................................................23
1.4.3
Future Biomedical Research Specimen Collection.........................................26
2
Objectives and Endpoints of the Study ................................................................................27
2.1
Objectives...........................................................................................................27
2.1.1
Primary ...........................................................................................................27
2.1.2
Secondary.......................................................................................................27
2.1.3
Exploratory......................................................................................................27
2.2
Endpoints............................................................................................................28
2.2.1
Primary ...........................................................................................................28

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2.2.2
Secondary.......................................................................................................28
2.2.3
Exploratory......................................................................................................29
3
Study Design........................................................................................................................29
3.1
Characteristics....................................................................................................29
3.2
Number of Subjects............................................................................................31
3.3
Eligibility Criteria.................................................................................................31
3.3.1
Inclusion Criteria.............................................................................................31
3.3.2
Exclusion Criteria............................................................................................33
3.4
Duration of Therapy............................................................................................36
3.5
Duration of Follow Up.........................................................................................36
3.6
Randomization Procedures ................................................................................36
3.7
Study Timeline (Primary Completion).................................................................36
4
Study Drugs..........................................................................................................................37
4.1
Description, Supply and Storage of Investigational Drugs .................................37
4.1.1
Pembrolizumab...............................................................................................37
4.1.2
Axitinib ............................................................................................................38
4.2
Drug Accountability.............................................................................................39
4.3
Drug Ordering.....................................................................................................39
4.4
Packaging and Labeling of Study Drugs ............................................................39
5
Treatment Plan.....................................................................................................................39
5.1
Dosage and Administration ................................................................................39
5.1.1
Cohort A: Pembrolizumab Monotherapy.........................................................41
5.1.2
Cohort B: Pembrolizumab + Axitinib...............................................................41
5.1.3
Cytoreductive Nephrectomy and/or Metastasectomy.....................................43
5.1.4
Continuation of Pembrolizumab-based Therapy Following CN/MET .............43

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5.2
Dose Modifications and Dosing Delays..............................................................44
5.2.1
Pembrolizumab...............................................................................................44
5.2.2
Axitinib ............................................................................................................53
5.3
Monitoring and Toxicity Management.................................................................53
6
Study Procedures and Observations....................................................................................54
6.1
Schedule of Procedures and Observations........................................................54
6.1.1
Pretreatment Period........................................................................................54
6.1.2
Treatment Period............................................................................................55
6.1.3
Post-Treatment Period....................................................................................61
6.2
Trial Flow Chart ..................................................................................................64
6.3
Discontinuation/Withdrawal Criteria....................................................................70
6.3.1
Discontinuation of Study Treatment................................................................70
6.3.2
Withdrawal from the Study..............................................................................71
6.3.3
Lost to Follow-up ............................................................................................71
6.4
Usage of Concurrent/Concomitant Medications/Vaccinations............................71
6.4.1
Acceptable Concomitant Medications.............................................................71
6.4.2
Prohibited Medications ...................................................................................72
6.5
Dietary Restrictions ............................................................................................73
6.6
Pregnancy and Contraception............................................................................73
6.6.1
Contraception .................................................................................................73
6.6.2
Use in Pregnancy ...........................................................................................74
6.6.3
Use in Nursing Women...................................................................................75
6.6.4
Pregnancy tests..............................................................................................75
6.7
Clinical Criteria for Early Trial Termination.........................................................75
6.8
Laboratory Procedures/Assessments.................................................................75

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6.8.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis, and 
Others)75
7
Reporting and Documentation of Results.............................................................................77
7.1
Evaluation of Efficacy: Antitumor Effect - Solid Tumors .....................................77
7.1.1
Initial Tumor Imaging ......................................................................................78
7.1.2
Tumor Imaging During the Study....................................................................78
7.1.3
Response Evaluation Following Surgery........................................................78
7.1.4
Disease Parameters .......................................................................................79
7.1.5
Methods for Evaluation of Measurable Disease .............................................79
7.1.6
Response Criteria...........................................................................................80
7.2
Evaluation of Safety............................................................................................81
7.3
Definitions of Adverse Events.............................................................................81
7.3.1
Adverse Event ................................................................................................81
7.3.2
Adverse reaction.............................................................................................82
7.3.3
Suspected Adverse Reaction .........................................................................82
7.3.4
Definition of an Overdose ...............................................................................84
7.3.5
Events of Clinical Interest ...............................................................................84
7.4
Recording of an Adverse Event..........................................................................85
7.5
Follow-up of Adverse Events..............................................................................85
7.6
Adverse Events Monitoring.................................................................................85
7.7
Expedited Reporting...........................................................................................85
7.8
Reporting Events to Merck .................................................................................86
7.8.1
Reporting of Pregnancy and Lactation ...........................................................88
7.8.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting................88
8
Statistical Considerations and Evaluation of Results ...........................................................89
8.1
Study Endpoints .................................................................................................89

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8.1.1
Study Design ..................................................................................................90
8.1.2
Randomization................................................................................................90
8.1.3
Stratification Factors.......................................................................................90
8.2
Determination of Sample Size and Accrual Rate ...............................................90
8.2.1
Sample Size and Power Estimate ..................................................................90
8.2.2
Replacement Policy........................................................................................91
8.2.3
Accrual estimates ...........................................................................................91
8.3
Interim Analyses and Stopping Rules.................................................................91
8.4
Analyses Plans...................................................................................................91
8.4.1
Analysis Population ........................................................................................91
8.4.2
Primary Analysis (or Analysis of Primary Endpoints)......................................92
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints)............................92
8.5
Evaluation of Safety............................................................................................92
9
Study Management ..............................................................................................................92
9.1
Pre-study Documentation...................................................................................92
9.2
Institutional Review Board Approval...................................................................93
9.3
Informed Consent...............................................................................................93
9.4
Changes in the Protocol .....................................................................................93
9.5
Handling and Documentation of Clinical Supplies..............................................93
9.6
Protection of Privacy...........................................................................................94
9.7
Case Report Forms (CRFs)................................................................................94
9.8
Oversight and Monitoring Plan ...........................................................................94
9.9
Record Keeping and Record Retention..............................................................95

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10
References...........................................................................................................................96
11
Appendices...........................................................................................................................99
Appendix 1:
Performance Status Criteria...............................................................................99
Appendix 2:
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study...........100
Appendix 3:
The Clavien-Dindo Classification of Surgical Complications............................103
List of Tables
Table 1
Adequate Organ Function Laboratory Values....................................................32
Table 2
Product Descriptions ..........................................................................................38
Table 3
Neoadjuvant Treatment Regimen Per Cohort....................................................40
Table 4
Adjuvant Treatment Regimen Per Cohort ..........................................................41
Table 5
Toxicity management guidelines for immune-related AEs associated with 
pembrolizumab45
Table 6
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
49
Table 7: Schedule of Activities ....................................................................................................62
Table 8
Laboratory Tests ................................................................................................73
Table 9
Response Criteria...............................................................................................78
Table 10
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events............................................................................................................84

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1
Introduction
1.1
Background on Indication
It is estimated that there are more than 60,000 new cases of kidney cancer and over 
14,000 deaths due to kidney cancer in the US each year[1], with the majority of cases being renal 
cell carcinoma (RCC). Tyrosine kinase inhibitors (TKIs) and allosteric mammalian target of 
rapamycin (mTOR) inhibitors have been the standard of care for subjects with advanced RCC for 
the past decade. Approved agents for advanced RCC in this class include axitinib in the second-
line setting, which showed a progression free survival (PFS) benefit versus sorafenib in a 
randomized phase III trial [2], lenvatinib in combination with everolimus after one prior line of anti-
angiogenic therapy, which demonstrated PFS and overall survival (OS) benefit over everolimus 
alone in an open-label phase II study [3], and more recently cabozantinib both after at least one 
line of anti-antiangiogenic therapy, where it showed an OS benefit over everolimus [4], and also 
in the first line, where it showed a PFS benefit versus sunitinib for intermediate- and poor-risk 
disease [5]. Unfortunately, approximately 20% of subjects never experience clinically significant 
benefit, and treatment-related resistance eventually emerges in the remainder of subjects [2-4]. 
Median overall survival (OS) for subjects with metastatic RCC (mRCC) is estimated to be 
approximately 22 months [5] in the TKI era.
More recently, checkpoint inhibitors have become standard of care treatments in this disease. 
Immunotherapy has long demonstrated its role in the treatment of RCC, including the experience 
with high-dose interleukin-2 (IL-2) [6]. The current era of immunotherapy with programmed cell 
death 1 (PD-1) and PD-1 ligand 1 (PD-L1) directed antibodies promises even greater rewards. 
Nivolumab (Opdivo®, Bristol Myers Squibb) received regulatory approval in the second line- 
setting in 2015, demonstrating survival benefit compared to everolimus in subjects who are 
refractory to previous TKI therapy in the CheckMate 025 study [[7]. Pembrolizumab as 
monotherapy has also demonstrated activity for previously untreated, advanced clear cell RCC; 
however, with a confirmed objective response rate of 34% [12], this is a population of patients in 
whom further therapeutic advances can be made.
Combination approaches using checkpoint inhibition as the backbone may hold the key to 
capturing a greater number of responders, resulting in a greater clinical impact. The combination 
of ipilimumab added to nivolumab received regulatory approval in 2018 for the first-line treatment 
of intermediate to poor risk [5] metastatic clear cell RCC. The CheckMate 214 study of nivolumab 
plus ipilimumab (3 mg/kg and 1 mg/kg, respectively) vs sunitinib was positive for its co-primary 
end points of objective response rate (42% vs 27%, p<0.0001), PFS (median 11.6 vs 8.4 mo., HR 
0.82, p=0.0331), and OS (median NR vs 26 mo., HR 0.63, p<0.0001); in addition, 9% of patients 
receiving the combination achieved a complete response [13]. IMmotion151 (NCT02420821), a 
phase III study of atezolizumab plus bevacizumab vs sunitinib also reported positive results, with 
the combination therapy improving PFS in PD-L1+ subjects with metastatic, untreated ccRCC 
(median 11.2 vs 7.7mo, HR 0.74, p=0.02)[8]. More recently, combinations of VEGFR TKIs with 
checkpoint inhibitors have been tested. These involve the TKI axitinib with the anti-PD-L1 
antibody avelumab or the anti-PD-1 antibody pembrolizumab, which showed promising response 
rates (55 and 73%, respectively) in phase Ib trials [15, 16]. These combinations have now been 
approved in the front-line RCC setting based on phase III trials. For the avelumab/axitinib 
combination, this was based on data which demonstrated improved ORR (51.4% vs 25.7%) and 
PFS (13.8 vs 8.4 mos., HR 0.61, p<0.001) with the combination compared to sunitinib [17]; the 
pembrolizumab/axitinib approval was based on data showing that the combination achieved an 

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ORR of 59.3% versus 35.7% and HR for overall survival of 0.53 versus sunitinib [18], as will be 
described in greater detail below. There are multiple, additional, ongoing phase III studies of 
immunotherapy-based combination approaches, including: pembrolizumab plus lenvatinib versus 
lenvatinib plus everolimus versus sunitinib (NCT02811861); and cabozantinib plus nivolumab 
versus sunitinib (NCT03141177).
To develop the most promising combinations, we must first understand the mechanistic 
underpinnings for response and resistance to immunotherapy-based combinations, which is 
currently lacking. Thus, we propose a perioperative study of pembrolizumab-based combination 
approaches in subjects with advanced RCC. Pre- and post-treatment tissue will be collected in all 
subjects to interrogate the in vivo immunologic impact of these treatments.
1.2
Background on the Compounds
1.2.1
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity of 
binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for 
PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
1.2.1.1
Pharmaceutical and Therapeutic Background on Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [9]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of cluster of differentiation 8 positive (CD8+) T cells and 
the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells (Tregs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and RCC.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses 
in cancers such as melanoma [10, 11].
The 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 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) [12, 13].
The structure of murine PD-1 has been resolved [14].  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif.  Following T cell 

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stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated 
protein kinase (ZAP70), which are involved in the CD3 T cell signaling cascade [13, 15-17]. The 
mechanism by which PD-1 down-modulates T cell responses is similar to, but distinct from, that 
of CTLA-4, because both molecules regulate an overlapping set of signaling proteins [18, 19].  As 
a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in 
RCC.
1.2.1.2
Preclinical and Clinical Trial Data
Refer to the IB for detailed Preclinical and Clinical data.
Clinical Trials Testing Pembrolizumab in Renal Cell Carcinoma
There are multiple clinical trials investigating pembrolizumab in the treatment of advanced RCC.  
These include results with pembrolizumab monotherapy described above [12], as well as the 
combination of pembrolizumab with axitinib, which will be described in further detail below [18]. 
The BTCRC-GU14-003 study is a phase Ib trial of pembrolizumab in combination with 
bevacizumab in advanced RCC. There are phase III studies comparing the efficacy of 
pembrolizumab-based combination therapies (pembrolizumab and axitinib; pembrolizumab and 
lenvatinib) vs sunitinib that are ongoing.
1.2.2
Axitinib
Axitinib is a TKI that potently targets the vascular endothelial growth factor (VEGF) receptors (as 
well as platelet-derived growth factor (PDGF) receptors and KIT) [20]. In a phase III study in 
patients with advanced RCC refractory to first-line therapy, axitinib demonstrated superior 
progression-free survival (PFS) compared to sorafenib, leading to regulatory approval in this 
indication around the world [21]. One of the novel aspects of axitinib compared to other TKIs that 
was demonstrated in this study was the ability to titrate dose individually, including dose 
escalation. Patients started on a dose of 5 mg by mouth (PO) twice daily (BID); in patients with 
well controlled blood pressure and without Grade >2 adverse events (AEs), dose increases up to 
7 mg and 10 mg PO BID were allowed.
Axitinib has been studied in the first-line setting for patients with advanced RCC [22]. In an 
international, randomized phase II trial, patients with treatment-naïve advanced RCC were treated 
with axitinib at the standard initial dosing of 5 mg BID during a 4-week lead-in period. Those 
without Grade 3/4 AEs and well controlled blood pressure were then randomized to either masked 
dose titration (to 7 mg BID, and then 10 mg BID if tolerated) or placebo dose titration. One 
hundred twelve patients were randomized (1:1). The ORR in the dosed titration group was 54%, 
vs 34% in the placebo titration group (p=0.019); interestingly, the ORR in patients who could not 
be randomized due to toxicities was 59%.  The results of this study not only demonstrated the 
feasibility of axitinib in the first-line setting, but further supported the importance of individualized 
dose-titration of axitinib in select patients.

