Phase II Study of Pembrolizumab Plus Capecitabine and Bevacizumab in Microsatellite Stable Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Microsatellite Stable, Mismatch Repair Protein Proficient, Stage III Colorectal Cancer AJCC v7, Stage IIIB Colorectal Cancer AJCC v7, Stage IIIC Colorectal Cancer AJCC v7, Stage IV Colorectal Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
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.
Phase II Study of Pembrolizumab Plus Capecitabine and 
Bevacizumab in Microsatellite Stable Metastatic Colorectal 
Cancer
Protocol Number: CC #174517
Study Drug: Pembrolizumab
Version Number: 9.0
Version Date: 03-30-2021
NCT Number: NCT03396926
IND Number: Exempt
Principal Investigator (Sponsor-Investigator)
Chloe Atreya, MD PhD
University of California San Francisco (UCSF) 
San Francisco, CA 94143 
Statistician
Li Zhang, PhD 
Revision History
Version 1.0
10/20/2016
Version 4.3
06/05/2018
Version 2.0
04/10/2017
Version 5.0
11/27/2018
Version 3.0
04/30/2017
Version 6.0
09/12/2019
Version 4.0
06/22/2017
Version 7.0
10/24/2019
Version 4.1
09/20/2017
Version 8.0
11/02/2020
Version 4.2
10/31/2017
Version 9.0
03/30/2021

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-30-2021
Protocol CC#: 174517
Phase II -- Pembrolizumab
Page 1 of 102
PROTOCOL SIGNATURE PAGE
Protocol No.: 174517
Version Date: 03/30/2021
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 in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and 
welfare of study participants.
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 in accordance with Good Clinical Practices (ICH-GCP), the 
applicable ethical principles, the Statement of Investigator (Form FDA 1572), and 
with local regulatory requirements. In accordance with the FDA Modernization Act, 
I will ensure the registration of the trial on the www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with IRB 
policies, Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date

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Version date: 03-30-2021
Protocol CC#: 174517
Phase II -- Pembrolizumab
Page 2 of 102
TRIAL SUMMARY
Title
Phase II Study of Pembrolizumab Plus Capecitabine and 
Bevacizumab in Microsatellite Stable Metastatic Colorectal 
Cancer
Trial Phase
Phase II
Clinical Indication
Metastatic or locally advanced unresectable microsatellite 
stable or mismatch repair proficient colorectal cancer with 
stable disease or progression on fluoropyrimidine-based 
therapy 
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV) pembrolizumab & bevacizumab; oral 
capecitabine (PO)
Trial Blinding
Unblinded open-label
Treatment Groups
Single arm study: Pembrolizumab (MK-3475) 200 mg IV every 3 
weeks (Q3W) capecitabine 1000 mg/m2 PO BID on days 1-14 
Q3W and bevacizumab 7.5 mg/kg IV Q3W
Number of trial subjects
Approximately 44-56 subjects will be enrolled
Estimated enrollment 
period
Q3 2017 – Q1 2020
Estimated duration of trial
54 months: from the time the first subject signs the informed 
consent until the last subject’s last study-related phone call or 
visit.
Duration of Participation
24 months
Estimated average length 
of treatment per patient
8 cycles (24 weeks)

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LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
Area under the curve
BUN
Blood urea nitrogen
CBC
Complete blood cell (count)
CR
Complete response
CRC
Clinical Research Coordinator
CRC
Colorectal cancer
CRF
Case report form
CSF
Cerebral spinal fluid
CT
Computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DCR
Disease control rate
DFS
Disease-free survival
DLT
Dose limiting toxicity
DOR
Duration of response
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBeAg
Hepatitis B “e” antigen
HBV
Hepatitis B virus
HCT
Hematocrit
HCV
Hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
Hemoglobin
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonization
IND
Investigational new drug application
IP
Investigational product
IRB
Institutional Review Board
iwCLL
International Workshop on Chronic Lymphocytic Leukemia
IV
Intravenous
LDH
Lactate dehydrogenase
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities

UCSF Helen Diller Family Comprehensive Cancer Center
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Phase II -- Pembrolizumab
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MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
ORR
Overall Response Rate
OS
Overall Survival
PFS
Progression Free Survival
PD
Disease Progression
PK
Pharmacokinetics
PO
Per OS (by mouth, orally)
PR
Partial Response
PRC
Protocol Review Committee (UCSF)
QOL
Quality of Life
RBC
Red Blood Cell (count)
SAE
Serious Adverse Event
SD
Stable Disease
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
WBC
White Blood Cell (count)

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Phase II -- Pembrolizumab
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Table of Contents
TRIAL SUMMARY........................................................................................................................2
LIST OF ABBREVIATIONS..........................................................................................................3
Table of Contents.............................................................................................................................5
1
TRIAL DESIGN......................................................................................................................9
1.1
Trial Design.......................................................................................................................9
1.2
Trial Diagram..................................................................................................................11
2
OBJECTIVE(S) & HYPOTHESIS(ES) ................................................................................11
2.1
Primary Objective(s) & Hypothesis(es)..........................................................................11
2.2
Secondary Objectives & Hypotheses (phase II expansion cohort).................................12
2.3
Exploratory Objectives ...................................................................................................12
3
BACKGROUND & RATIONALE .......................................................................................13
3.1
Background on Indication...............................................................................................13
3.1.1
Colorectal Cancer ....................................................................................................13
3.2
Background on Compounds............................................................................................13
3.2.1
Pembrolizumab........................................................................................................13
3.2.2
Capecitabine ............................................................................................................15
3.2.3
Bevacizumab............................................................................................................15
3.2.4
Capecitabine Plus Bevacizumab in Colorectal Cancer............................................16
3.2.5
Trials of Pembrolizumab in Combination with Capecitabine .................................17
3.2.6
Trials of Pembrolizumab in Combination with Bevacizumab ................................17
3.3
Rationale .........................................................................................................................17
3.3.1
Rationale for the Trial and Selected Subject Population.........................................17
3.3.2
Rationale for Pembrolizumab in Combination with Capecitabine..........................18
3.3.3
Rationale for Pembrolizumab in Combination with Bevacizumab .........................18
3.3.4
Rationale for Combining Pembrolizumab with Capecitabine and Bevacizumab in 
Colorectal Cancer ..................................................................................................................18
3.3.5
Rationale for Dose Selection/Regimen/Modification for Pembrolizumab..............19
3.3.6
Rationale for Capecitabine and Bevacizumab Doses in Combination with 
Pembrolizumab......................................................................................................................20
3.3.6
Rationale for Endpoints ...........................................................................................20
4
METHODOLOGY ................................................................................................................22
4.1
Entry Criteria...................................................................................................................23