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1.2.2.1
Axitinib and Pembrolizumab
A notable result that was recently reported was the combination of axitinib with pembrolizumab 
versus sunitinib in an open-label phase III trial for patients with treatment-naïve advanced RCC 
[18]. The estimated percentage of patients alive at 12 months was significantly higher with axitinib 
+ pembrolizumab (89.9% versus 78.3%, HR 0.53), as was median PFS (15.1 versus 11.1 months, 
HR 0.69), with an objective response rate of 59% with axitinib + pembrolizumab. Grade 3 or higher 
adverse events of any cause were seen in 76% of patients receiving axitinib + pembrolizumab, 
with 63% of patients experiencing a Grade 3 or higher adverse event attributed to the combination 
therapy. Most frequent treatment-related adverse events (>=Grade 3) were hypertension (21%), 
elevations in alanine aminotransferase (12%), diarrhea (7%), and elevations in aspartate 
aminotransferase (7%). Adverse events regardless of attribution led to discontinuation of either 
drug (31%), discontinuation of both drugs (11%), interruption of either drug (70%), and dose 
reduction of axitinib (20%).
1.3
Rationale for the Proposed Study
1.3.1
Rationale for a Perioperative Study in Subjects Eligible for CN/MET
Historical studies have demonstrated the clinical efficacy of CN in association with 
immunotherapy. In SWOG-8949, advanced RCC subjects treated with CN in addition to 
interferon-alpha (IFN-α) had a significant improvement in OS (11 vs 8 months) compared to those 
treated with IFN-α alone [23]. Similar results were seen in a European Organisation for Research 
and Treatment of Cancer (EORTC) study (same treatment as SWOG study), with a significant 
improvement in OS in favor of CN in addition to immunotherapy [24]. The clinical benefit of CN 
appears to persist in the TKI era as well; results from the International Metastatic Renal Cell 
Carcinoma Database Consortium showed a median OS of 20.6 months for subjects who 
underwent CN vs 9.5 months for those who received only systemic therapy [25]. 
Furthermore, small studies of MET in select patient populations with limited tumor burden, either 
upfront or as consolidation (in addition to either systemic TKI or immunotherapy), may provide 
additional clinical benefit [26, 27]. No prospective studies exist, but multiple retrospective 
analyses, both in the pre-TKI and TKI era, have demonstrated the significant clinical benefit of 
MET, particularly in cases where a complete (R0) resection could be achieved [28-32].
Finally, the efficacy and safety of perioperative treatment for subjects with metastatic and 
advanced RCC prior to CN has been shown in multiple prospective studies. Perioperative TKI 
treatment has demonstrated tumor shrinkage in the range of 13-22%, with a significant proportion 
of subjects who were previously deemed unresectable able to proceed with surgical resection 
[27, 33-36]. Just as importantly, there does not appear to be increased risk of overall surgical 
morbidity or mortality associated with perioperative therapy. One specific concern is the risk of 
delayed wound healing in subjects receiving TKI therapy; the results of existing studies are 
conflicting, as some studies have shown delayed wound healing in up to 20-25% of subjects, 
while other studies have shown no evidence of delayed wound healing.
1.3.1.1
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W followed by 400 mg Q6W.

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Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is 
the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk profile 
as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is currently 
appropriate [37]. Specifically, the dosing regimen of 400 mg Q6W for pembrolizumab is 
considered adequate based on modeling and simulation (M&S) analyses, given the following 
rationale:

Pharmacokinetic (PK) simulations demonstrating that in terms of pembrolizumab 
exposures:
-
Average concentration over the dosing interval (Cavg) (or area under the curve [AUC]) 
at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus bridging efficacy 
between dosing regimens.
-
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
-
Peak concentrations (Cmax) at 400mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
-
Exposure-response (E-R) for pembrolizumab has been demonstrated to be flat across 
indications, and OS predictions in melanoma and non-small cell lung cancer (NSCLC) 
demonstrate that efficacy at 400 mg Q6W is expected to be similar to 200 mg or 
2mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W is expected to be 
efficacious across indications.
1.3.2 Overarching Objective
Here we propose perioperative therapeutic combinations, with pembrolizumab (KEYTRUDA, 
Merck) as the treatment backbone, in patients with locally advanced or metastatic RCC who are 
eligible for CN or MET. The study will include multiple treatment cohorts into which subjects will 
be accrued, and after 9 weeks of preoperative therapy, subjects will undergo CN or MET. Paired 
tumor specimens (pre- and on-treatment) will be collected for molecular analysis and allow for 
unprecedented translational investigation of combination immune therapeutic approaches in 
human mRCC specimens. Subjects who experience clinical benefit (CR, PR, or SD) during the 
preoperative treatment period will be offered continued pembrolizumab-based therapy (400 mg 
Q6W) following CN or MET.

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1.4
Correlative Studies
1.4.1 Correlative Studies Background
Correlative science to understand the biologic and immunologic impact of pembrolizumab-based 
therapy in advanced RCC, and to identify candidate biomarkers of response, resistance, or 
toxicity, is an integral part of this study. Sample collection for the correlative studies are outlined 
in the Procedure Manual. Correlative studies may include but are not limited to:

Clinical correlatives:
o
Pathologic response rate and R0 resection rates
o
Clinical efficacy of continued pembrolizumab-based therapy

Scientific correlatives:
o
Changes in tumor-infiltrating immune cells (TIICs)
o
Changes in frequency and numbers of circulating T cells
o
Comprehensive assessment of the tumor microenvironment
o
Transcriptional profiling of tumor microenvironment constituents
o
Changes in T cell repertoire
o
Molecular profiling to explore biomarkers of response
o
Change in neoepitope burden

Correlative research will be performed on: 
1.
Baseline primary and/or metastatic biopsies.
2.
CN and/or MET specimens.

If CN or MET is not feasible, post-treatment tumor core biopsies should be 
performed when safe and feasible to allow acquisition of adequate specimens for 
correlative studies 
3.
Serial blood samples.
4.
Archival tumor samples originally obtained prior to study consent (when available).
1.4.2 Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. However, 
the mechanism of action of these exciting new therapies is not completely understood and much 

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remains to be learned regarding how best to leverage these new drugs in treating patients. Thus, 
to aid future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in the 
course of our clinical studies. These efforts may identify novel predictive/PD biomarkers and 
generate information that may better guide single-agent and combination therapy with immuno-
oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, tumor 
material) will be collected to support analyses of cellular components (eg, protein, DNA, RNA, 
metabolites) and other circulating molecules. Investigations may include but are not limited to:
Tumor PD-L1 Expression
To date, tumor PD-L1 expression had not proven itself as a reliable predictive biomarker of 
response in mRCC. In the phase III CheckMate 025 study, responses to nivolumab were identical 
in the PD-L1 negative and positive groups. More recently, the preliminary analysis of the ongoing 
phase II study of atezolizumab and bevacizumab in treatment-naïve mRCC (NCT01984242) was 
reported. In the atezolizumab monotherapy arm, again, there was no significant difference in 
response rate between the PD-L1 negative and positive groups. However, in the 
atezolizumab/bevacizumab combination arm, the response rate of PD-L1 positive subjects was 
much higher[38]. Thus in this study, we propose an investigation of tumor PD-L1 expression as a 
potential biomarker in subjects who receive combination checkpoint inhibitor/VEGF-inhibitor 
therapy.
Immune-related Gene Expression Profile (GEP)
Intratumoral expression levels of select genes will be analyzed using an analytically validated 
platform. Association between the immune-related GEP and response to pembrolizumab has 
been established using these genes in melanoma and in cancers from clinical studies KN012 
(head and neck, bladder, and gastric cancers) and KN028 (ovarian, esophageal, and other 
cancers). Data from these cohorts has been used to derive a GEP, which combines the 
expression levels of several key genes into a single scalar score [40]. The pattern of association 
in the esophageal cohort of KN028 using a prototype GEP suggested the ability to identify patients 
who may not respond to pembrolizumab by identifying tumors that have low values of the GEP. 
The GEP includes genes from immune-regulatory pathways and a GEP score will be tested for 
association with response to pembrolizumab in retrospective fashion. The relationship between 
GEP and the probability of response will be used to develop cut-offs that may have high clinical 
utility. 
Tumor and Blood RNA Analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue and 
in blood may be performed to define gene signatures that correlate to clinical response to 
treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a response in 
tumors that likely reflects an inflamed/immune phenotype. Specific immune-related gene sets (ie, 
those capturing interferon-gamma transcriptional pathways) may be evaluated and new 
signatures may be identified. Individual genes related to the immune system may also be 
evaluated (eg, IL-10). MicroRNA profiling may also be pursued as well as exosomal profiling.

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Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an IVD device has been developed for 
use with pembrolizumab in NSCLC. Preliminary data indicates that this association may also be 
true in additional cancer types (ie, triple negative breast cancer, head and neck, and gastric). 
Additional tumor or blood-derived proteins may also correlate with response to pembrolizumab. 
Therefore, tumor tissue may be subjected to proteomic analyses using a variety of platforms that 
could include but are not limited to immunoassays and liquid chromatography/mass spectrometry. 
This approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab therapy.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided scientists 
the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation status, 
microsatellite instability). Key molecular changes of interest to immuno-oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the tumor 
microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-mutated’ 
state) may generate neo-antigen presentation in the tumor microenvironment. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all genes in 
the tumor genome. Thus, genome-wide approaches may be used for this effort. Note that in order 
to understand tumor-specific mutations, it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability may also be evaluated as this is an important 
biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or RNA may also 
be evaluated from blood samples.
Germline (blood) genetic analyses (e.g., single-nucleotide polymorphism [SNP] analyses, whole 
exome sequencing, whole genome sequencing)
This research may evaluate whether genetic variation within a clinical study population correlates 
with response to the treatment(s) under evaluation. If genetic variation is found to predict efficacy 
or AEs, the data might inform optimal use of therapies in the patient population. Furthermore, it is 
important to evaluate germline DNA variation across the genome in order to interpret tumor-
specific DNA mutations. Finally, MSI may be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer).
Planned Genetic Analysis 
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and Institutional Review Board (IRB)/Ethics Review Committee (ERC) allow, a sample 
will be collected for DNA analysis from consenting subjects.
DNA samples will be used for research related to the study treatment(s), the disease under study 
and related diseases. They may also be used to develop tests/assays including diagnostic tests 

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related to the disease under study, related diseases, and study drug(s). Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to understand study disease or related conditions.
Microbiome Analysis of Stool
Stool samples will be collected and a stool questionnaire will be completed to assess the 
microbiome associated with clinical activity. This research may help identify factors predictive of 
pembrolizumab response and resistance and novel targets for cancer immunotherapy.
1.4.3 Future Biomedical Research Specimen Collection
The investigator will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for FBR is 
to explore and identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, more 
effective drugs/vaccines, and/or to ensure that participants receive the correct dose of the correct 
drug/vaccine at the correct time. Decisions on Future Biomedical Research will be made by the 
Joint Steering Committee.
1.4.3.1
Future Biomedical Research Samples
The following specimens could be obtained as part of Future Biomedical Research:

Leftover tumor for future research

Leftover DNA and RNA from Correlative Studies

Leftover plasma and serum from Biomarker Studies

Leftover peripheral blood mononuclear cells (PBMC) from whole blood from correlative 
studies

Microbiome

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2
Objectives and Endpoints of the Study
2.1
Objectives
2.1.1 Primary

To determine the impact of pembrolizumab-based therapy on the composition, phenotype, 
and function of tumor-infiltrating immune cells (TIICs) in subjects with advanced RCC 
undergoing CN/MET
2.1.2 Secondary

To determine the clinical efficacy of preoperative pembrolizumab-based therapy in 
subjects with advanced RCC undergoing CN/MET

To explore the clinical efficacy of continued pembrolizumab-based therapy following 
CN/MET in subjects with advanced RCC
o
Subjects who achieve R0 resection (NED, negative margins) or R1 resection 
(microscopic disease, positive margins) after preoperative treatment will receive 
continued pembrolizumab-based combination therapy for up to 1 year (9 cycles) 
following CN/MET, or until disease progression, death, unacceptable toxicity, or 
withdrawal from study, whichever occurs first.
o
Subjects who achieve R2 resection (macroscopic disease after surgery) after 
preoperative treatment, or who do not undergo nephrectomy after achieving pre-
operative radiographic CR, will receive continued pembrolizumab-based combination 
therapy for up to 2 years (18 cycles) following CN/MET, or until disease progression, 
death, unacceptable toxicity, or withdrawal from study, whichever occurs first.

To determine the safety and tolerability of pembrolizumab-based therapy in subjects with 
advanced RCC undergoing CN/MET
2.1.3 Exploratory
2.1.3.1
Clinical

To explore the clinical efficacy of preoperative pembrolizumab-based therapy in subjects 
with advanced RCC, by pathologic response
2.1.3.2
Scientific

To explore the relationship between changes in TIICs and clinical efficacy in subjects with 
advanced RCC treated with pembrolizumab-based therapy

To characterize changes in the frequency and number of circulating T cells induced by 
pembrolizumab-based therapy in subjects with advanced RCC

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
To determine the impact of pembrolizumab-based therapy on the composition and 
phenotype of the tumor microenvironment (including tumor and stromal cells) in subjects 
with advanced RCC

To determine whether locally advanced versus metastatic RCC exhibit differences in 
immune composition or phenotype at baseline and in response to pembrolizumab-based 
therapy

To determine the change in T cell repertoire within the tumor and blood induced by 
pembrolizumab-based therapy in subjects with advanced RCC

To explore molecular profiles to identify potentially predictive biomarkers for subjects with 
advanced RCC treated with immunotherapy
2.2
Endpoints
2.2.1 Primary

The proportion of subjects with ≥2-fold increase in the number of TIICs between pre- and 
post-treatment tumor specimens.
2.2.2 Secondary

The clinical efficacy of preoperative pembrolizumab-based therapy in subjects with 
advanced RCC will be assessed by ORR, defined as CR or PR per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1, modified to allow a maximum of 10 target lesions 
or 5 target lesions per organ.

The clinical efficacy of continued pembrolizumab-based therapy in subjects with advanced 
RCC will be assessed as follows:
o
In subjects who obtain CR or PR/SD with R0 resection and are treated 1 year of 
pembrolizumab-based therapy: 

1-year and 2-year disease-free survival (DFS) rate, and median DFS
o
In subjects who obtain PR/SD and have residual disease following CN/MET and are 
treated with 1 year of pembrolizumab-based therapy: 

1-year and 2-year PFS rate, and median PFS

Safety will be assessed and reported using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0
o
Surgical complications will be assessed according to the Clavien-Dindo classification 
(Appendix 3)

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2.2.3 Exploratory
2.2.3.1
Clinical

Pathologic response
o
Clinical to pathologic downstaging rate following preoperative therapy, including CR 
rate
o
R0 resection rate, following preoperative therapy
2.2.3.2
Scientific

The relationship between clinical efficacy (by above measures) and changes in TIICs (by 
above measures will be explored).

The changes in frequency and numbers of circulating T cells will be assessed by flow 
cytometry.

Comprehensive assessment will be performed to explore the tumor microenvironment, 
including PD-L1 status. Transcriptional profiling of tumor microenvironment constituents 
(including T cell subsets, tumor, stroma) in pre- and post-treatment specimens will be 
analyzed.

Changes in the T cell repertoire will be explored via high resolution T cell receptor (TCR) 
sequencing, in both blood and tumor specimens.

Molecular profiling of pre- and post-treatment tumor and normal tissue to explore 
biomarkers of response. Neoepitope burden will be assessed. 