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4.1.1
Diagnosis/Condition for Entry into the Trial...........................................................23
4.1.2
Subject Inclusion Criteria ........................................................................................23
4.1.3
Subject Exclusion Criteria .......................................................................................24
4.2
Trial Treatments..............................................................................................................27
4.2.1
Dose Selection .........................................................................................................27
4.2.2
Timing of Dose Administration.................................................................................5
4.2.3
Trial Blinding/Masking .............................................................................................8
4.3
Randomization or Treatment Allocation...........................................................................8
4.4
Stratification......................................................................................................................8
4.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)....................................8
4.5.1
Acceptable Concomitant Medications.......................................................................8
4.5.2
Prohibited Concomitant Medications ........................................................................9
4.6
Rescue Medications & Supportive Care .........................................................................10
4.6.1
Supportive Care Guidelines for Pembrolizumab.....................................................10
4.7
Diet/Activity/Other Considerations ................................................................................14
4.7.1
Diet ..........................................................................................................................14
4.7.2
Contraception...........................................................................................................14
4.7.3
Use in Pregnancy .....................................................................................................16
4.7.4
Use in Nursing Women ...........................................................................................16
4.8
Subject Withdrawal/Discontinuation Criteria.................................................................16
4.8.1
Discontinuation of Study Therapy after CR ............................................................17
4.9
Subject Replacement Strategy ........................................................................................17
4.10
Clinical Criteria for Early Trial Termination..................................................................17
5
TRIAL PROCEDURES.........................................................................................................18
5.1
Trial Procedures ..............................................................................................................18
5.1
Study Calendar................................................................................................................19
5.1.1
Administrative Procedures.......................................................................................22
5.1.2
Clinical Procedures/Assessments ............................................................................23
5.1.3
Tumor Tissue Collection and Correlative Studies Blood Sampling........................27
5.1.4
Laboratory Procedures/Assessments .......................................................................28
5.1.5
Other Procedures .....................................................................................................30
5.1.6
Visit Requirements ..................................................................................................30

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5.2
Assessing and Recording Adverse Events......................................................................31
5.2.1
Definition of an Overdose for this Protocol and Reporting of Overdose to the 
Sponsor-Investigator and Merck............................................................................................32
5.2.2
Reporting of Pregnancy and Lactation to the Sponsor-Investigator and Merck .....33
5.2.3
Immediate Reporting of Adverse Events to the Sponsor-Investigator and Merck..33
5.2.4
Evaluating Adverse Events......................................................................................35
5.2.5
Sponsor-Investigator Responsibility for Reporting Adverse Events.......................40
6
STATISTICAL ANALYSIS PLAN......................................................................................40
6.1
Statistical Analysis Plan Summary .................................................................................40
6.2
Statistical Analysis Plan..................................................................................................40
6.3
Analysis Endpoints .........................................................................................................41
6.3.1
Efficacy Endpoints...................................................................................................41
6.4
Analysis Populations.......................................................................................................42
6.4.1
Efficacy Analysis Populations.................................................................................42
6.4.2
Safety Analysis Populations ....................................................................................43
6.5
Statistical Methods..........................................................................................................43
6.5.1
Statistical Methods for Efficacy Analyses...............................................................43
6.5.2
Statistical Methods for Safety Analyses..................................................................44
6.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses.........44
6.5.4
Analysis of Immunocorrelative Data.......................................................................44
6.5.5
Interim Analyses......................................................................................................45
6.5.6
Multiplicity ..............................................................................................................45
6.5.7
Sample Size and Power Calculations ......................................................................45
6.6
Subgroup Analyses and Effect of Baseline Factors........................................................45
6.6.1
Compliance (Medication Adherence)......................................................................45
6.6.2
Extent of Exposure ..................................................................................................46
7
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES......46
7.1
Pembrolizumab ...............................................................................................................46
7.1.1
Packaging and Labeling Information.......................................................................46
7.1.2
Clinical Supplies Disclosure....................................................................................46
7.1.3
Storage and Handling Requirements .......................................................................46
7.1.4
Returns and Reconciliation......................................................................................46
7.2
Bevacizumab...................................................................................................................47

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7.2.1
Form.........................................................................................................................47
7.2.2
Storage and Stability................................................................................................47
7.2.3
Preparation...............................................................................................................47
7.2.4
Administration .........................................................................................................47
7.2.5
Accountability..........................................................................................................47
7.3
Capecitabine....................................................................................................................47
7.3.1
Form.........................................................................................................................47
7.3.2
Storage and Stability................................................................................................47
7.3.3
Preparation...............................................................................................................47
7.3.4
Administration .........................................................................................................47
7.3.5
Accountability..........................................................................................................48
8
ADMINISTRATIVE AND REGULATORY DETAILS......................................................48
8.1
Pre-Study Documentation...............................................................................................48
8.2
Institutional Review Board Approval .............................................................................48
8.3
Informed Consent............................................................................................................48
8.4
Changes in the Protocol ..................................................................................................49
8.5
Handling and Documentation of Clinical Supplies.........................................................49
8.6
Case Report Forms (CRFs).............................................................................................49
8.7
Oversight and Monitoring Plan.......................................................................................50
8.8
Record Keeping and Record Retention...........................................................................50
9
REFERENCES ......................................................................................................................51
APPENDIX A: Data and Safety Monitoring Plan: Institutional (Single Site) Phase II Trial with 
Safety Lead-In Phase .....................................................................................................................55
APPENDIX B: ECOG Performance Status...................................................................................59
APPENDIX C: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..................60
APPENDIX D: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors...........................................................................................61
APPENDIX E: Response Evaluation by Immune-related RECISE (irRECIST) ..........................62
APPENDIX F: Immunocorrelative Biomarker Specimen Guidance ............................................64

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1
TRIAL DESIGN
1.1
Trial Design
This is a single-arm, open-label; single-site trial of pembrolizumab, capecitabine, and 
bevacizumab in previously treated subjects who have locally advanced unresectable or metastatic 
(Stage IV) microsatellite stable (MSS) colorectal carcinoma (CRC) who experienced stable 
disease or progression on fluoropyrimidine-based therapy, either 5-fluorouracil (5-FU) or 
capecitabine. Subjects who have withdrawn from standard treatment due to unacceptable toxicity 
from an agent other than 5-FU, capecitabine, or bevacizumab or warranting discontinuation of 
that treatment and precluding retreatment with the same agent before progression of disease will 
also be eligible. Regimens given with adjuvant intent will be counted as treatment for metastatic 
disease if the patient’s disease had progressed within 6 months following treatment. Subjects 
with MSS or mismatch repair proficient (pMMR) CRC are eligible to enroll. Subjects will be 
required to have at least one measurable lesion by Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) for response assessment, and have been previously treated with approved standard 
therapies, which must include a fluoropyrimidine with or without bevacizumab.  Subjects 
enrolled in the phase II must have a lesion that is safely accessible for biopsy.
Initially, a safety lead-in will be conducted because pembrolizumab has not been previously 
administered with both capecitabine and bevacizumab.  Phase II doses for pembrolizumab plus 
capecitabine and pembrolizumab plus bevacizumab are available; capecitabine plus bevacizumab 
is a standard of care regimen for metastatic colorectal cancer.  The adverse event profiles of 
pembrolizumab, capecitabine, and bevacizumab do not appear to interact, thus the three agents 
are anticipated to be tolerable when administered together at standard dose levels.  In the safety 
lead-in, 3 subjects will be treated with full-dose pembrolizumab (200 mg IV q21 days), 
bevacizumab (7.5 mg/kg IV q21 days), and capecitabine (1000 mg/m2 PO BID on days 1-14) for 
1 cycle (3 weeks) prior to enrolling additional patients.  If 0-1 patients experience an unexpected 
dose-limiting toxicity (DLT), 3 additional patients will be enrolled, treated at full dose, and 
followed for 3 weeks before enrolling additional patients.  If two or more of the first 6 patients 
experience a DLT, then the capecitabine dose will be reduced.
The safety lead-in will determine the recommended phase II dose (RP2D)/maximum tolerated 
dose (MTD) of capecitabine administered with pembrolizumab and bevacizumab.
Approximately 44-56 subjects will be allocated in this study to receive pembrolizumab with 
capecitabine and bevacizumab.  Patients in the safety lead-in cohort treated at MTD will be 
included in the phase II study. Following the safety lead-in, all subjects enrolled in the phase II 
study prior to the interim analysis will undergo a tumor biopsy prior to the start of treatment. 
Patients with an evaluable pre-treatment biopsy, and in whom repeat biopsy is feasible and not 
associated with excessively high procedural risk, will undergo a second biopsy at mid-cycle 1 
(day 10-14). In order to avoid bleeding complications from the biopsy, cycle 1 will be 
administered without bevacizumab. After interim analysis, if the total number of biopsies already 
performed is <46, additional pre-treatment (but not on-treatment) biopsies will be required in 
post interim analysis patients until the total number of tumor biopsies performed reaches 46.  
Post interim analysis, bevacizumab will be administered starting at cycle 1. 

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The primary objective of this trial is to determine the overall response rate (ORR) of 
pembrolizumab given with capecitabine and bevacizumab versus the appropriate historical 
controls among patients with metastatic CRC and stable (SD) or progressive disease (PD) on 
prior fluoropyrimidine-based therapy with or without bevacizumab.  Secondary objectives 
include safety and tolerability, duration of response (DOR), disease control rate (DCR), 
progression-free survival (PFS), and overall survival (OS). Beginning with screening, all 
imaging assessments will be evaluated using RECIST 1.1 for determining eligibility and 
assessment of response.  On study imaging assessments will be performed every 9 weeks (Q9W), 
calculated from the first dose and independent of treatment delays.  RECIST 1.1 will be used by 
the site for treatment decisions until first radiologic evidence of PD. Following the first evidence 
of radiologic PD, treatment decisions may be made by the adaption of RECIST 1.1 as described 
in Section 11.5, termed immune-related RECIST (irRECIST) to accommodate for the tumor 
response patterns seen with pembrolizumab treatment (e.g., tumor flare).  For a clinically stable 
subject with first radiologic evidence of PD, it is at the discretion of the site investigator to 
continue treating the subject with pembrolizumab, capecitabine, and bevacizumab, until PD is 
confirmed at least 4 weeks from the date of the first tumor imaging suggesting PD.  If radiologic 
PD is confirmed by the subsequent tumor imaging the subject should be discontinued from 
treatment unless, in the opinion of the investigator, the subject is achieving a clinically 
meaningful benefit; an exception to continue treatment may be considered following consultation 
with the Principal Investigator.
Subjects will continue to be treated with pembrolizumab, capecitabine, and bevacizumab until 
progressive disease, unacceptable toxicity, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, 
administrative reasons, or until the subject has received 35 trial treatments (approx. 2 years) with 
pembrolizumab.  Subjects who discontinue treatment for reasons other than progressive disease 
will have post-treatment follow-up visits for disease status until disease progression, initiation of 
a non-study cancer treatment, withdrawal of consent, or loss of subject to follow-up. All subjects 
will be followed for survival until death, withdrawal of consent, or the end of the study, 
whichever comes first.
Subjects who attain a confirmed complete response (assessed by the site) by 2 tumor imaging 
assessments at least 4 weeks apart, and who have received at least 8 treatments (approximately 6 
months) with pembrolizumab, may discontinue treatment at the discretion of the investigator 
after receiving at least 2 treatments beyond the initial determination of a CR.
Adverse events (AE) will be monitored throughout the trial and graded in severity according to 
the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 (Section 7.2.4). After the end of treatment, each subject 
will be followed for 30 days for AE monitoring. Serious adverse events (SAEs) and events of 
clinical interest (ECIs) will be collected for 90 days after the end of treatment or 30 days after 
last dose of trial treatment if the subject initiates new anticancer therapy, whichever is earlier.