These correlative objectives will also be explored in subjects who continue 
pembrolizumab-based therapy following CN and/or MET; subjects will be consented to 
tissue collection at the time of disease progression

Exploratory qualitative comparisons will be conducted between subjects with locally 
advanced versus metastatic disease for the above measures.
3
Study Design
3.1
Characteristics
This is an open-labeled, single center, phase II study, in which eligible subjects will be treated 
with pembrolizumab-based therapy. The treatment cohorts will be accrued concurrently once 6 
patients are enrolled in Cohort A (see study schema). Subjects with advanced RCC (locally 
advanced or metastatic) in whom CN/MET is feasible are eligible for this study. Eligible subjects 
must also have evaluable pre-treatment tumor specimen adequate for analysis, or consent to 
tumor specimen collection prior to enrollment.
Subjects enrolled into Cohort A will receive pembrolizumab monotherapy (200 mg Q3W). The 
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advanced RCC undergoing CN/MET. Of particular interest are surgical complications. The first 6 
subjects accrued to Cohort A will be evaluated in a safety lead-in for the safety of pembrolizumab 
prior to planned CN/MET. For the first 6 patients in the safey lead-in, if ≥2 subjects experience 
Grade IV and V surgical complications according to the Clavien-Dindo classification (Appendix 
3), the study will be halted to accrual. Given the complexity of surgery, it will be difficult to attribute 
surgical complications to the preoperative administration of pembrolizumab. Thus, the occurrence 
of these events may not require an early end to the study, but will be discussed amongst members 
of the Joint Steering Committee, Merck, and the Sponsor to consider whether the study can re-
open to accrual.
After 6 patients are enrolled into Cohort A, Cohort B will open to concurrent enrollment where 
subjects will receive pembrolizumab in combination with axitinib. The pembrolizumab-based 
combination for cohort C has not yet been determined. Cohort C will be determined by discussion 
between the Joint Steering Committee, Merck, and the Sponsor, based on emerging data 
regarding promising combination approaches. 
Enrolled subjects will begin their assigned preoperative pembrolizumab-based therapy (200 mg 
Q3W). After 9 weeks (3 × 3-week cycles of treatment), subjects will be assessed for response per 
RECIST 1.1 criteria (Section 7.1). Subjects will then proceed as follows:

Subjects who achieve CR during the preoperative treatment period and have locally 
advanced disease will proceed with CN.

Subjects with PR/SD during the preoperative treatment period will proceed with CN/MET.

Subjects with PD during the preoperative treatment period who, in the opinion of the 
treating physician and principal investigator, are likely to benefit from CN/MET AND in 
whom surgery is safe and feasible, may proceed with CN/MET on study. Subjects in whom 
CN/MET is unlikely to provide benefit OR surgery is not safe and feasible, may proceed 
with tumor biopsy on study, if safe and feasible. Subjects will withdraw from study 
participation following CN/MET or tumor biopsy. If CN/MET and tumor biopsy are not safe 
and feasible and not in the best interests of the subject, the subject will withdraw from 
study participation immediately. The risk of disease progression during the preoperative 
treatment period is 10% [18]. The use of anti-PD-1 antibodies has now become standard 
of care. As a result, participants are receiving treatment that is deemed standard of care.

Subjects with PR/SD in whom CN/MET is not safe and feasible: in rare cases, subjects 
who were deemed eligible for CN/MET prior to study participation and have PR/SD to 
preoperative therapy may not be able to undergo CN/MET (for example, due to adverse 
events). These subjects will be required to provide a tumor biopsy, unless deemed unsafe 
or delays appropriate standard of care, in lieu of CN/MET. Subjects may continue study 
treatment with pembrolizumab 400 mg Q6W for up to 1 year (9 cycles), or until disease 
progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs first. 
The chance of experiencing severe toxicities related to study drug(s) that might preclude 
or delay surgery is less than 5%.
Following CN/MET, post-operative therapy for patients who achieved pre-operative CR/PR/SD 
will proceed as follows:

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
Subjects with an R0 resection (NED, margins negative) or R1 resection (microscopic 
disease, margins positive) will continue receiving their assigned pembrolizumab-based 
combination therapy (with pembrolizumab dosing as 400 mg Q6W) for up to 9 cycles or 
until disease progression, death, unacceptable toxicity, or withdrawal of consent, 
whichever occurs first.

Subjects with an R2 resection (macroscopic disease after surgery), or who had a pre-
operative CR but did not undergo CN, will continue receiving their assigned 
pembrolizumab-based combination therapy (with pembrolizumab dosing as 400 mg Q6W) 
for up to 18 cycles or until disease progression, death, unacceptable toxicity, or withdrawal 
of consent, whichever occurs first. 

The first dose of study treatment following CN/MET may be no sooner than 3 weeks and 
no later than 6 weeks following surgery, to allow for postoperative recovery (adequate 
wound healing and recovery from any postoperative complications) as assessed by the 
treating surgeon. Subjects who cannot resume therapy within 42 days for any reason will 
discontinue study participation, any exception will be discussed with the PI and approved 
on a case-by-case basis.  
At the time of disease progression (or death, unacceptable toxicity, or withdrawal of consent, 
whichever occurs first) on postoperative pembrolizumab-based therapy, subjects will discontinue 
study participation. Prior to study discontinuation, all subjects will be consented for an additional 
optional tissue collection.
3.2
Number of Subjects
Up to 84 subjects in total will be enrolled.  Up to twelve subjects will be accrued into Cohort A, 
with the first 6 subjects undergoing a safety lead-in to evaluate the safety of pembrolizumab 
monotherapy and potential surgical complications as assessed per the Clavien-Dindo 
classification (Appendix 3). After six (6) subjects have been enrolled into Cohort A, up to 36 
evaluable subjects will be accrued concurrently to each pembrolizumab-based combination 
cohort. based on group sequential design. See section 8.2.1 for details regarding sample size 
determination.
3.3
Eligibility Criteria
Subjects must have baseline evaluations performed prior to the first dose of study treatment and 
must meet all of the inclusion and none of the exclusion criteria. In addition, subjects must be 
thoroughly informed about all aspects of the study, including the study visit schedule, and required 
evaluations and all regulatory requirements for informed consent. The written informed consent 
must be obtained from subjects prior to enrollment. The following criteria apply to all subjects 
enrolled onto the study unless otherwise specified.
3.3.1
Inclusion Criteria
1.
Histologically confirmed RCC with a clear cell component.
2.
Locally advanced or metastatic disease (primary intact or status post nephrectomy with 
recurrent disease)

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3.
Planned CN and/or MET.
4.
Must have a tumor lesion amenable to biopsy at pre-treatment and subjects must consent 
to acquisition of fresh tumor specimens obtained using the following approaches:
i.
Core biopsy
ii.
Nephrectomy 
iii.
Metastasectomy (MET)
Note: Subjects who undergo nephrectomy or metastasectomy prior to study 
enrollment must still have measurable disease (RECIST 1.1) that is amenable to 
cytoreductive nephrectomy or metastasectomy to be eligible for study participation.
iv.
FNA specimens are not acceptable
5.
Measurable disease per RECIST 1.1 as assessed by the investigator. Lesions situated in 
a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
6.
Subject (or legally acceptable representative if applicable) must provide written informed 
consent for the trial. 
7.
≥18 years of age on day of signing informed consent.
8.
Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale (Appendix 1).
9.
Adequate organ function as defined in Table 1; all screening labs should be performed 
within 10 days of treatment initiation.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment)
Renal
Serum creatinine OR
≤1.5 × upper limit of normal (ULN) OR

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System
Laboratory Value
Measured or calculateda creatinine 
clearance (CrCl)
(GFR can also be used in place of 
creatinine or CrCl)
≥60 mL/min for subject with creatinine levels >1.5 × 
institutional ULN
Hepatic
Serum total bilirubin
≤1.5 × ULN OR Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN  
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 × ULN unless subject is receiving anticoagulant therapy 
as long as PT or aPTT is within therapeutic range of intended 
use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
10. Negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of 
study medication (Day 1) (female subjects of childbearing potential).  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Male and female subjects of childbearing potential must be willing to use an adequate 
method of contraception* as outlined in Section 6.6, for the course of the study through 
120 days after the last dose of study medication.
*Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
3.3.2
Exclusion Criteria
1.
RCC WITHOUT a clear cell component
2.
Prior systemic therapy for the treatment of RCC
3.
No measurable disease (e.g. only bone metastases)
4.
Not a candidate for CN and/or MET

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5.
Currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment.
Note:  Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
6.
Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment.
7.
Known history of active TB (Bacillus Tuberculosis).
8.
Severe hypersensitivity (≥Grade 3) to pembrolizumab/axitinib or any of their excipients.
9.
Prior systemic anti-cancer mAb, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to the first dose of study treatment (Day 1).
Note: Subjects must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Subjects with ≤Grade 2 neuropathy may be eligible.
Note: If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment.
Subjects must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is permitted 
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
10. Known additional malignancy that is progressing or has required active treatment within 
the past 2 years.
Note:  Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are not excluded.
11. Known active CNS metastases and/or carcinomatous meningitis.  Subjects with previously 
treated brain metastases may participate provided they are radiologically stable, i.e., 
without evidence of progression for at least 4 weeks by repeat imaging (note that the 
repeat imaging should be performed during study screening), clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment.  
This exception does not include carcinomatous meningitis, which is excluded regardless 
of clinical stability.
12. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.

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13. History of (non-infectious) pneumonitis that required treatment with steroids or has current 
pneumonitis.
14. Active infection requiring systemic therapy.
15. Any arterial thromboembolic events, including but not limited to myocardial infarction, 
transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months 
prior to randomization.
16. Uncontrolled or poorly controlled hypertension despite standard medical therapy.
17. Serious or non-healing wound, ulcer, or bone fracture within 28 days of study enrollment.
18. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration 
of the trial, or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator.
19. Known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial.
20. Pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days 
after the last dose of trial treatment.
21. Any prior therapy with an anti–PD-1, anti–PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T cell receptor (e.g., CTLA-4, OX-40, and 
CD137).  
22. Known history of human immunodeficiency virus (HIV) infection.  No HIV testing is 
required unless mandated by local health authority.  
23. Known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known 
active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. No testing 
for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
24. Live vaccine within 30 days prior to the first dose of study drug.  Examples of live vaccines 
include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed.
25. History of grade 3-4 gastrointestinal (GI) bleeding within 12 weeks prior to study 
enrollment
26. Solid organ or hematologic transplant.
27. Encephalopathy in the last 6 months. Those subjects on rifaximin or lactulose to control 
their encephalopathy are not allowed.
28. Evident ascites on physical examination.

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Note: Medically controlled ascites and ascites detectable on imaging studies only is 
allowed.
29. Female of childbearing potential who has a positive urine pregnancy test within 72 hours 
prior to allocation.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
30. Has had an allogenic tissue/solid organ transplant.
3.4
Duration of Therapy
The preoperative treatment regimen consists of 3 cycles (9 weeks) of treatment (as described 
under “Treatment Plan,” in Section 5). Following CN and/or MET (or biopsy if CN and/or MET is 
not feasible), all subjects will be offered the option of continuing pembrolizumab-based therapy 
(400 mg Q6W) as described in Section 3.1 unless the subject meets any of the 
discontinuation/withdrawal criteria outlined in Section 6.3.
3.5
Duration of Follow Up
Duration of follow up:

Those subjects who complete preoperative therapy and achieve either CR/PR/SD with R0 
or R1 resection, and complete 9 cycles of continued pembrolizumab-based combination 
therapy (with pembrolizumab dosing as 400 mg Q6W) will be followed for up to 12 
additional months, or until disease progression, death, unacceptable toxicity or withdrawal 
of consent, whichever occurs first.

Those subjects who complete preoperative therapy and achieve either CR/PR/SD with R2 
resection, or achieve a pre-operative CR but do not undergo CN, and complete 18 cycles 
of continued pembrolizumab-based combination therapy (with pembrolizumab dosing as 
400 mg Q6W) will be followed for up to 12 additional months, or until disease progression, 
death, unacceptable toxicity or withdrawal of consent, whichever occurs first.

Subjects who experience disease progression will have the mandatory safety follow-up 
visit 30 days (+7 days) after the last dose of study treatment.  All AEs that occur prior to 
the Safety Follow-Up Visit should be recorded. Subjects with an AE of Grade >1 will be 
followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 
anticancer therapy, whichever occurs first. Serious AEs that occur within 90 days of the 
end of treatment should also be followed and recorded.

Subjects removed from study for any reason other than disease progression, death, or 
AEs will have a mandatory safety follow-up visit within 30 days for the final study treatment.
3.6
Randomization Procedures
There will be no randomization. After enrolling six (6) subjects into cohort A as per Section 5.1, 
enrollment will proceed concurrently into the remaining treatment cohorts. 

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3.7
Study Timeline (Primary Completion)
Each cohort is expected to reach primary completion 36 months after opening to accrual..
4
Study Drugs
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1 Pembrolizumab
Details on the preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Refer to the package insert for complete information. Refer to the IB for additional 
information on pembrolizumab.
Classification
PD-L1 inhibitor, immunotherapy
Mechanism of Action
Pembrolizumab (MK-3475) is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2.  Based on preclinical in vitro 
data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  For more 
details, see Section 1.2.1 and the IB.
Contraindications
Immunodeficiency, autoimmune diseases requiring treatment with disease modifying agents, 
corticosteroids or immunosuppressive drugs, active infections.  
Availability
Pembrolizumab will be provided to subjects enrolled on this study by Merck.
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorized site staff may 
supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).

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For all trial sites, the local country Merck personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard and 
destruction if appropriate.  Where local discard and destruction is appropriate, the investigator is 
responsible for ensuring that a local discard/destruction procedure is documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by Merck.
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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by Merck, as summarized in Table 2.
Table 2
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/4 mL
Solution for Injection
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, Merck and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
4.1.2 Axitinib
Please refer to the prescribing information for information and administration of the drug.
Classification
VEGF-targeting TKI
Mechanism of Action
Axitinib is a TKI indicated for the treatment of advanced RCC after failure of one prior systemic 
therapy. It inhibits multiple receptor tyrosine kinases, including VEGFR-1, VEGFR-2, and VEGFR-
3.
Contraindications
There are no specific contraindications listed in the manufacturer’s United States labeling. 
Availability
Commercial supply of axitinib will be provided to subjects on this study by UCSF.

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Storage and Handling
The investigator shall assume 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.
Axitinib is available as 1 mg and 5 mg tablets. 
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, Merck and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the amount dispensed to and 
returned by the subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
4.2
Drug Accountability
The Investigational Pharmacist will manage drug accountability records.
4.3
Drug Ordering
UCSF will obtain pembrolizumab directly from Merck as study supply. Commercial drug will be 
supplied by UCSF.
Axitinib will be obtained as commercial supply. 
4.4
Packaging and Labeling of Study Drugs
Study drugs will be labeled by sponsor prior to receipt at UCSF. Prior to administration or 
dispensing of drug, UCSF Investigational Drug Pharmacy will affix an appropriate clinical label 
with patient identifiers per UCSF institutional standards, adhering to applicable local and federal 
laws. 
5
Treatment Plan
5.1
Dosage and Administration
In all subjects, pembrolizumab will be administered as a flat dose of 200 mg for 3 cycles prior to 
surgery and 400 mg for 9 or 18 cycles after surgery, as an IV infusion. The Pharmacy manual 

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contains specific instructions for the preparation of pembrolizumab infusion fluid as well as the 
administration of the infusion solution.
On Day 1 of each cycle, pembrolizumab will be administered once as a 30-minute IV infusion. 
Every effort will be made to keep infusion timing as close to 30 minutes as possible. However, 
given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e. 
infusion time is 30 minutes: -5 min/+10 min).
The treatment to be used during the study is outlined below in Table 3 and Table 4.
Table 3
Neoadjuvant Treatment Regimen Per Cohort
Cohort
Drug/Dose
Dose 
Frequency
Route of 
Administration
Schedule
Dose Levels
A/B/C
Pembrolizumab 
200 mg
Q3W
IV
Day 1 of each 
21-day cycle 
(Q3W)
N/A
B
Axitinib 5 mg 
titratable
BID
PO
Days 1-21 of 
each 21-day 
cycle
DL -2: 1 mg BID
DL -1: 3 mg BID
DL 1: 5 mg BID
DL 2: 7 mg BID
DL 3: 10 mg BID
C
TBD (agent to 
be determined)
TBD
TBD
TBD
TBD
Abbreviations: BID = twice daily; DL = dose level; IV = intravenous; N/A = not applicable; PO = by mouth; 
Q3W = every 3 weeks; TBD = to be determined
Table 4
Adjuvant Treatment Regimen Per Cohort
Cohort
Drug/Dose
Dose 
Frequency
Route of 
Administration
Schedule
Dose Levels
A/B/C
Pembrolizumab 
400 mg
Q6W
IV
Day 1 of each 
42-day cycle 
(Q6W)
N/A
B
Axitinib 5 mg 
titratable
BID
PO
Days 1-42 of 
each 42-day 
cycle
DL -2: 1 mg BID
DL -1: 3 mg BID
DL 1: 5 mg BID

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Cohort
Drug/Dose
Dose 
Frequency
Route of 
Administration
Schedule
Dose Levels
DL 2: 7 mg BID
DL 3: 10 mg BID
C
TBD (agent to 
be determined)
TBD
TBD
TBD
TBD
Abbreviations: BID = twice daily; DL = dose level; IV = intravenous; N/A = not applicable; PO = by mouth; Q6W = 
every 6 weeks; TBD = to be determined.
5.1.1 Cohort A: Pembrolizumab Monotherapy
Up to twelve subjects will be enrolled into Cohort A. The first 6 subjects accrued to Cohort A will 
be evaluated in a safety lead-in for the safety of pembrolizumab prior to planned CN/MET. After 
six (6) subjects are enrolled into Cohort A, the pembrolizumab-based combination cohorts will 
open to concurrent enrollment. 
Administer pembrolizumab doses according to Table 3 and Table 4. See section 5.2 for details 
regarding dose modifications and dosing delays.
During neoadjuvant treatment, subjects will receive 3 cycles of pembrolizumab (200 mg Q3W), 
given on Day 1 of each 21-day cycle. Of particular interest are surgical complications (Appendix 
3). For the first 6 patients in the safey lead-in, if ≥2 subjects experience Grade IV and V surgical 
complications according to the Clavien-Dindo classification (Appendix 3), or if ≥2 subjects 
experience a delay in surgery beyond the specified 14-21 day window following the end of the 
preoperative treatment period (that is, 14-21 days from Cycle 3, Day 21; delays for scheduling, 
operating room scheduling or patient preference are not included), the study will be halted to 
accrual. Given the complexity of surgery, it will be difficult to attribute surgical complications to 
the preoperative administration of pembrolizumab. Thus, the occurrence of these events may not 
require an early end to the study, but will be discussed amongst the members of the Joint Steering 
Committee, Merck, and the Sponsor to determine whether study can re-open to accrual.
5.1.2 Cohort B: Pembrolizumab + Axitinib
5.1.2.1
Safety Lead-In
The first 6 subjects accrued to Cohort B will be evaluated to test the safety of the combination of 
pembrolizumab and axitinib. All 6 subjects in Cohort B will be followed for 28 days after surgery 
for excessive post-operative complications before additional subjects are enrolled to each 
combination cohort. If ≤1 subject experience Grade IV/V surgical complications per the Clavien-
Dindo classification (Appendix 3), then 11 additional evaluable subjects will be accrued to the 
cohort. If ≥2 subjects experience Grade IV/V surgical complications, or if ≥2 subjects experience 
a delay in surgery beyond the specified 14-21 day window following the end of the preoperative 
treatment period (that is, 14-21 days from Cycle 3, Day 21; delays for scheduling, operating room 
scheduling or patient preference are not included), then the cohort will be halted to accrual, and 
the safety data reviewed to modify the protocol as appropriate, including changes in dose level 

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(Section 5.1). If the cohort is re-opened with a change in dose level, an additional 6 subjects will 
be accrued to evaluate safety. If ≤1 subject experience a Grade IV/V surgical complication, then 
11 additional subjects will be accrued to the cohort at the reduced dose. If ≥2 subjects experience 
a Grade IV/V surgical complication, the cohort will be terminated for lack of safety. Therefore, a 
minimum of 4, and a maximum of 36 subjects may be accrued into Cohort B.
5.1.2.2
Treatment Plan
Administer pembrolizumab and axitinib doses according to Table 3 and Table 4. On Day 1 of each 
cycle, administer axitinib after the subject completes their pembrolizumab infusion. Axitinib may 
be administered as soon as the pembrolizumab infusion is completed. Additional details regarding 
the treatment plan are provided below.
Preoperative treatment period (3 cycles):
Subjects will begin treatment with pembrolizumab 200 mg Q3W, administered on Day 1 of each 
21-day cycle. Axitinib will be self-administered twice daily. After 3 cycles of therapy, subjects will 
have a 2-week treatment break prior to CN and/or MET. 
During the preoperative treatment period, subjects who experience toxicities requiring study 
discontinuation will proceed immediately to CN and/or MET, as soon as it is determined to be safe 
and feasible per the treating physicians and PI. Subjects who experience toxicities requiring dose 
delays must be able to resume treatment within 42 days of the prior dose of pembrolizumab. 
Subjects unable to resume treatment within 42 days of the prior dose of pembrolizumab must 
discontinue treatment participation.
CN/MET:
CN/MET will be performed per institutional standard of care, 14 to 21 days following the end of 
the preoperative treatment period (14-21 days from Cycle 3, Day 21). 
Post-CN/MET treatment:
Following CN/MET (or continued therapy in metastatic subjects who achieve CR during the 
preoperative treatment period), subjects will be offered the option to continue treatment on study 
as summarized in Section 3.1 (see Section 6.3 for exceptions).
The first dose of post-CN/MET therapy will be no sooner than 21 days, and no later than 42 days, 
following CN/MET, based on adequate postoperative recovery (including wound healing), as 
assessed by the treating physicians. Subjects with metastatic disease who achieve CR during the 
preoperative treatment period (obviating the need for metastasectomy) will continue with their 
pembrolizumab-based therapy without a break allowing for surgery and recovery. Subjects will 
receive pembrolizumab 400 mg Q6W, administered on Day 1 of each 42-day cycle.

In subjects who continue on the combination of pembrolizumab and axitinib as continued 
therapy following CN/MET (or following CR during preoperative therapy in metastatic 
patients), axitinib dose-titration (as well as dose modification and delays) should be 
managed by the treating physician per standard of care.

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
Subjects treated with the combination of pembrolizumab and axitinib may experience AEs 
attributable to axitinib that require holding or discontinuing axitinib. Dose delays or 
discontinuation of axitinib should be managed per standard of care. In cases where axitinib 
must be discontinued permanently due to toxicity, subjects may remain on study and 
receive pembrolizumab monotherapy. In cases where axitinib is held due to toxicity:

Subjects who resume axitinib within 42 days may continue to receive combination therapy

Subjects who do not resume axitinib within 42 days may remain on study and receive 
pembrolizumab monotherapy (400 mg Q6W), and axitinib must be discontinued for the 
remainder of the study duration

Subjects treated with the combination of pembrolizumab and axitinib may also experience 
AEs attributable to pembrolizumab that require holding or discontinuing pembrolizumab. 
Dose delays, modifications, and discontinuations are discussed in Section 5.2. In cases 
where pembrolizumab must be discontinued due to toxicity, subjects may remain on study 
and receive axitinib monotherapy. In cases where pembrolizumab is held due to toxicity:
o
Subjects who resume adjuvant pembrolizumab within 42 days may continue to receive 
combination therapy; subjects will begin treatment with pembrolizumab 400 mg Q6W, 
administered on Day 1 of each 42-day cycle. The total duration of adjuvant 
pembrolizumab (either 9 cycles for R0/R1 resection, or 18 cycles for R2 resection) 
reflects the total number of pembrolizumab doses administered, even if doses are 
withheld for toxicity and then pembrolizumab is resumed.  Subjects who do not resume 
adjuvant pembrolizumab within 42 days may remain on study and receive axitinib 
monotherapy, and pembrolizumab must be discontinued for the remainder of the study 
duration
5.1.3 Cytoreductive Nephrectomy and/or Metastasectomy
All subjects participating in this study must have been deemed eligible for CN and/or MET prior 
to study enrollment, as determined by the treating surgical team(s). It is strongly recommended 
that this decision be made through a Multidisciplinary Tumor Board, although this may not always 
be feasible.
CN and/or MET will be performed 14 to 21 days after the third and final cycle of preoperative 
pembrolizumab-based therapy. Tissue collection procedures will be outlined in an accompanying 
Laboratory Manual.
5.1.4 Continuation of Pembrolizumab-based Therapy Following CN/MET
Following CN/MET, post-operative therapy for patients who achieved pre-operative CR/PR/SD 
will proceed as follows (see Section 6.3):

Subjects with an R0 resection (NED, margins negative) or R1 resection (microscopic 
disease, margins positive) will continue receiving pembrolizumab-based combination 
therapy (with pembrolizumab dosing as 400 mg Q6W) for up to 9 cycles or until disease 
progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs first.

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
Subjects with an R2 resection (macroscopic disease after surgery), or who had a pre-
operative CR but did not undergo CN, will continue receiving pembrolizumab-based 
combination therapy (with pembrolizumab dosing as 400 mg Q6W) for up to 18 cycles or 
until disease progression, death, unacceptable toxicity, or withdrawal of consent, 
whichever occurs first.

Subjects will begin their first post-operative treatment no sooner than 21 days and no later 
than 42 days following CN and/or MET.
All subjects will be consented for optional tissue and blood collection at the time of disease 
progression.
5.2
Dose Modifications and Dosing Delays
5.2.1 Pembrolizumab
5.2.1.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These 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. 
Dose modification and toxicity management guidelines for irAEs associated with pembrolizumab 
monotherapy, coformulations, or IO combinations are provided in Table 5.

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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations and IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations, or IO combinations must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations has been withheld, study intervention may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-
up
Grade 2
Withhold
Pneumonitis 
Recurrent Grade 2, 
Grade 3 or 4 
Permanently discontinue
  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics 
for opportunistic infections
  Monitor participants for signs 
and symptoms of 
pneumonitis
  Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment

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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-
up
Grade 2 or 3
Withhold
Diarrhea/Colitis 
Recurrent Grade 3 or 
Grade 4
Permanently discontinue
  Administer corticosteroids 
(initial dose of 1 to 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 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
Grade 2 a
Withhold
  Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
AST or ALT Elevation 
or Increased Bilirubin
Grade 3 b or 4 c
Permanently discontinue
  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
  Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable)

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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-
up
prednisone or equivalent) 
followed by taper
T1DM 
or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
  Initiate insulin replacement 
therapy for participants with 
T1DM
  Administer antihyperglycemic 
in participants with 
hyperglycemia
  Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or permanently 
discontinue d
  Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or permanently 
discontinue d
  Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
  Monitor for signs and 
symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard of 
care
  Monitor for signs and 
symptoms of thyroid 
disorders
Nephritis:
Grade 2
Withhold
  Administer corticosteroids 
  Monitor changes of renal 

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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-
up
grading according to 
increased creatinine or 
acute kidney injury
Grade 3 or 4
Permanently discontinue
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
function
Grade 2
Withhold
Neurological Toxicities
Grade 3 or 4
Permanently discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (which was 
previously myocarditis 
Grade 1 using CTCAE 
v4.0)
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes
Suspected SJS, TEN, 
or DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, TEN, 
or DRESS
Permanently discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation to 
confirm etiology or exclude 
other causes
Persistent Grade 2
Withhold
Grade 3
Withhold or discontinue 
based on the event e 
All Other irAEs
Recurrent Grade 3 or 
Grade 4 
Permanently discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation to 
confirm etiology or exclude 
other causes

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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-
up
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal;
bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal
c
AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; 
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations, or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing 
cholangitis).

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5.2.1.2
Toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of infusion completion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 6.

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Table 6
Pembrolizumab Infusion Reaction Dose modification and 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 
subject is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion.
Additional appropriate medical therapy may include but is not limited 
to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms 
resolve and the subject should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment
Subject may be premedicated 1.5 h 
(±30 minutes) prior to infusion of 
pembrolizumab with:

Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).

Acetaminophen 500-1000 mg PO 
(or equivalent dose of analgesic).

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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited 
to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Subject is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = non-steroidal anti-
inflammatory drugs; PO = by mouth.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov

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5.2.1.3
Other Allowed Dose Interruptions for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks for Q3W or 6 weeks for Q6W 
(21 days or 42 days) of the originally scheduled dose and within 42 or 84 days of the previously 
administered dose, unless otherwise discussed with the Sponsor. The reason for study 
intervention interruption is to be documented in the participant's study record. 
5.2.2 Axitinib 
Dose levels for axitinib is described in Table 3.
Dosing modifications/delays should be managed per standard of care at the discretion of the 
treating physician.
5.3
Monitoring and Toxicity Management
Each subject receiving pembrolizumab-based therapy will be evaluable for safety.  The safety 
parameters include all laboratory tests and hematological abnormalities, physical findings, and 
spontaneous reports of adverse events reported to the investigator by subjects.
Each subject will be assessed periodically for the development of any toxicity as outlined in 
Section 6. Toxicity will be assessed according to the NCI CTCAE v5.0.  Dose adjustments will be 
made according to the system showing the greatest degree of toxicity. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in Section 
5.2, (Table 5).  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, 
which might require additional supportive care.  The treatment guidelines are intended to be 
applied when the Investigator determines the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance.  Refer to Table 5 in Section 5.2 for 
guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 

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6
Study Procedures and Observations
6.1
Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in Section 6.2.  Screening 
assessments must be performed within 28 days prior to the first dose of investigational product.  
Any results falling outside of the reference ranges may be repeated at the discretion of the 
investigator. All on-study visit procedures are allowed a window of ±3 days unless otherwise 
noted.  Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation.
A written, signed, ICF and a Health Insurance Portability and Accountability Act (HIPAA) 
authorization must be obtained before any study-specific assessments are initiated.  A copy of 
the signed ICF will be given to the subject and a copy will be filed in the medical record.  The 
originals will be kept on file with the study records.  
All subjects who are consented will be registered in OnCore®, the UCSF HDFCC Clinical Trial 
Management System (CTMS).  The system is password protected and meets HIPAA 
requirements.
6.1.1 Pretreatment Period
6.1.1.1
Screening
The Screening procedures and assessments must be completed within 28 days of the first dose 
of pembrolizumab-based therapy.
Screening procedures and assessments:

Demographics

Complete medical history

Baseline conditions assessment

Complete physical examination

Baseline medications taken within 14 days of Day 1. For stool correlative analysis, it 
should be noted if antibiotics were taken within 90 days before the first dose of study 
drug(s).