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Phase II -- Pembrolizumab
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There is one interim analysis planned in this study after 29 patients have been accrued at the 
MTD/RP2D.  If there are 1 or fewer responses in these 29 patients, the study will be stopped. 
Otherwise, 15 additional patients will be accrued. See Section 8.2 for details about the timing 
and purpose of the interim analysis.  Enrollment will not be paused when interim analysis is 
conducted.  Results will be reviewed by study team.
This study will be conducted in conformance with Good Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart – Section 6.1. Details of each 
procedure are provided in Section 7.0– Trial Procedures.
1.2
Trial Diagram
Key Eligibility
-
Unresectable/metastatic 
colorectal adenocarcinoma
-
Microsatellite stable
-
Prior 5-FU/capecitabine
-
Measurable disease
-
ECOG 0/1
Pembrolizumab 200 mg IV Q3W 
Capecitabine at MTD/RP2D 
Bevacizumab 7.5 mg/kg IV Q3W 
N=44
Includes 6 pts treated at MTD/RP2D
-
Imaging Q9 weeks
Interim analysis after 29 pts accrued 
Pre-interim analysis:
-
Biopsies pre-tx and D14
-
Cycle 1 without bevacizumab 
Post-interim analysis:
-
Biopsies pre-tx (46 biopsies total)
-
Cycle 1 with bevacizumab
Dose Level 0
Pembrolizumab 200 mg IV Q3W 
Capecitabine 1000 mg/m2 bid, D1-14 
Bevacizumab 7.5 mg/kg IV Q3W
Phase II 
Study
Dose Level -1
Pembrolizumab 200 mg IV Q3W 
Capecitabine 800 mg/m2 bid, D1-14 
Bevacizumab 7.5 mg/kg IV Q3W
Dose Level -2
Pembrolizumab 200 mg IV Q3W 
Capecitabine 600 mg/m2 bid, D1-14 
Bevacizumab 7.5 mg/kg IV Q3W
Safety Lead-In
If ≤1/ 6 DLT
If >1/ 6 DLT
If ≤1/ 6 DLT
If >1/ 6 DLT
If ≤1/ 6 DLT
If >1/ 6 DLT
Discontinue Capecitabine
2
OBJECTIVE(S) & HYPOTHESIS(ES)
2.1
Primary Objective(s) & Hypothesis(es)
(1)
Objective of the safety lead-in cohort: To determine the RP2D/MTD of 
capecitabine when administered with pembrolizumab and bevacizumab.
(2)
Objective of the phase II expansion cohort: to evaluate the overall response rate 
(ORR) to pembrolizumab plus capecitabine and bevacizumab (complete or partial 
response rate per RECIST 1.1) in subjects with metastatic or locally advanced 
unresectable MSS/pMMR CRC that is stable or progressing on 5FU-based therapy.

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Hypothesis: The ORR based on RECIST 1.1 in subjects with locally advanced 
unresectable or metastatic MSS/pMMR CRC is at least 15%.
2.2
Secondary Objectives & Hypotheses (phase II expansion cohort)
In subjects with metastatic or locally advanced unresectable MSS/pMMR CRC treated with 
pembrolizumab, capecitabine, and bevacizumab:
(1)
To determine the safety and tolerability of pembrolizumab in combination with 
capecitabine and bevacizumab.
(2)
To evaluate ORR per irRECIST.
(3)
To evaluate duration of response (DOR), disease control rate (DCR), and 
progression-free survival (PFS) per RECIST 1.1 and irRECIST and overall survival 
(OS).
2.3
Exploratory Objectives
(1)
Correlation of outcomes to line of therapy; stable disease or progression on a prior 
regimen containing infusional 5-FU or capecitabine; prior exposure to bevacizumab; 
primary tumor location; and on-study administration of bevacizumab starting in cycle 
1 or cycle 2
(2)
To explore baseline immune profiles via PD-L1, and multiplex IHC 
(immunohistochemistry) for identification of potentially predictive biomarkers in 
patients with metastatic or locally advanced, unresectable CRC treated with 
pembrolizumab-based combination therapy.
(3)
To characterize the change in the populations of tumor-infiltrating immune cells 
(TIICs) by IHC induced by pembrolizumab-based combination therapy in paired pre- 
and on-treatment tumor biopsies from patients with metastatic or locally advanced, 
unresectable MSS/pMMR CRC.
Hypothesis: We hypothesize that combination of chemotherapy plus immunotherapy 
will induce increased populations of TIICs within CRC patient samples and will be 
associated with objective responses.
(4)
To determine the change in T cell repertoire via next-generation sequencing (NGS) 
within blood and tumor biopsy samples induced by pembrolizumab-based 
combination therapy in patients with metastatic or locally advanced, unresectable 
MSS/pMMR CRC.
(5)
To establish human immune system (HIS) patient-derived xenograft (PDX) models 
from pre-treatment biopsies to a) analyze change in immune cell profiles HIS PDX 
models using the same techniques as described for corresponding patients, above and 
b) correlate response to pembrolizumab-containing therapy in patients and HIS PDX