Vital signs, height, and weight

ECOG performance status within 7 days of Cycle 1 Day 1

Laboratory assessments (within 10 days of treatment initiation):
o
Complete blood count (CBC) with differential and platelet count

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o
Blood chemistry assessment, including:

Alkaline 
phosphatase 
(ALP), 
aspartate 
aminotransferase/alanine 
aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood 
urea nitrogen (BUN), creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, bicarbonate, uric acid, lactate dehydrogenase 
(LDH)
o
Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4), 
triiodothyronine (T3)
o
Coagulation assessment (prothrombin time [PT], partial thromboplastin time [PTT], 
and international normalized ratio [INR])
o
Urinalysis (including microscopic exam if abnormal results are noted)

Serum or urine pregnancy test within 72 hours prior to the start of study drug

Imaging evaluation (computed tomography [CT] chest, abdomen and pelvis; magnetic 
resonance imaging [MRI] if CT is contraindicated; IV contrast given unless 
contraindicated; Bone scan if clinical indicated; MRI brain if clinically indicated), for tumor 
assessment

Request of archival specimen originally obtained prior to consent for banking (formalin-
fixed paraffin-embedded [FFPE] tumor specimen, if available)

Biopsy of primary or metastatic lesion (see Section 3.3.1, Inclusion Criteria)

Blood for correlative studies (including immune monitoring)

Correlative Studies Stool Collection
6.1.2 Treatment Period
Subjects who experience unequivocal disease progression without clinical benefit during the 
preoperative treatment period or withdraw consent will be removed from the study (see Sections 
6.1.3 and 6.1.3.2). Subjects who have unacceptable toxicities during the pre-operative treatment 
period or decline continued therapy will discontinue treatment but continue to be followed on study 
(Section 6.3).
6.1.2.1
Preoperative Therapy, Cycle 1 Day 1
Preoperative Cycle 1 Day 1, week 1 (±3 days) study procedures:

Directed physical examination

Vital signs and weight

ECOG performance status

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
Evaluation of AEs

Concomitant medications

CBC with differential and platelet count**

Blood chemistry assessment**, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Coagulation assessment (PT, PTT, INR)**

Blood for correlative studies (including immune monitoring)

Treatment:
o
Cohort A:

Pembrolizumab 200 mg IV (Day 1)
o
Cohort B:

Pembrolizumab 200 mg IV (Day 1)

Axitinib (Days 1-21); 5mg BID PO
**Note: Laboratory evaluations may be omitted if they were already performed within 7 days 
of Cycle 1, Day 1
6.1.2.2
Preoperative Therapy, Cycle 2 Day 1
Preoperative Cycle 2 Day 1, week 4 (±3 days) study procedures:

Directed physical examination

Vital signs and weight

ECOG performance status

Evaluation of AEs

Concomitant medications

CBC with differential and platelet count

Blood chemistry assessment, including:

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o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid Function Tests: TSH, FT4, T3

Blood for correlative studies (including immune monitoring)

Urinalysis, (including microscopic exam, if abnormal results are noted)

Treatment:
o
Cohort A:

Pembrolizumab 200 mg IV (Day 1) Q3W
o
Cohort B: 

Pembrolizumab 200 mg IV (Day 1) Q3W

Axitinib (Days 1-21). Dose titration per “Treatment Plan” in select patients, see 
Section 5.1.
6.1.2.3
Preoperative Therapy, Cycle 3 Day 1
Preoperative Cycle 3 Day 1, week 7 (±3 days) study procedures:

Directed physical examination

Vital signs and weight

ECOG performance status

Evaluation of AEs

Concomitant medications

CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Blood for correlative studies

Treatment: 
o
Cohort A:

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
Pembrolizumab 200 mg IV (Day 1)
o
Cohort B: 

Pembrolizumab 200 mg IV (Day 1)
6.1.2.4
Axitinib (Days 1-21). Dose titration per “Treatment Plan” in select 
patients, see Section 5.1.Preoperative Visit, Week 10
Preoperative visit, week 10 (±3 days) study procedures:

ECOG performance status

Evaluation of AEs

Concomitant medications

Imaging evaluation (CT chest, abdomen and pelvis; MRI if CT is contraindicated; IV 
contrast given unless contraindicated; Bone scan if clinical indicated; MRI brain if clinically 
indicated) must be performed after the final cycle and prior to CN and/or MET.

Correlative studies stool collection
6.1.2.5
Cytoreductive Nephrectomy and/or Metastasectomy
Complete the following tests within 14 days of CN and/or MET:

CBC with differential and platelet count

Blood chemistry assessment, including:

ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid Function Tests: TSH, FT4, T3

Coagulation assessment (PT, PTT, INR)

Immune parameter assessments

Urinalysis, (including microscopic exam, if abnormal results are noted)
Subjects will undergo CN and/or MET no sooner than 2 weeks following the final cycle of 
preoperative pembrolizumab-based therapy. The final cycle of preoperative therapy concludes 
after the conclusion of the last day (21st day) of the 3rd cycle of pembrolizumab-based therapy. A 
window of 7 days will be allowed for surgical planning and scheduling (thus, CN and/or MET will 
occur 14 days [+7 days] following the final cycle of preoperative therapy). Complete the following 
procedures on the day of surgery:

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
CN and/or MET (performed per standard of care).

Tissue collection for study purposes (see Laboratory Manual for details).

Pathology assessment (as clinically indicated, per standard of care).
The subject may be consented for core tumor biopsies if CN and/or MET cannot be performed 
following preoperative pembrolizumab-based therapy for any reason, including:

Unequivocal disease progression

AEs 

Development of a concurrent, unrelated medical illness that deems subject inoperable

Subject withdrawal of consent

Investigator or surgeon deems inoperable for any reason

Subjects may be consented for multiple tumors to be biopsied if safe and feasible. 

Subjects who achieve a radiographic CR and have locally advanced disease will proceed 
with CN.
Subjects who become ineligible for CN and/or MET while on study, and do not consent to provide 
a tumor biopsy (if safe and feasible), will be removed from study. See section 8.2.2 for details 
regarding replacement policy.
6.1.2.6
Postoperative Therapy, Day 1 of Each Cycle
Following CN/MET, continuation of pembrolizumab-based therapy for patients who achieved pre-
operative CR/PR/SD will proceed as follows:

Subjects with an R0 resection (NED, margins negative) or R1 resection (microscopic 
disease, margins positive) will continue receiving their assigned pembrolizumab-based 
combination therapy for up to 9 cycles or until disease progression, death, unacceptable 
toxicity, or withdrawal of consent, whichever occurs first

Subjects with an R2 resection (macroscopic disease after surgery), or who had a pre-
operative CR but did not undergo CN, will continue receiving their assigned 
pembrolizumab-based combination therapy for up to 18 cycles or until disease 
progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs first.

Subjects may resume therapy following CN/MET as soon as 21 days following surgery 
(subjects with metastatic disease who have a CR during the preoperative period and 
therefore do not undergo MET will have no interruption in their therapy). Prior to resuming 
therapy, the subject must be evaluated by their surgeon and appropriate wound healing 
must be documented. Subjects with wound healing complications that have not resolved 
with 42 days of CN and/or MET will discontinue study participation. Any subject who 

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cannot resume study therapy within 42 days of CN/MET will discontinue study 
participation.
Perform the following study procedures on Day 1 of each cycle (±3 days) unless stated otherwise:

Directed physical examination

Vital signs and weight

ECOG performance status

Evaluation of AEs

Concomitant medications

CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid Function Tests: TSH, FT4, T3 

Blood for correlative studies (including immune monitoring) at week 15 only

Urinalysis (including microscopic exam, if abnormal results are noted

Treatment:
o
All cohorts, metastatic disease and achieved CR:

Pembrolizumab 400 mg IV (Day 1) Q6W
o
Cohort A (all other subjects continuing therapy):

Pembrolizumab 400 mg IV (Day 1) Q6W
o
Cohort B (all other subjects continuing therapy):

Pembrolizumab 400 mg IV (Day 1) Q6W

Axitinib (Days 1 - 42). Dose titration per standard of care

Imaging evaluation (CT chest, abdomen and pelvis; MRI if CT is contraindicated; IV 
contrast given unless contraindicated; Bone scan if clinical indicated; MRI brain if clinically 
indicated) for tumor assessment will be performed every 2 cycles (as indicated in study 
flow chart [Section 6.2])

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6.1.3 Post-Treatment Period
6.1.3.1
End-of-Treatment
The following study procedures should be completed within 7 days of the last dose of study drug 
or discontinuation:

Directed physical examination

Vital signs and weight

ECOG performance Status

Evaluation of AEs

Concomitant medications

Urinalysis (including microscopic exam if abnormal results are noted)

CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid function tests: TSH, FT4, T3

Imaging evaluation (CT chest, abdomen and pelvis; MRI if CT is contraindicated; IV 
contrast given unless contraindicated; Bone scan if clinical indicated; MRI brain if clinically 
indicated), for tumor assessment. If prior scan was done within 6 weeks, does not have to 
repeated (per physician discretion)

Newly obtained (biopsy) tissue collection (subjects will require additional consent) at the 
time of disease progression.

Blood for correlative studies (including immune monitoring)

Correlative Studies Stool Collection
6.1.3.2
Safety Follow-Up
The mandatory Safety Follow-up Visit should be conducted 30 days (+7 days) after the last dose 
of study treatment or before initiation of a new anticancer treatment, whichever comes first.  All 
AEs that occur prior to the Safety Follow-up Visit should be recorded. Subjects with an AE of 
Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a 
new anticancer therapy, whichever occurs first. Serious AEs (SAEs) that occur within 90 days of 
the end of treatment or before initiation of a new anticancer treatment should also be followed 
and recorded.

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The following procedures will be performed at the Safety Follow-up Visit:

Directed physical examination

Vital signs and weight

ECOG performance Status

Evaluation of AEs

Concomitant medications

Urinalysis (including microscopic exam if abnormal results are noted)

CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid function tests: TSH, FT4, T3
6.1.3.3
1-Year Follow-Up
Those subjects who complete preoperative therapy and achieve either CR/PR/SD with R0 or R1 
resection, and complete 1 year (9 cycles) of continued pembrolizumab-based therapy will be 
followed for up to 1 additional year (12 months), or until disease progression, death, unacceptable 
toxicity or withdrawal of consent, whichever occurs first.
Those subjects who complete preoperative therapy and achieve either CR/PR/SD with R2 
resection, or achieve a pre-operative CR but do not undergo CN, and complete 2 years (18 cycles) 
of continued pembrolizumab-based therapy (400 mg Q6W) will be followed for up to 12 additional 
months, or until disease progression, death, unacceptable toxicity or withdrawal of consent, 
whichever occurs first.
During the 1-year follow-up period, the following procedures will be performed every 12 
weeks(±14 days) from the date of last dose of study treatment or discontinuation:

Directed physical examination

Vital signs and weight

ECOG performance status

Evaluation of AEs

Concomitant medications

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
CBC with differential and platelet count

Blood chemistry assessment, including:
o
ALP, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, 
albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH

Thyroid Function Tests: TSH, FT4, T3

Urinalysis (including microscopic exam, if abnormal results are noted)

Imaging evaluation (CT chest, abdomen and pelvis; MRI if CT is contraindicated; IV 
contrast given unless contraindicated; Bone scan if clinical indicated; MRI brain if clinically 
indicated) for tumor assessment will be performed as specified in study flow chart [Table 
7])

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6.2
Trial Flow Chart
Table 7: Schedule of Activities
Trial Period:
Screening 
Phase
Preoperative Treatment Period
Visit Number
CN/
MET
Postoperative Continued Treatment
Visit Numberf
Post-Treatment
Up to 9 cyclesq
OR
Up to 18 cyclesr
Screening
1
(W1)
2
(W4)
3
(W7)
4
(W10)
(W12)
5 
(W15)v
6 
(W21)
7 
(W27)
8-40
(W33-125)
END OF 
TXk
Safety 
F/U
F/U for 
subjects who 
complete 1Yq 
or 2Yr of 
continued TX
Scheduling Window:
-28d to -1d
D1
D1 ±3d
D1 ±3d
D1 ±3d
+7d
D1 ±3d
D1 ±3d
D1 ±3d
D1 ±3d
At DCw 
+7d
30d after 
DCw +7d
Q12W after 
DCw ±7d, for 
up to 1Y
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Demographics/Medical 
History and Baseline 
Conditions Assessment
X
Prior and Concomitant 
Medication Review
Xo
X
X
X
X
X
X
X
X
X
X
X
X

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Trial Period:
Screening 
Phase
Preoperative Treatment Period
Visit Number
CN/
MET
Postoperative Continued Treatment
Visit Numberf
Post-Treatment
Up to 9 cyclesq
OR
Up to 18 cyclesr
Screening
1
(W1)
2
(W4)
3
(W7)
4
(W10)
(W12)
5 
(W15)v
6 
(W21)
7 
(W27)
8-40
(W33-125)
END OF 
TXk
Safety 
F/U
F/U for 
subjects who 
complete 1Yq 
or 2Yr of 
continued TX
Scheduling Window:
-28d to -1d
D1
D1 ±3d
D1 ±3d
D1 ±3d
+7d
D1 ±3d
D1 ±3d
D1 ±3d
D1 ±3d
At DCw 
+7d
30d after 
DCw +7d
Q12W after 
DCw ±7d, for 
up to 1Y
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
Xd
X
X
X
X
X
X
X
Complete Physical 
Examination
X
Directed Physical Exam
X
X
X
X
X
X
X
X
X
X
X
Vital Signs, Heights, and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
Xa
X
X
X
X
Xd
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
Pregnancy Test – Urine or 
Serum β-HCGe
X

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Trial Period:
Screening 
Phase
Preoperative Treatment Period
Visit Number
CN/
MET
Postoperative Continued Treatment
Visit Numberf
Post-Treatment
Up to 9 cyclesq
OR
Up to 18 cyclesr
Screening
1
(W1)
2
(W4)
3
(W7)
4
(W10)
(W12)
5 
(W15)v
6 
(W21)
7 
(W27)
8-40
(W33-125)
END OF 
TXk
Safety 
F/U
F/U for 
subjects who 
complete 1Yq 
or 2Yr of 
continued TX
Scheduling Window:
-28d to -1d
D1
D1 ±3d
D1 ±3d
D1 ±3d
+7d
D1 ±3d
D1 ±3d
D1 ±3d
D1 ±3d
At DCw 
+7d
30d after 
DCw +7d
Q12W after 
DCw ±7d, for 
up to 1Y
PT/INR and aPTTx
X
Xc
Xd
CBC with Differential and 
Platelet Countx
X
Xc
X
X
Xd
X
X
X
X
X
X
X
Comprehensive Serum 
Chemistry Panelb,x
X
Xc
X
X
Xd
X
X
X
X
X
X
X
Urinalysisn,x
X
X
Xd
X
X
X
X
X
X
T3, FT4, and TSHx
X
X
Xd
X
X
X
X
X
X
Study Treatment
Pembrolizumab
X
X
X
X
X
X
X
Axitinib (Cohort B Only)
X
X
X
X
X
X
X
CN/MET
X
Efficacy Measurements
Tumor Imagingj
X
X
X
Xg
Xh,i
Xh,i

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Trial Period:
Screening 
Phase
Preoperative Treatment Period
Visit Number
CN/
MET
Postoperative Continued Treatment
Visit Numberf
Post-Treatment
Up to 9 cyclesq
OR
Up to 18 cyclesr
Screening
1
(W1)
2
(W4)
3
(W7)
4
(W10)
(W12)
5 
(W15)v
6 
(W21)
7 
(W27)
8-40
(W33-125)
END OF 
TXk
Safety 
F/U
F/U for 
subjects who 
complete 1Yq 
or 2Yr of 
continued TX
Scheduling Window:
-28d to -1d
D1
D1 ±3d
D1 ±3d
D1 ±3d
+7d
D1 ±3d
D1 ±3d
D1 ±3d
D1 ±3d
At DCw 
+7d
30d after 
DCw +7d
Q12W after 
DCw ±7d, for 
up to 1Y
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood and Stool
Archival or Newly 
Obtained Tissue 
Collection
Xt
Xu
Xm
Correlative Studies Blood 
Collection (including 
immune monitoring)
X
X
X
X
X
X
X
Correlative Studies Stool 
Collection and 
Questionnaire
X
X
X
Abbreviations: aPTT = activated partial thromboplastin time; β-HCG = beta human chorionic gonadotropin; CBC = complete blood count; DC = discontinuation; 
ECOG = Easter Cooperative Oncology Group; FT4 = free thyroxine; F/U = follow-up; INR = international normalized ratio; PT = prothrombin time; Q12W = every 
12 weeks; SD = stable disease; T3 = triiodothyronine; TSH = thyroid stimulating hormone; Tx = treatment; D = day; W = week; Y = year.
a.
To be done within 7 days of Cycle 1 Day 1
b.
Includes alkaline phosphatase (ALP), aspartate aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood urea nitrogen 
(BUN), creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, lactate dehydrogenase (LDH)
c.
Laboratory evaluations may be omitted if they were already performed within 7 days of Cycle 1, Day 1
d.
Window for these specific assessments is within the 14 days prior to CN and/or MET
e.
Women of childbearing potential require a negative urine test within 72 hours prior to the first dose of study treatment. Serum test is only required if urine test is 
positive or is not evaluable. Additional urine pregnancy testing can be conducted if required by local regulations or clinically indicated.