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Phase II -- Pembrolizumab
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3
BACKGROUND & RATIONALE
3.1
Background on Indication
3.1.1
Colorectal Cancer
Colorectal cancer (CRC) is a major global public health problem. Approximately 1 in 20 
Americans will be diagnosed with CRC in their lifetime.   Metastatic CRC is the second leading 
cause of cancer death in the U.S., with over 50,000 deaths attributed to this disease each year. 
The 5-year survival rate is only 13% for patients with distant metastases1. Chemotherapy is the 
mainstay of treatment for patients with metastatic CRC. The backbone of therapy for nearly 40 
years has been the fluoropyrimidine, 5-fluorouracil (5-FU).
Capecitabine, the orally administered pro-drug of 5-FU is now also an FDA approved therapy. 
The most broadly used FDA approved biologic agent is bevacizumab, an antibody that binds 
vascular endothelial growth factor (VEGF), thereby preventing the interaction of VEGF and its 
receptors and inhibiting angiogenesis. With the addition of biologics to chemotherapy, the 
median overall survival of patients with metastatic CRC has increased to about 2.5 years 2,3.  
Nonetheless, there remains a significant unmet need for new agents which may both extend 
survival and maintain quality of life among patients receiving long-term therapy. The need is 
particularly great for the 96% of patients with MSS/pMMR metastatic CRC, whose cancers do 
not respond to pembrolizumab monotherapy 4. As detailed below, there is evidence of immune-
stimulatory effects induced by both capecitabine and bevacizumab, which we hypothesize will 
promote tumor response following the addition of pembrolizumab in MSS/pMMR metastatic 
CRC.
3.2
Background on Compounds
3.2.1
Pembrolizumab
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475.
3.2.1.1 Pharmaceutical and Therapeutic Background on Pembrolizumab
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 

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Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM), and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70 
which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down 
modulates T- cell responses is similar to but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs, and Natural Killer 
cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors. Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non- hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD- 
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United States 
for the treatment of patients with unresectable or metastatic melanoma, first- and second-line 
non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and 
relapsed/refractory Hodgkin’s disease.
3.2.1.2 Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for detailed Preclinical and Clinical data.
Clinical Trials Testing Pembrolizumab in Colorectal Cancer
Immune checkpoint inhibitors such as pembrolizumab have shown robust single-agent antitumor 
activity in the ~4% of patients with metastatic CRCs harboring microsatellite instability (MSI- 
high) or mismatch repair deficiency (dMMR). Preliminary reporting indicated an (immune-
related) objective response rate of 40% (4 of 10 patients).  On the other hand, 0% (0 of 18 
patients) with MSS or pMMR metastatic CRCs achieved an objective response 
(NCT01876511)4. As a result, additional studies are underway for patients with metastatic CRC 

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and MSI-high or dMMR to test pembrolizumab monotherapy in the previously-treated with 
chemotherapy setting (KEYNOTE-164; NCT02460198)5 or pembrolizumab vs. standard 
chemotherapy in the first-line setting (KEYNOTE-177; NCT02563002)6.  Pembrolizumab has 
been added to the 2017 National Comprehensive Cancer Network guidelines for treatment of 
dMMR/MSI-high metastatic CRC.
Identification of new strategies to augment immune-related responses in the broader population 
of metastatic CRC patients, without dMMR or MSI-high tumors, is essential7.  A recent Phase 1b 
study of the anti-PD-L1 antibody, atezolizumab, plus the MEK inhibitor, cobimetinib, found an 
overall response rate (ORR) of 17% (4 PR) in 23 patients with metastatic CRC 
(NCT01988896)8. Because neither atezolizumab nor cobimetinib-alone would be expected to 
induce responses in patients with MSS CRC, this study represents proof-of-concept that 
combining immunotherapy with other therapies can induce responses. Preclinical data suggest 
that pembrolizumab may combine effectively with an approved regimen for metastatic CRC, 
capecitabine plus bevacizumab (NCCN Guidelines V.2.2016).  As discussed below, the 
combinations of pembrolizumab plus capecitabine and pembrolizumab plus bevacizumab have 
already been evaluated in other disease settings; phase II doses are available, and no unexpected 
toxicities have been observed.  Like pembrolizumab, capecitabine plus bevacizumab is a regimen 
with a 3-week cycle, so if effective, pembrolizumab in combination with capecitabine and 
bevacizumab would be a convenient regimen for patients that would avoid additional infusion 
center visits.
3.2.2
Capecitabine
Capecitabine is classified as an antineoplastic agent, antimetabolite (pyrimidine analog). 
Capecitabine is an oral pro-drug of 5-FU: it undergoes hydrolysis in the liver and tissues to the 
active moiety, 5-FU.  In turn, 5-FU is a fluorinated pyrimidine antimetabolite that inhibits 
thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, which 
interferes with DNA, and to a lesser degree, RNA synthesis.  5-FU appears to act specifically at 
the G1 and S phases of the cell cycle.
Capecitabine is available as 150 and 500 mg tablets and should be taken orally with water within 
30 minutes of meals to improve absorption.  Capecitabine is commercially available and FDA 
approved for patients with metastatic CRC in contexts where fluoropyrimidine therapy is 
indicated, based on non-inferiority of capecitabine to 5-FU and leucovorin (5-FU/LV) in the 
adjuvant setting. Refer to the package insert for more detailed information on capecitabine.
3.2.3
Bevacizumab
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active 
isoforms of human VEGF (or VEGF-A) with high affinity (kd = 1.1 nM).  The antibody consists 
of a human IgG1 framework and the antigen-binding complementarity-determining regions from 
the murine anti-VEGF MAb A.4.6.1.16-18.  Bevacizumab is commercially available, and FDA 
approved for patients with metastatic CRC, including in combination with 5-FU and following 
progression on a prior bevacizumab-containing regimen.  Refer to the package insert for more 
detailed information on bevacizumab.

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3.2.4
Capecitabine Plus Bevacizumab in Colorectal Cancer
Capecitabine entered the National Comprehensive Cancer Network (NCCN) colon cancer 
guidelines via a study showing at least equivalent disease control as compared to IV 
5FU/leucovorin (NCCN Guidelines V.2.2016)9. Bevacizumab plus fluoropyrimidine-based 
regimens has been the subject of several prospective and observational studies10-16. Combined 
analysis of three independent multicenter randomized trials of patients with previously untreated 
metastatic CRC compared efficacy of the 5-FU/leucovorin (LV) or Irinotecan/5-FU/LV (IFL) 
regimens (control) vs. 5-FU/LV plus bevacizumab.  Addition of bevacizumab was found to 
improve response rate in the first-line setting (34.1% v 24.5%; P .019), together with improved 
median PFS and OS10-12. Response rates were similar with or without the addition of 
bevacizumab to first-line oxaliplatin-based chemotherapy regimens (5-FU/leucovorin or 
capecitabine plus oxaliplatin), although PFS was significantly improved with addition of 
bevacizumab13.  Among patients previously treated with a fluoropyrimidine plus irinotecan, 
ORR for FOLFOX4+bevacizumab, FOLFOX4, or bevacizumab alone were 22.7%, 8.6%, and 
3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison)14.  
The Bevacizumab Regimens: Investigation of Treatment Effects and Safety (BRiTE) study and 
the subsequent ML18147 trial found that continuing bevacizumab beyond first progression is 
associated with improved overall survival in metastatic CRC15,17. Among patients with advanced 
CRC that had progressed after irinotecan- and oxaliplatin-based chemotherapy, the response rate 
to bevacizumab plus 5-FU/LV was 1%16.
Capecitabine plus bevacizumab became a standard of care regimen following the European 
Bevacizumab Expanded Access Trial (BEAT), showing safety and improved survival with 
addition of bevacizumab to first-line FOLFOX, XELOX, FOLFIRI, and fluoropyrimidines 
(NCCN Guidelines V.2.2016)18 showing that the efficacy and safety of bevacizumab in routine 
clinical was similar to that in prospective randomized clinical trials.  In the Avastin in the Elderly 
with Xeloda (AVEX), patients 70 years or older with previously untreated, unresectable 
metastatic CRC who were not candidates for oxaliplatin or irinotecan-based regimens, were 
randomized to receive capecitabine (1000 mg/m2 twice daily on days 1-14 of a 21-day cycle) or 
capecitabine plus bevacizumab (7.5 mg/kg every 21 days), with tumor assessments every 9 
weeks.  The combination of capecitabine plus bevacizumab was well-tolerated and resulted in 
significantly longer progression-free survival.  Of note, the ORR in this first-line setting was 
19% in the capecitabine plus bevacizumab group vs. 10% in patients with capecitabine 
monotherapy (p=0·04)19.
Capecitabine plus bevacizumab is also used as a maintenance strategy after 5FU-based induction 
therapy20. Maintenance capecitabine plus bevacizumab resulted in a longer time to second 
progression and global quality of life was reportedly not compromised by maintenance therapy, 
although 23% of patients developed hand-foot syndrome. Subsequent fluoropyrimidine plus 
bevacizumab or bevacizumab alone maintenance studies have also found increased time to 
progression as compared to no treatment21,22. As above, the NCCN recommended dosing of 
capecitabine and bevacizumab in colorectal cancer is capecitabine 850-1250 mg/m2 PO twice 
daily on days 1-14 of a 21-day cycle, and bevacizumab 7.5 mg/kg every 21 days (NCCN 
Guidelines V.2.2016).

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3.2.5
Trials of Pembrolizumab in Combination with Capecitabine
Pembrolizumab plus capecitabine is being studied in a number of cancers including rectal cancer 
with radiation (NCT02586610), breast cancer (NCT02734290), and gastric or gastroesophageal 
junction (GEJ) adenocarcinomas (KEYNOTE-059, NCT02335411; and KEYNOTE-062, 
NCT02494583)23,24.  No dose-reduction was required in determination of the RP2D of 
capecitabine in combination with pembrolizumab. The dose of capecitabine used in the phase II 
and phase III gastric and GEJ studies, in combination with pembrolizumab (200 mg IV, every 3 
weeks) is 1000 mg/m2 twice daily on days 1-14 of each 3-week cycle.  This capecitabine dose is 
consistent with the recommended dose of capecitabine in combination with bevacizumab for 
patients with metastatic colorectal cancer (850-1250 mg/m2 twice daily on days 1-14 of each 3-
week cycle).
3.2.6
Trials of Pembrolizumab in Combination with Bevacizumab
Pembrolizumab plus bevacizumab is being tested in other cancers including renal cell carcinoma 
(NCT01633970; NCT02348008)25,26, glioblastoma (NCT02337491)27, melanoma, and non-small 
cell lung cancer (NCT02681549).  The combination of pembrolizumab and bevacizumab has 
been well-tolerated, without unexpected side-effects or dose-limiting toxicities. The RP2D dose 
of bevacizumab in combination with pembrolizumab (200 mg IV every 3 weeks) is 15 mg/kg 
every 3 weeks (renal cell carcinoma) or 10 mg/kg every 2 weeks (glioma).  Both of these 
bevacizumab doses exceed the recommended dose of bevacizumab in combination with 
capecitabine for patients with metastatic colorectal cancer: 7.5 mg/kg every 3 weeks. 
Combination of the anti-PD- L1 antibody, atezolizumab, with bevacizumab was found to be safe 
in patients with MSI-high metastatic CRC28. In untreated metastatic renal cell carcinoma, 
atezolizumab plus bevacizumab resulted in higher PFS and ORR compared to atezolizumab 
alone or sunitinib29.
3.3
Rationale
3.3.1
Rationale for the Trial and Selected Subject Population
Metastatic CRC is the second leading cause of cancer death in the U.S., accounting for over 
50,000 deaths each year.  Approximately 96% of patients with metastatic CRC have 
MSS/pMMR disease and are in need of new therapies with manageable side-effects which can 
produce durable treatment responses, as has been observed with pembrolizumab monotherapy in 
patients with dMMR CRC1.  First and second-line standard of care regimens for metastatic CRC 
are FOLFOX and FOLFIRI with or without a biologic agent (bevacizumab or, if RAS wild-type, 
an EGFR- targeted antibody). Patients may be treated to disease progression with FOLFOX and 
FOLFIRI or, due to toxicities, patients may be treated to disease stabilization and then switched 
to a maintenance regimen, commonly capecitabine plus bevacizumab. Recently FDA-approved 
third-line therapies are regorafenib and TAS-102. Regorafenib was approved based on a median 
OS of 6.4 months compared to 5 months with placebo and is associated with a median PFS of 2 
months and ORR of 1% 30. TAS-102 was approved based on a median OS of 7.1 months, vs. 5.3 
months with placebo; with a median PFS of 2 months and OOR of 1.6%31.
As above, capecitabine plus bevacizumab is a standard of care regimen for patients with 
metastatic or locally advanced, unresectable CRC, typically administered after disease 