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f.
Administered for up to 1 year (9 cycles) (for patients who undergo CN/MET with R0 or R1 resection), or up to 2 years (18 cycles) (for patients who undergo 
CN/MET with R2 resection or who had a pre-operative CR but did not undergo CN), or until death, disease progression, unacceptable toxicity, or withdrawal of 
consent.
g.
To be done every 2 cycles (i.e., about every 3 months) during postoperative pembrolizumab-based treatment
h.
If prior scan was done within 6 weeks, does not have to repeated (per physician discretion)
i.
Those subjects who undergo CN/MET with R0 or R1 resection who complete 1 year (9 cycles) of postoperative pembrolizumab-based therapy, or those patients 
who undergo CN/MET with R2 resection or who had a pre-operative CR but did not undergo CN and complete 2 years (18 cycles) of postoperative 
pembrolizumab-based therapy, will have scans Q12W for up to 12 additional months, or until disease progression, death, unacceptable toxicity or withdrawal of 
consent, whichever occurs first.
j.
Imaging evaluation (CT chest, abdomen and pelvis; MRI if CT is contraindicated; IV contrast given unless contraindicated; Bone scan if clinical indicated; MRI 
brain if clinically indicated), for tumor assessment
k.
In subjects who complete postoperative pembrolizumab-based therapy: end of treatment visit will be performed within 7 days of the last dose of study drug or 
discontinuation
l.
In subjects who complete postoperative pembrolizumab-based therapy: additional safety follow-up visit is not necessary; the follow-up visit will be done during 
the 12 month follow-up period
m.
At the time of disease progression (subjects will require additional consent)
n.
Urinalysis (including microscopic exam if abnormal results are noted)
o.
Record baseline medications taken within 14 days of Cycle 1 Day 1. For stool correlative analysis, it should be noted if antibiotics were taken within 90 days 
before the first dose of study drug(s).
p.
To be done within 72 hours prior to the start of study drug
q.
Subjects with an R0 resection (NED, margins negative) or R1 resection (microscopic disease, margins positive) will continue receiving their assigned 
pembrolizumab-based therapy for up to 9 cycles or until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs first. 
They will then enter the 1-Year Follow-Up Period.
r.
Subjects with an R2 resection (macroscopic disease after surgery), or who had a pre-operative CR but did not undergo CN, will continue receiving their assigned 
pembrolizumab-based therapy for up to 18 cycles or until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs first. 
They will then enter the 1-Year Follow-Up Period.
s.
Record height at screening only
t.
Newly obtained tissue will be a fresh biopsy of primary or metastatic lesion at study baseline and must be collected from all enrolled subjects. Archival tissues 
will be prior tissues from primary or metastatic lesions that were originally obtained prior to study consent (where available).
u.
Subject may be consented for core tumor biopsies if CN and/or MET cannot be performed following preoperative pembrolizumab-based therapy. See section 
6.1.2.4 for details.
v.
The first dose of study treatment following CN/MET may be no sooner than 3 weeks and no later than 6 weeks following surgery, to allow for postoperative 
recovery (adequate wound healing and recovery from any postoperative complications) as assessed by the treating surgeon. Subjects who cannot resume 
therapy within 42 days for any reason will discontinue study participation
w. The timing of the End of Treatment, Safety Follow-Up and every 12 week visits during the 1-Year Follow-Up Period is relative to the last dose of study drug 
dosing or discontinuation.

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x. 
These specific screening laboratory assessments (CBC with Differential and Platelet Count, Comprehensive Serum Chemistry Panel, PT/INR and aPTT, T3, 
FT4, and TSH, urinalysis) should be performed within 10 days of treatment initiation.

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6.3
Discontinuation/Withdrawal Criteria
6.3.1 Discontinuation of Study Treatment
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the subject 
has discontinued study treatment. Therefore, all subjects who discontinue study treatment prior 
to completion of the protocol-specified treatment period regimen will still continue to participate in 
the trial as specified in Sections 6.1.3 and 6.1.3.2.
Subjects may discontinue study treatment at any time for any reason or be dropped from the study 
treatment at the discretion of the investigator should any untoward effect occur. In addition, a 
subject may be discontinued from study treatment by the investigator or Merck if study treatment 
is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. Specific 
details regarding procedures to be performed at study treatment discontinuation are provided in 
Sections 6.1.3 and 6.1.3.2.
A subject must be discontinued from study treatment but continue to be monitored (see Sections 
6.1.3 and 6.1.3.2) in the study for any of the following reasons:

The subject or subject’s legally acceptable representative requests to discontinue study 
treatment

There is evidence of unequivocal disease progression without evidence of clinical benefit 
during the adjuvant treatment period (i.e., postoperative pembrolizumab-based therapy)

There is(are) unacceptable AE(s), which requires discontinuation from study treatment at 
that time (the subject may still be consented to post-treatment tissue collection, if safe and 
feasible)

General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Any AE requiring discontinuation outlined in Section 5.2

Subject has a confirmed positive serum pregnancy test

For subjects who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the trial flowchart (Section 6.2), should be 
completed.

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6.3.2 Withdrawal from the Study
A subject must be withdrawn from the study if the subject or subject’s legally acceptable 
representative withdraws consent from the study.
A subject must be withdrawn from the study if there is evidence of unequivocal disease 
progression without evidence of clinical benefit during the preoperative treatment period. Subjects 
with PD during the preoperative treatment period who, in the opinion of the treating physician and 
principal investigator, are likely to benefit from CN/MET AND in whom surgery is safe and feasible, 
may proceed with CN/MET on study. Subjects in whom CN/MET is unlikely to provide benefit OR 
surgery is not safe and feasible, may still be consented to core tumor biopsy on study, if safe and 
feasible and, in the judgment of the treating physician, the biopsy will not delay appropriate 
standard of care. Subjects will withdraw from study participation following CN/MET or tumor 
biopsy. If CN/MET and tumor biopsy are not safe and feasible and not in the best interests of the 
subject, the subject will withdraw from study participation immediately.
If a subject withdraws from the study, they will no longer receive study treatment or be followed 
at scheduled protocol visits.
6.3.3 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to contact 
the subject, the following procedures are to be performed:
●
The site must attempt to contact the subject and reschedule the missed visit.  If the subject 
is contacted, the subject should be counseled on the importance of maintaining the protocol-
specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the subject at 
each missed visit (e.g., phone calls and/or a certified letter to the subject’s last known mailing 
address or locally equivalent methods). These contact attempts should be documented in 
the subject’s medical record.
Note: A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject. The amount of missing data for the subject will be managed via the 
pre-specified data handling and analysis guidelines.
6.4
Usage of Concurrent/Concomitant Medications/Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be required. The 
investigator should discuss any questions regarding this with the Merck Clinical Director. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician. However, the decision to continue the subject on study treatment requires the 
mutual agreement of the investigator, Merck, and the subject. 

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6.4.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) including 
all prescription, over the counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded. For stool correlative analysis, it 
should be noted if antibiotics were taken within 90 days before the first dose of study drug(s). 
Concomitant medications administered after 90 days following the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 7.3.5.
6.4.2 Prohibited Medications
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response progression) of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.  

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, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed

Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with Merck.

Rifaximin or lactulose to control encephalopathy

Strong inhibitors of CYP3A4/5 (e.g. ketoconazole, grapefruit or grapefruit juice)

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
Strong/moderate inducers of CYP3A4/5 (e.g. rifampin, dexamethasone, phenytoin, 
carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort, bosentan, efavirenz, 
etravirine, modafinil, nafcillin)*

* Subjects enrolled on Arm A (pembrolizumab monotherapy), who may require the use of 
any CYP3A4/5 inducer, may be permitted to do so for clinical management of symptoms 
as determined by the Investigator. These medications are prohibited in Arm B 
(pembrolizumab + axinitib).
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
6.5
Dietary Restrictions
There are no dietary restrictions on this study. Subject should maintain a normal diet unless 
modifications are required to manage an AE such as diarrhea, nausea or vomiting.
6.6
Pregnancy and Contraception
6.6.1 Contraception
Pembrolizumab and/or axitinib may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab and/or axitinib have transient adverse effects on the composition of 
sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age, a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) Has a congenital or acquired condition that prevents childbearing.

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Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
(1) Practice abstinence† from heterosexual activity; 
OR 
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (1 of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin 
Combination method (requires use of 2 of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and IRBs/ERCs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects should be informed that taking the study medications may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study, subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 

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of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
6.6.2
Use in Pregnancy
If a subject inadvertently becomes pregnant while on study treatment, the subject will be 
immediately discontinued from study treatment.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to Merck without delay and within 24 hours if the 
outcome is a SAE (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study Investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn 
to Merck.  If a male subject impregnates his female partner, the study personnel at the site must 
be informed immediately and the pregnancy must be reported to Merck and followed as described 
in Section 7.8.
6.6.3 Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment.
6.6.4 Pregnancy tests
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of trial 
treatment and 30 days post treatment.  If a urine test is positive or not evaluable, a serum test will 
be required.  Subjects must be excluded/discontinued from the study in the event of a positive or 
borderline-positive test result.  
6.7
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1.
Quality or quantity of data recording is inaccurate or incomplete
2.
Poor adherence to protocol and regulatory requirements
3.
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4.
Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made.
6.8
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of the 

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trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected 
by visit and by sample type per subject can be found in the laboratory manual.  
Refer to the Trial Flow Chart - Section 6.2 for the schedule of laboratory assessments.
6.8.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis, and Others)
Laboratory tests for hematology, chemistry, urinalysis and others are specified here in Table 8.
Table 8
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human 
chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase 
(ALP)
Glucose
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC (total and differential)
Aspartate 
aminotransferase (AST)
Specific gravity 
Total 
triiodothyronine 
(T3)
Red Blood Cell Count
Lactate dehydrogenase 
(LDH)
Microscopic exam (If 
abnormal results are 
noted)
Free tyroxine (T4)
Absolute Neutrophil Count
Carbon Dioxide (CO2 or 
biocarbonate)
Urine pregnancy test †
Thyroid stimulating 
hormone (TSH)
Absolute Lymphocyte 
Count
Uric Acid
Blood for 
correlative studies
Calcium
Chloride
Glucose
Phosphorus
 
Potassium  
 
Sodium
 
 

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Hematology
Chemistry
Urinalysis
Other
Total Bilirubin
 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal)
 
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed 
as negative, a serum pregnancy test will be required.  
Laboratory tests for screening should be performed within 10 days prior to treatment. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to 
dose of trial treatment. Unresolved abnormal laboratory values that are drug-related AEs should 
be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment 
if laboratory results are within normal range.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy: Antitumor Effect - Solid Tumors
Subject eligibility will be determined using local assessment (Investigator assessment) based on 
RECIST 1.1. RECIST 1.1 will also be used by the investigator as the primary measure for 
assessment of tumor response, date of PD, and as a basis for all protocol guidelines related to 
disease status (e.g., discontinuation of study treatment). 
Only those subjects who have measurable disease present at baseline have received at least 
1 treatment with pembrolizumab-based therapy, and have had their disease re-evaluated, will be 
considered evaluable for response. Subjects who exhibit objective disease progression prior to 
the end of Cycle 1 will also be considered evaluable.
While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred tumor imaging 
technique in this study. For the abdomen and pelvis, contrast-enhanced MRI may be used when 
CT with iodinated contrast is contraindicated, or when mandated by local practice. Images 
(including via other modalities) that are obtained at an unscheduled time point to determine 
disease progression, as well as imaging obtained for other reasons, but which demonstrate 
radiologic progression, should also be reviewed by the Investigator. MRI is the strongly preferred 
modality for imaging the brain. The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a subject throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the accuracy of 
the assessment of response or progression based on imaging.
Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this 
protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to 
enable a broader sampling of tumor burden.

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If the Investigator identifies radiographic progression per RECIST 1.1, treatment should continue 
until PD has been verified.
RECIST guideline version 1.1 is published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
7.1.1 Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of allocation.  
The site study team must review screening images to confirm the subject has measurable disease 
per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to the date 
of allocation and can be assessed by the investigator.
If brain imaging is performed to document the stability of existing metastases, MRI should be used 
if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable alternative.
7.1.2 Tumor Imaging During the Study
The schedule of on-trial imaging is outlined in Section 6.1 and Table 6.2. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should 
continue to be performed until disease progression, the start of new anticancer treatment, 
withdrawal from study, death, or end of study, whichever occurs first.  All supplemental imaging 
must be reviewed by the investigator.
7.1.3 Response Evaluation Following Surgery
Following CN/MET, little to no residual tumor may be present.  Progressive disease is defined as 
the growth of the primary tumor or appearance of any new tumors following CN/MET as assessed 
by the Investigator per RECIST 1.1.
Objective response (PR and CR) should be confirmed in subjects with residual disease following 
CN/MET by a repeat imaging assessment.  The imaging for confirmation of response may be 
performed no earlier than 4 weeks after the first indication of a response is observed.  Subjects 
will then return to the regular imaging schedule, starting with the next scheduled imaging time 
point.  Subjects who receive additional imaging for confirmation do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point.
First evidence of PD by RECIST 1.1 should be confirmed by repeat imaging assessment at 4-8 
weeks in clinically stable subjects. Clinically stable subjects may continue study treatment until 
the repeat imaging assessment to confirm PD. In clinically unstable subjects, per the investigator’s 
assessment, neither repeat imaging assessment nor continuation of study treatment may be 
feasible or in the best interest of the subject.

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See section 7.1.6 for further details regarding RECIST 1.1 response criteria.
7.1.4 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at least 
1 dimension (longest diameter [LD] to be recorded) with a minimum size of 10 mm by CT scan 
(irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 
10 mm), and/or 10 mm caliper measurement by clinical exam (when superficial).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Target lesions
All measurable lesions up to a maximum of 10 lesions total (and a maximum of 5 lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the LD) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  A sum of the LD for all target lesions will be calculated and reported as the baseline 
sum LD.  The baseline sum LD will be used as reference by which to characterize the objective 
tumor response.
Non-target lesions
All other lesions (or sites of disease), including any measurable lesions over and above the 
10 target lesions, should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a single 
item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”).  Bone lesions may be measurable if ≥1 cm on MRI.  Measurements of these lesions 
are not required, but the presence or absence of each will be noted throughout follow-up.
Non-measurable disease
Non-measurable disease is all other lesions (or sites of disease), including small lesions (LD <20 
mm with conventional techniques or <10 mm using spiral CT scan).  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 are all non-measurable.
7.1.5 Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.