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stabilization on a 5FU-based regimen. The RR for capecitabine plus bevacizumab in this 
maintenance setting, or following progression on a 5FU-based regimen, is estimated to be 4% or 
less14,16.
Pembrolizumab alone is not anticipated to produce responses in patients with MSS/pMMR 
metastatic CRC1.  Due to immune-stimulatory effects induced by both capecitabine and 
bevacizumab, we hypothesize that addition of pembrolizumab will effectively promote tumor 
shrinkage. An ORR of 15% is targeted as a clinically meaningful benefit following disease 
stabilization or progression on 5-FU-based therapy and is comparable to the ORR of 17% 
reported with atezolizumab plus cobimetinib in a similar patient population8. Subjects with MSS 
or pMMR metastatic or locally advanced, unresectable CRC will be included in this study.
3.3.2
Rationale for Pembrolizumab in Combination with Capecitabine
In preclinical models, 5FU depletes myeloid-derived suppressor cells (immature myeloid cells 
with intratumoral systemic and immunosuppressive functions) and has immunostimulatory 
effects32-34.  Direct immune-stimulatory effects are attributed to increased levels of tumor-
associated macrophages, reprogrammed toward an immune-stimulatory phenotype, and 
increased tumor infiltration by regulatory T cells35.  A related nucleoside analog, gemcitabine 
(not used in CRC), also increases antigenicity by stimulating the expression of MHC class I 
molecules by tumor cells36.  Gemcitabine upregulated immune-specific genes and improved anti-
tumor activity of pembrolizumab in mouse models37.
3.3.3
Rationale for Pembrolizumab in Combination with Bevacizumab
Growing data demonstrate that VEGF contributes significantly to the immunosuppressive ability 
of tumors38-40. Specifically, VEGF can inhibit dendritic cell maturation and antigen presentation, 
induce apoptosis of CD8+ T cells, enhance Treg activity, and diminish T cells infiltration into 
tumor deposits 40-45,46. Preclinical and emerging clinical data suggest that anti-VEGF therapies 
may enhance effectiveness of immunotherapy 25,40-44,47-53. The rationale underlying the 
combination of immunotherapy approaches with anti-angiogenic agents is based on the ability of 
VEGF inhibition to diminish immunosuppressive features of tumors 39-44,51-53, and enhance the 
anti-tumor activity of immunotherapies48,50-53. Moreover, preclinical strategies to normalize 
tumor vasculature, including administration of anti-VEGF therapy, can shift tumor-associated 
macrophages from immune-inhibitory M2-like phenotype toward an immune-stimulatory M1- 
phenotype, increase tumor-infiltrating CD8+ T cells and enhance survival following whole tumor 
cell vaccination49. A recently published phase I study found that administration of bevacizumab 
with ipilimumab, an inhibitor of the CTLA-4 immune checkpoint, led to improved overall 
survival and evidence of increased immune cell trafficking into tumor deposits in patients with 
metastatic melanoma47.
3.3.4
Rationale for Combining Pembrolizumab with Capecitabine and Bevacizumab in 
Colorectal Cancer
Approximately 95% of individuals with metastatic CRC have MSS/pMMR tumors, which are 
unlikely to respond to pembrolizumab monotherapy4.  New therapies to improve survival and 
maintain quality of life for this sizeable patient population are urgently needed7. As discussed 
above, capecitabine plus bevacizumab is an approved regimen for metastatic CRC. There is 

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preclinical rationale for combining pembrolizumab with capecitabine and pembrolizumab with 
bevacizumab; phase II doses for each doublet are available. Due to non-overlapping toxicities, 
triplet therapy with pembrolizumab, capecitabine, and bevacizumab is expected to be well- 
tolerated.  Patients with MSS/pMMR tumors and stable disease or progression on 5-FU-based 
therapies are not expected to achieve tumor response with pembrolizumab monotherapy4 or with 
capecitabine plus bevacizumab.  Tumor responses with triplet therapy (pembrolizumab plus 
capecitabine and bevacizumab) would thus represent a significant advance, as would increased 
duration of disease control.  Like pembrolizumab, capecitabine plus bevacizumab is 
administered on a 3-week cycle, making this a convenient regimen for patients.
3.3.5
Rationale for Dose Selection/Regimen/Modification for Pembrolizumab
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single-agent MK-3475. The dose-escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated, and no dose-limiting toxicities 
were observed.  This first in-human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg, and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in 
PN001, will be the dose and schedule utilized in Cohorts A, B, C, and D of this protocol to test 
for initial tumor activity.  Recent data from other clinical studies within the MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provide scientific rationale for testing a Q2W and Q3W dosing 
schedule.
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients.  Within the resulting population PK model, clearance, and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both bodyweight normalized dosing or a fixed-dose across all body 
weights.  MK-3475 has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed-dose regimen relative to a 2 mg/kg 
Q3W bodyweight-based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure.  In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings.