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The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment.
7.1.6 Response Criteria
Evaluation of Target Lesions
Complete Response
Disappearance of all target lesions determined by 2 separate observations conducted not less 
than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  There can 
be no appearance of new lesions.
Partial Response
At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline 
sum of the LD.  There can be no appearance of new lesions.
Progressive Disease
At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest 
sum of the LD recorded since the treatment started and minimum 5 mm increase over the nadir, 
or the appearance of 1 or more new lesions.
Stable Disease
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum of the LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (<10 mm short axis).
Incomplete Response/Stable Disease
Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits.
Progressive Disease
Appearance of 1 or more new lesions and/or unequivocal progression of existing non-target 
lesions.

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Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
PD/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started).  The subject's best response assignment will depend on the achievement of 
both measurement and confirmation criteria (Table 9).
Table 9
Response Criteria
Target 
Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Response for this 
Category Also Requires
CR
CR
No
CR
>4 weeks confirmation
CR
Non-CR/
Non-PD
No
PR
PR
Non-PD
No
PR
>4 weeks confirmation
SD
Non-PD
No
SD
documented at least once 
>4 weeks from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression
7.2
Evaluation of Safety
Analyses will be performed for all patients having received at least 1 dose of study drug.  Safety 
parameters commonly used for evaluating investigational systemic anticancer treatments are 
included as safety endpoints including, but not limited to, the incidence of, causality, and outcome 
of AEs/ SAEs, and changes in vital signs and laboratory values. Investigators who are qualified 
physicians will assess adverse events as defined by NCI CTCAE, Version 5.0 
(http://ctep.cancer.gov/reporting/ctc.html). Any AE that changes NCI CTCAE grade over the 
course of a given episode will have each change of grade recorded on the AE CRFs/worksheets.
All AEs regardless of NCI CTCAE grade must also be evaluated for seriousness.
7.3
Definitions of Adverse Events
7.3.1 Adverse Event
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting condition 
that is temporally associated with the use of the Merck’s product, is also an AE.

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Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered adverse events. Examples of this may 
include, but are not limited to, teething, typical crying in infants and children, and onset of menses 
or menopause occurring at a physiologically appropriate time.
Merck’s product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use.
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal.
Progression of the cancer under trial is not considered an AE.
7.3.2 Adverse reaction
An adverse reaction is defined as any AE caused by the use of a drug.  Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.
7.3.3 Suspected Adverse Reaction
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction.
7.3.3.1
Unexpected 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the IB or 
package insert(s), or is not listed at the specificity or severity that has been observed, or, if an IB 
is not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application.
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
AEs that would be anticipated to occur as part of the disease process are considered unexpected 
for the purposes of reporting because they would not be listed in the IB.  For example, a certain 
number of non-acute deaths in a cancer trial would be anticipated as an outcome of the underlying 
disease, but such deaths would generally not be listed as a suspected adverse reaction in the IB.
Some AEs are listed in the IB as occurring with the same class of drugs, or as anticipated from 
the pharmacological properties of the drug, even though they have not been observed with the 
drug under investigation. Such events would be considered unexpected until they have been 

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observed with the drug under investigation. For example, although angioedema is anticipated to 
occur in some subjects exposed to drugs in the angiotensin-converting enzyme (ACE) inhibitor 
class and angioedema would be described in the investigator brochure as a class effect, the first 
case of angioedema observed with the drug under investigation should be considered unexpected 
for reporting purposes.
7.3.3.2
Serious
An AE or suspected adverse reaction is considered serious if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes: 

Death;

Life-threatening (i.e., results in an immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Permanent or significant disability/incapacity;

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above;

Event occurring in a gene therapy study;

Event that changes the risk/benefit ratio of a study;

Any other event the Principal Investigator judges to be serious or which would suggest 
a significant hazard, contraindication, side effect, or precaution
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in subject hospitalization, or the development of drug dependency 
or drug abuse.
Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per International Council for Harmonisation (ICH) definition, are reportable to Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Additionally, if an Investigator who is a qualified physician considers an SAE to be related to 
Merck's product, and the SAE is brought to the attention of the Investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph above, 
or at any time outside of the time period specified in the previous paragraph, also must be reported 
immediately to the Merck clinical team. All subjects with SAEs must be followed up for outcome.

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7.3.3.3
Life-threatening
An AE or suspected adverse reaction is considered life-threatening if, in the view of either the 
investigator or Merck, its occurrence places the subject or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death.
7.3.4 Definition of an Overdose
For this trial, an overdose of pembrolizumab will be defined as any dose of 1000 mg or greater 
(≥5 times the indicated dose). An overdose of other study treatment will be defined as the 
administration of a dose that exceeds the dose described in the protocol.
No specific information is available on the treatment of overdose of pembrolizumab.  In the event 
of overdose, the subject should be observed closely for signs of toxicity.  In the event of an 
overdose of any study treatment, appropriate supportive treatment should be provided if clinically 
indicated.
7.3.5 Events of Clinical Interest
Selected non-serious and SAE are also known as ECIs and must be reported to Merck.
For the time period beginning when the ICF is signed until treatment allocation/randomization, 
any ECI, or follow up to an ECI, that occurs to any patient must be reported within 24 hours to the 
Merck clinical team if it causes the patient to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to Merck’s product, must be 
reported within 24 hours to the Merck clinical team, either by electronic media or paper.
Events of clinical interest for this trial include: 
1.
An overdose of Merck's product, as defined in Section 7.3.4, 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 3 × ULN and an elevated 
total bilirubin lab value that is greater than or equal to 2 × ULN and, at the same time, an 
ALP lab value that is less than 2 × ULN, 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 Investigator Trial File Binder (or 
equivalent).

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7.4
Recording of an Adverse Event
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.5
Follow-up of Adverse Events
All AEs will be followed with appropriate medical management until resolved.  Subjects removed 
from study for unacceptable AEs will be followed until resolution or stabilization of the AE.  For 
selected AEs for which administration of the investigational drug was stopped, a re-challenge of 
the subject with the investigational drug may be conducted if considered both safe and ethical by 
the Investigator.
7.6
Adverse Events Monitoring 
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
7.7
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be made via phone 
or e-mail.
Reporting to UCSF Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected adverse 
reaction that is both serious and unexpected. The Sponsor needs to ensure that the event meets 
all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.

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The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information 
is available (21 CFR 312.32(d)(2)).
Reporting to Merck
See section 7.8.
7.8
Reporting Events to Merck
All AEs, SAEs and other reportable safety events that occur after the ICF is signed but before 
treatment allocation must be reported by the investigator if the subject is receiving placebo run-in 
or other run-in treatment, if the event causes the subject to be excluded from the study, or is the 
result of a protocol-specified intervention, including but not limited to washout or discontinuation 
of usual therapy, diet, or a procedure. 

All AEs from the time of treatment allocation through 30 days following cessation of study 
treatment must be reported by the investigator. 

All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the subject initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator. 

All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the subject initiates new anticancer 
therapy, must be reported by the investigator. 

Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the Merck clinical team if the 
event is considered to be drug related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must promptly 
notify the Merck clinical team.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Merck clinical team or designee within the timeframes as indicated in Table 10.

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Table 10
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the 
Protocol 
Specified 
Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
Mercka:
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- subject is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome.)
Within 24 hours 
of learning of 
event
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- subject is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 days of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (Do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 days of 
learning of 
event

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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the 
Protocol 
Specified 
Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
Mercka:
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 days of 
learning of 
event
Pregnancy/Lact
ation Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously 
reported – 
Follow to 
completion/termi
nation; report 
outcome
Within 24 hours 
of learning of 
event
a.
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229.
7.8.1 Reporting of Pregnancy and Lactation
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a subject (spontaneously reported to the 
investigator or their designee) that occurs during the trial is reportable to the Merck clinical team.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Such events must be reported within 24 hours to the Merck clinical team by either electronic media 
or paper.  Electronic reporting procedures can be found in the EDC data entry guidelines.  Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
7.8.2 Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Merck clinical team. See 
Table 10 for events that are reportable to Merck.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.

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The investigator will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the patients in the trial.  Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck as an SAE within 24 hours of 
determination that the event is not progression of the cancer under study.
8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
Primary endpoint: The proportion of subjects with ≥2-fold increase in the number of TIICs 
between baseline and CN/MET specimens.
Secondary endpoints:

The clinical efficacy of preoperative pembrolizumab-based therapy in subjects with 
advanced RCC will be assessed by ORR, defined as CR or PR by RECIST 1.1 criteria.

The clinical efficacy of:
o
Continued pembrolizumab-based therapy will be assessed as follows:

In subjects who achieve CR or PR/SD followed by R0 resection: proportion 
of subjects who remain disease-free at the end of the 1 year continued 
treatment period (1-year DFS rate), and at 1 year following the end of the 
continued treatment period (2-year DFS rate), and the median DFS.

In subjects who achieve PR/SD with residual disease following CN/MET: 
proportion of subjects who remain progression-free at the end of the 1 year 
continued treatment period (1-year PFS rate) and at 1 year following the 
end of the continued treatment period (2-year PFS rate), and the median 
PFS.

Safety will be assessed and reported using NCI CTCAE version 5.0. 
o
Surgical complications using Clavien-Dindo classification (Appendix 3)
Exploratory endpoints

The relationship between clinical efficacy (by above measures) and changes in TIICs (by 
above measures) will be explored.

Clinical efficacy: pathologic response rate, R0 resection rate

The changes in frequency and numbers of circulating T cells will be assessed by flow 
cytometry.

Comprehensive assessment will be performed to explore the tumor microenvironment, 
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constituents (including T cell subsets, tumor, and stroma) in pre- and post-treatment 
specimens will be analyzed .

Changes in the T cell repertoire will be explored via high resolution TCR sequencing, in 
both blood and tumor specimens.

Molecular profiling of pre- and post-treatment tumor and normal tissue will be performed 
to explore biomarkers of response. Neoepitope burden will be assessed.  

Wilcoxon rank-sum test will be used to assess whether there is a relationship between 
any of the immune cell subsets and objective radiographic response as well as pathologic 
response. Cox-proportional hazard models will be applied to assess if there is relationship 
between any of the immune cell subsets and PFS. Parallel analysis will be performed for 
PD-L1 expression. Wilcoxon rank-sum test will also be used to assess whether the T cell 
receptor clonality diversity index is different between responders vs. non-responders 
(defined by objective radiographic response or pathologic response), and between 
subjects who have progression within 1-year vs. those whose disease has not progressed. 
Additional analyses of immunocorrelative data are detailed in the procedures manual.
8.1.1 Study Design
This is an open-labeled phase II study, in which eligible subjects with treatment-naïve, advanced 
RCC will be treated with perioperative pembrolizumab-based therapy prior to and after CN/MET. 
After safety lead in for each cohort, group sequential design will be applied for each combination 
cohort.
8.1.2 Randomization
This is a non-randomized study. Cohorts will be accrued concurrently.
8.1.3 Stratification Factors
There are no planned stratification factors.
8.2
Determination of Sample Size and Accrual Rate
8.2.1 Sample Size and Power Estimate
For the primary objective, there will be a binary classification. A subject will be considered to have 
a “positive response” if there is a ≥2-fold increase (from pre- to post-treatment) in the number of 
TIICs, and a “negative response” if there is <2-fold increase.
For Cohort A, with 12 subjects, if the true response rate is 30%, the 90% confidence interval of 
the response rate is (8%, 52%).
For each of the combination cohorts (cohorts B and C), the expanded part will be accrued based 
on group sequential design. In the first stage, 12 subjects (including the 6 subjects in safety lead-
in) will be accrued at the dose level decided at safety lead in. If there are one or fewer responses 
in these 12 subjects, the study will be stopped due to futility, and if there are 5 or more responses, 

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the study will be stopped due to efficacy (one-sided alpha spending =0.0004). The final decision 
to terminate the cohort or continue accruing after these first 12 subjects will be based on 
discussion amongst members of the Joint Steering Committee, which is comprised of 
representatives for both Merck and the Sponsor. If accrual to the cohort is continued, additional 
subjects will be accrued for up to 36 evaluable subjects (or up to 30 if no dose reductions occur).
The null hypothesis of a 10% response rate will be rejected if 6 or more responses are observed 
in 30 subjects. This design yields a one-side type I error rate of 0.05 and power of 82.3% when 
the true response rate is 30%. Additionally, the first 6 subjects will be considered the “safety lead-
in” for each cohort. If there are ≥2 DLTs in these first 6 subjects, then dose reduction will proceed 
as described in Section 5.1 and an additional 6 subjects will be accrued. The 6 subjects accrued 
as the safety lead-in are evaluable. Therefore, a minimum of 4, and a maximum of 36 subjects 
will be accrued to each pembrolizumab-based combination cohort.
8.2.2 Replacement Policy
A replacement subject may be enrolled if deemed appropriate by the Sponsor-Investigator. Up to 
2 subjects may be replaced if they are not evaluable for the primary outcome.
8.2.3 Accrual estimates
Based on current estimates of the number of eligible subjects, we estimate approximately 
2 subjects to accrue per month, and anticipate completing accrual to the first cohort within 
12 months. 
8.3
Interim Analyses and Stopping Rules
Each cohort will be stopped early for lack of safety, if the safety lead-in portion cannot be 
completed as outlined in the Study Design (Section 3).
The planned interim analysis for both futility and efficacy will be included based on group 
sequential design for the combination cohorts. 12 subjects (including the 6 subjects in safety lead-
in) will be accrued at the dose level decided at safety lead-in. If there are one or fewer responses 
in these 12 subjects, the study will be stopped due to futility, and if there are 5 or more responses, 
the study will be stopped due to efficacy (one-sided alpha spending =0.0004). The final decision 
to terminate the cohort or continue accruing after these first 12 subjects will be based on 
discussion amongst members of the Joint Steering Committee, which is comprised of 
representatives for both Merck and the Sponsor.
8.4
Analyses Plans 
8.4.1 Analysis Population

The analysis population for the primary outcome will be all subjects with pre- and post-
pembrolizumab treatment tumor specimens that are evaluable for TIICs. 

The All Subjects as Treated (APaT) population will be used for the analysis of the 
secondary endpoints of clinical efficacy (ORR) and safety/toxicity outcomes. The APaT 
population consists of all subjects who received at least 1 dose of pembrolizumab-based 
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dose of study treatment is required for inclusion in the analysis of each specific parameter.  
To assess change from baseline, a baseline measurement is also required.

Subjects who undergo CN and/or MET will be evaluable for the exploratory clinical efficacy 
endpoints: pathologic response rate and R0 resection rate

Additionally, subjects who receive continued pembrolizumab-based therapy will be 
evaluable for additional exploratory clinical endpoints (DFS/PFS at 1 and 2 years, median 
DFS and PFS)
8.4.2 Primary Analysis (or Analysis of Primary Endpoints)
TIICs will be analyzed in pre- and post-pembrolizumab-based treatment tumor specimens. The 
proportion of subjects with a ≥2-fold increase (from pre- to post-treatment) in the number of TIICs 
will be calculated. 
8.4.3 Secondary Analysis (or Analysis of Secondary Endpoints)
The study will use descriptive statistics to report on the ORR (by RECIST 1.1) following 
preoperative therapy; DFS/PFS rate at 1-year and 2-years following CN/MET; safety/toxicity of 
preoperative pembrolizumab-based therapy by NCI CTCAE. Median DFS/PFS following CN/MET 
will reported using the Kaplan-Meier estimate. 
8.5
Evaluation of Safety
Analyses will be performed for all subjects having received at least 1 dose of pembrolizumab-
based therapy.  The study will use the NCI CTCAE v5.0.
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4), consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional Review 
Board for the protocol, written informed consent form, subject recruitment materials, and any other 
written information to be provided to subjects before any protocol related procedures are 
performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the FDA has determined that the 
study is exempt from IND requirements. 
The PI must comply with the applicable regulations in Title 21 of the Code of Federal Regulations 
(21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements.  
The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.

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9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of subject-facing materials 
related to the study (e.g. advertisements used to recruit subjects) will be reviewed and approved 
by the UCSF IRB.  Prior to obtaining IRB approval, the protocol must be approved by the Helen 
Diller Family Comprehensive Cancer Center Site Committee and by the Protocol Review 
Committee (PRC).  The initial protocol and all protocol amendments must be approved by the IRB 
prior to implementation.  
9.3
Informed Consent
All subjects must be provided a consent form describing the study with sufficient information for 
each subject to make an informed decision regarding their participation.  Subjects must sign the 
IRB -approved informed consent form prior to participation in any study specific procedure.  The 
subject must receive a copy of the signed and dated consent document.  The original signed copy 
of the consent document must be retained in the medical record or research file.
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.
If it becomes necessary to alter the protocol to eliminate an immediate hazard to subjects, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.
9.5
Handling and Documentation of Clinical Supplies
The UCSF PI and each participating site will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs.  The date, quantity and batch 
or code number of the drug, and the identification of subjects to whom study drug has been 
dispensed by subject number and initials will be included.  The sponsor-investigator will maintain 
written records of any disposition of the study drug.
The PI shall not make the investigational drug available to any individuals other than to qualified 
study subjects. Furthermore, the PI will not allow the investigational drug to be used in any manner 
other than that specified in this protocol.
The PI will maintain complete records showing the receipt, dispensation, return, or other 
disposition of all investigational drugs at the site.  The date, quantity and batch or code number 
of the drug, and the identification of subjects to whom the investigational product has been 
dispensed by subject number and initials will be included.
The PI shall not make the investigational drug available to any individuals other than to qualified 
study subjects. Furthermore, the PI will not allow the investigational product to be used in any 
manner other than that specified in this protocol.

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9.6
Protection of Privacy
Subjects will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the subject’s medical records, and each subject will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document.
9.7
Case Report Forms (CRFs)
The PI and/or designee will prepare and maintain adequate and accurate subject case histories 
with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will 
document safety and treatment outcomes for safety monitoring and data analysis.  All study data 
will be entered into OnCore® via standardized CRFs in accordance with the CTMS study 
calendar, using single data entry with a secure access account. Study personnel will complete 
the CRFs; the PI will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the subject’s medical records maintained by study 
personnel. All source documentation should be kept in separate research files for each subject.
In accordance with federal regulations, the PI is responsible for the accuracy and authenticity of 
all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to 
attest that the information contained on the CRFs is true and accurate. 
The PI will be responsible for ensuring the accurate capture of study data. At study completion, 
when the CRFs have been declared to be complete and accurate, the database will be locked.  
Any changes to the data entered into the CRFs after that time can only be made by joint written 
agreement among the PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
9.8
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity 
for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-approved Data 
and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse events and 
suspected adverse reactions considered “serious.”  The DSMC will audit study-related activities 
to ensure that the study is conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable. See Appendix 2 - Data and Safety 
Monitoring Plan.

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9.9
Record Keeping and Record Retention
The PI is required to maintain adequate records of the disposition of the drug, including dates, 
quantity, and use by subjects, as well as written records of the disposition of the drug when the 
study ends.  
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the case 
report forms and supporting data including, for example, signed and dated consent forms and 
medical records such as the physician’s progress notes, the individual's hospital chart(s), and the 
nurses' notes. The case history for each individual shall document that informed consent was 
obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed subject consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date on which a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and FDA is notified.

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10
References
1.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 
66(1): p. 7-30.
2.
Motzer, R.J., et al., Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N 
Engl J Med, 2007. 356(2): p. 115-24.
3.
Sternberg, C.N., et al., Pazopanib in locally advanced or metastatic renal cell carcinoma: 
results of a randomized phase III trial. J Clin Oncol, 2010. 28(6): p. 1061-8.
4.
Motzer, R.J., L. McCann, and K. Deen, Pazopanib versus sunitinib in renal cancer. N Engl 
J Med, 2013. 369(20): p. 1970.
5.
Heng, D.Y., et al., Prognostic factors for overall survival in patients with metastatic renal 
cell carcinoma treated with vascular endothelial growth factor-targeted agents: results 
from a large, multicenter study. J Clin Oncol, 2009. 27(34): p. 5794-9.
6.
Fyfe, G., et al., Results of treatment of 255 patients with metastatic renal cell carcinoma 
who received high-dose recombinant interleukin-2 therapy. J Clin Oncol, 1995. 13(3): p. 
688-96.
7.
Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N 
Engl J Med, 2015. 373(19): p. 1803-13.
8.
Motzer, R., et al., IMMotion151: A Randomized Phase III Study of Atezolizumab Plus 
Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin 
Oncol, 2018. 36: p. (suppl 6S; abstr 578).
9.
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8.
10.
Dudley, M.E., et al., Adoptive cell transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment of patients with refractory metastatic 
melanoma. J Clin Oncol, 2005. 23(10): p. 2346-57.
11.
Hunder, N.N., et al., Treatment of metastatic melanoma with autologous CD4+ T cells 
against NY-ESO-1. N Engl J Med, 2008. 358(25): p. 2698-703.
12.
Greenwald, R.J., G.J. Freeman, and A.H. Sharpe, The B7 family revisited. Annu Rev 
Immunol, 2005. 23: p. 515-48.
13.
Okazaki, T., et al., PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by 
recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. 
Proc Natl Acad Sci U S A, 2001. 98(24): p. 13866-71.
14.
Zhang, X., et al., Structural and functional analysis of the costimulatory receptor 
programmed death-1. Immunity, 2004. 20(3): p. 337-47.

Version date: 01/30/2024
Protocol CC#: 197017
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15.
Chemnitz, J.M., et al., SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based 
switch motif of programmed death 1 upon primary human T cell stimulation, but only 
receptor ligation prevents T cell activation. J Immunol, 2004. 173(2): p. 945-54.
16.
Sheppard, K.A., et al., PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004. 
574(1-3): p. 37-41.
17.
Riley, J.L., PD-1 signaling in primary T cells. Immunol Rev, 2009. 229(1): p. 114-25.
18.
Parry, R.V., et al., CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol, 2005. 25(21): p. 9543-53.
19.
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42.
20.
Sonpavde, G., T.E. Hutson, and B.I. Rini, Axitinib for renal cell carcinoma. Expert Opin 
Investig Drugs, 2008. 17(5): p. 741-8.
21.
Rini, B.I., et al., Comparative effectiveness of axitinib versus sorafenib in advanced renal 
cell carcinoma (AXIS): a randomised phase 3 trial. Lancet, 2011. 378(9807): p. 1931-9.
22.
Rini, B.I., et al., Axitinib with or without dose titration for first-line metastatic renal-cell 
carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol, 2013. 14(12): p. 1233-
42.
23.
Flanigan, R.C., et al., Nephrectomy followed by interferon alfa-2b compared with interferon 
alfa-2b alone for metastatic renal-cell cancer. N Engl J Med, 2001. 345(23): p. 1655-9.
24.
Mickisch, G.H., et al., Radical nephrectomy plus interferon-alfa-based immunotherapy 
compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. 
Lancet, 2001. 358(9286): p. 966-70.
25.
Heng, D.Y., et al., Cytoreductive nephrectomy in patients with synchronous metastases 
from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma 
Database Consortium. Eur Urol, 2014. 66(4): p. 704-10.
26.
Lee, S.E., et al., Metastatectomy prior to immunochemotherapy for metastatic renal cell 
carcinoma. Urol Int, 2006. 76(3): p. 256-63.
27.
Karam, J.A., et al., Metastasectomy after targeted therapy in patients with advanced renal 
cell carcinoma. J Urol, 2011. 185(2): p. 439-44.
28.
Alt, A.L., et al., Survival after complete surgical resection of multiple metastases from renal 
cell carcinoma. Cancer, 2011. 117(13): p. 2873-82.
29.
Dabestani, S., et al., Local treatments for metastases of renal cell carcinoma: a systematic 
review. Lancet Oncol, 2014. 15(12): p. e549-61.

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30.
Daliani, D.D., et al., Prospective assessment of systemic therapy followed by surgical 
removal of metastases in selected patients with renal cell carcinoma. BJU Int, 2009. 
104(4): p. 456-60.
31.
Naito, S., et al., Prognostic factors of patients with metastatic renal cell carcinoma with 
removed metastases: a multicenter study of 556 patients. Urology, 2013. 82(4): p. 846-
51.
32.
Zaid, H.B., et al., Outcomes Following Complete Surgical Metastasectomy for Patients 
with Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. J Urol, 
2017. 197(1): p. 44-49.
33.
Rini, B.I., et al., The effect of sunitinib on primary renal cell carcinoma and facilitation of 
subsequent surgery. J Urol, 2012. 187(5): p. 1548-54.
34.
Rini, B.I., et al., A Phase II Study of Pazopanib in Patients with Localized Renal Cell 
Carcinoma to Optimize Preservation of Renal Parenchyma. J Urol, 2015. 194(2): p. 297-
303.
35.
Powles, T., et al., The outcome of patients treated with sunitinib prior to planned 
nephrectomy in metastatic clear cell renal cancer. Eur Urol, 2011. 60(3): p. 448-54.
36.
Powles, T., et al., Safety and Efficacy of Pazopanib Therapy Prior to Planned 
Nephrectomy in Metastatic Clear Cell Renal Cancer. JAMA Oncol, 2016. 2(10): p. 1303-
1309.
37.
Lala, M., et al., A six-weekly (Q6W) dosing schedule for pembrolizumab based on an 
exposure-response (E-R) evaluation using modeling and simulation. Journal of Clinical 
Oncology, 2018. 36(15_suppl): p. 3062-3062.
38.
McDermott, D.F., et al., A phase II study of atezolizumab (atezo) with or without 
bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma 
(mRCC) patients (pts). Journal of Clinical Oncology, 2017. 35(6_suppl): p. 431-431.

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11
Appendices
Appendix 1: Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance without 
restriction
90
Able to carry on normal activity; minor 
signs or symptoms of disease
80
Normal activity with effort; some signs 
or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
2
In bed < 50% of the time
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities
Up and about more than 50% of 
waking hours
50
Requires 
considerable 
assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours
30
Severely 
disabled, 
hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, 
fatal 
processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2: Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
1. Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 

Review of all participant data in safety lead-in phase

Approval to enroll past safety lead-in phase by DSMC Chair or Vice Chair

Semiannual auditing after safety lead-in phase

Review of serious adverse events

Minimum of biennial regulatory auditing
2. Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.
All institutional Phase II studies with a lead-in are designated with a high-risk assessment during 
the safety lead-in phase and a moderate risk assessment afterwards.  During the safety lead-in 
phase, the DSMC will audit all visits through the first cycle of treatment for all participants enrolled 
in this phase of the trial.
After the completion of enrollment in the safety lead-in phase, the Principal Investigator will submit 
a report to the DSMC Chair outlining all AEs, SAEs, and DLTs (as defined in the protocol) with a 
request to proceed onto the next phase of the study.  Within two business days of receipt, the 
DSMC Chair or designee will review the report and issue written authorization to proceed or a 
request for more information.  The report is then reviewed at the subsequent DSMC meeting.
After DSMC authorization to enroll beyond the safety lead-in phase is granted, study data is 
audited semiannually, with a random selection of twenty percent of the participants reviewed (or 
at least three participants if the calculated value is less than three).  The DSMC Monitor/Auditor 
will audit a maximum of 5 cycles of treatment in participants selected for review or until the 
selected participants discontinue study participation or the trial is closed with the IRB. The 
assigned DSMC Monitor/Auditor will review no more than 10 total participant charts during the 
course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the study team 
within 20 business days after the auditing visit is complete for the PI and the study team to resolve 
all action items from this report within 20 business days.  Additionally, a regulatory audit will occur 
on a biennial basis to review all regulatory documents for the trial.
3. Review and Oversight Requirements
3.1 Adverse Event Monitoring
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the investigational 

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agent(s) or study procedure, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System.
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment 
of attribution or relationship to the investigational agent(s) or study procedure.  Attribution 
categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.

Possible – The adverse event may be related to the investigational agent(s) or 
study procedure.

Unrelated – The adverse event is clearly not related to the investigational agent(s) 
or study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Coordinating Center’s Site Committee.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution assignment.
3.2 Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed 
above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event

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Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, All SAEs are reviewed and 
monitored by the DSMC on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE was sent to all required reporting agencies 
will be documented in OnCore®.
If an SAE involves death, and occurs during the treatment phase of the study or within 30 
days after the last administration of the study drug(s), and is determined to be possibly, 
probably, or definitely related either to the investigational drug or any research related 
procedure, then the event must be reported to the DSMC Chair (or Vice Chair) and DSMC 
Director within one business day.
3.3 Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Principal Investigator 
is responsible for notifying the DSMC via report at the time the increased rate is identified. 
The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator’s Brochure or package insert.
If at any time the Principal Investigator stops enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and DSMC Director must be notified within one 
business day.
Data and Safety Monitoring Committee Contacts:
Katie Kelley, MD (DSMC Chair)
UCSF HDFCCC
San Francisco, CA 94158
John McAdams (DSMC Director)
UCSF HDFCCC
San Francisco, CA 94143

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Appendix 3: The Clavien-Dindo Classification of Surgical Complications
Full Scale 
Contracted Form 
Grades 
Definition 
Grades
Definition
Any deviation from the normal 
postoperative course without 
the need for pharmacological 
treatment or surgical, 
endoscopic and radiological 
interventions. 
Grade  I: 
Allowed therapeutic regimens 
are: drugs as antiemetics, 
antipyretics, analgetics, 
diuretics and electrolytes and 
physiotherapy. This grade also 
includes wound infections 
opened at the bedside. 
Grade  I: 
Same as for Full Scale 
Grade  II: 
Requiring pharmacological 
treatment with drugs other than 
such allowed for grade I 
complications.
Blood transfusions and total 
parenteral nutrition are also 
included. 
Grade  II:
Same as for Full Scale 
Grade  III: 
Requiring surgical, endoscopic 
or radiological intervention 
    Grade III-a: 
intervention not under general 
anesthesia 
    Grade III-b: 
intervention under general 
anesthesia 
Grade  III: 
 
Grades IIIa & IIIb 
Grade IV: 
Life-threatening complication 
(including CNS complications)‡ 
requiring IC/ICU-management 
    Grade IV-a: 
single organ dysfunction 
(including dialysis) 
Grade IV: 
Grades IVa & IVb 

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    Grade IV-b: 
multi organ dysfunction 
Grade V: 
Death of a subject 
Grade V: 
Same as for Full Scale 
Suffix 'd': 
If the subjects suffers from a 
complication at the time of 
discharge, the suffix  “d”  (for 
‘disability’) is added to the 
respective grade of 
complication. This label 
indicates the need for a follow-
up to fully evaluate the 
complication.