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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that is 
well-tolerated and safe.
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.
3.3.6
Rationale for Capecitabine and Bevacizumab Doses in Combination with 
Pembrolizumab
The recommended dosing of capecitabine in combination with bevacizumab for metastatic CRC 
is capecitabine 850-1250 mg/m2 PO twice daily on days 1-14 of a 21-day cycle (NCCN 
Guidelines V.2.2016).  The RPD2 dose of capecitabine in combination with pembrolizumab in 
gastric and GEJ tumors (with cisplatin) is 1000 mg/m2 PO twice daily on days 1-14 of a 21-day 
cycle. Therefore, 1000 mg/m2 PO twice daily on days 1-14 of a 21-day cycle will be the starting 
dose of capecitabine in combination with pembrolizumab and capecitabine.  Capecitabine dose 
reduction recommendations are provided in the event that DLTs are observed in the safety lead-
in.
Bevacizumab is FDA approved in metastatic CRC for dosing at 7.5 mg/kg every 3 weeks in 
combination with fluoropyrimidine-based chemotherapy, including in patients who have 
progressed on a first-line bevacizumab-containing regimen. The standard CRC dose is lower 
than the RP2D of bevacizumab in combination with pembrolizumab, 15 mg/kg every 3 weeks in 
renal cell carcinoma, so a dose of 7.5 mg/kg will be administered in combination with 
pembrolizumab and bevacizumab.  There is no role for bevacizumab dose reduction, however, 
criteria for holding or discontinuing bevacizumab are provided.
3.3.6
Rationale for Endpoints
3.3.6.1 Efficacy Endpoints
3.3.6.1.1
Primary Endpoint
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in combination with capecitabine and bevacizumab in subjects with locally 

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advanced unresectable or metastatic (Stage IV) CRC.  Overall response rate (ORR) will be used 
as the primary endpoint per RECIST 1.1.
3.3.6.1.2
Secondary Endpoints
The secondary efficacy objectives of this study are to evaluate the endpoints ORR per irRECIST 
and DOR, DCR, PFS per RECIST 1.1 and irRECIST, and OS in subjects with locally advanced 
unresectable or metastatic (Stage IV) CRC.
3.3.6.2 Safety Endpoints
An important secondary objective of this study is to characterize the safety and tolerability of 
pembrolizumab when administered with capecitabine and bevacizumab among subjects with 
locally advanced unresectable or metastatic (Stage IV) CRC. The safety analysis will be based 
on subjects who experience toxicities as defined by CTCAE 4.0 criteria.  Safety will be assessed 
by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab with capecitabine and bevacizumab, including serious adverse events (SAEs) 
and events of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to all 
AEs, SAEs, and fatal AEs.  Furthermore, specific immune-related adverse events (irAEs) will be 
collected and designated as immune-related events of clinical interest (ECIs) as described in 
Section 7.2.3.2.
3.3.6.3 Correlative Studies Background
Correlative science to inform optimal use of pembrolizumab with capecitabine and bevacizumab 
in the patients with metastatic or locally advanced unresectable CRC and to identify candidate 
biomarkers of response, resistance or toxicity, is an integral part of this study. Correlative 
research will be performed on archival tumor samples (when available), paired baseline and on-
treatment (prior to cycle 2) tumor biopsies, as well as serial blood samples (baseline, on-
treatment, and at progression or treatment discontinuation). Goals of the correlative research 
include baseline profiling of PD-L1 and other potentially predictive biomarkers via IHC; 
characterization of change tumor-infiltrating immune cells via IHC following treatment with 
pembrolizumab plus chemotherapy; characterization of treatment-associated changes in T cell 
repertoire via NGS, and establishment of human immune system patient-derived xenografts.
After study initiation, molecular correlates of response to atezolizumab alone or in combination 
with bevacizumab in renal cell carcinoma was published in Nature Medicine29.  It was observed 
that myeloid inflammatory gene expression signatures were strongly associated with PFS: 
patients with TeffHigh/MyeloidHigh tumors experienced significantly longer PFS if they received 
atezolizumab plus bevacizumab as compared atezolizumab or sunitinib alone. This offers a 
mechanistic explanation for how blocking VEGF may overcome resistance to immune 
checkpoint blockade.  We hypothesize that high expression of myeloid inflammation-associated 
genes may contribute to resistance to pembrolizumab monotherapy in MSS/pMMR CRC, and 
that administration of bevacizumab in Cycle 1 of combination therapy with pembrolizumab + 

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capecitabine may be essential to overcome resistance to checkpoint inhibitor immunotherapy. In 
order to explore the hypothesis that efficacy may depend on the schedule of bevacizumab, blood-
based biomarkers, and clinical outcomes in patients who do or do not receive bevacizumab in 
Cycle 1 will be compared. 
3.3.6.4 Future Biomedical Research
The investigators will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial. This research may include flow cytometry, genetic 
analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma), 
characterization of circulating cell-free DNA, and/or the measurement of other analytes. Such 
research is for biomarker testing to address emergent questions not described elsewhere in the 
protocol (as part of the main trial) and will only be conducted on specimens from appropriately 
consented subjects. The objective of collecting specimens for Future Biomedical Research 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 and/or to ensure that subjects receive the correct dose of the correct drug at the 
correct time.
The following specimens could be obtained as part of Future Biomedical Research:

DNA for future research.

Leftover tumor for future research

Leftover DNA and RNA from Correlative Studies

Leftover plasma and serum from Biomarker Studies

Leftover PBMC from whole blood from correlative studies
3.3.6.4.1
Withdrawal from Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their specimens 
and all derivatives destroyed. Subjects may withdraw consent at any time by contacting the 
principal investigator for the main trial. Subsequently, the subject's specimens will be removed 
from the biorepository and be destroyed. A letter will be sent from a responsible party of the 
biorepository to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction. Any analyses in progress at the 
time of request for destruction or already performed prior to the request being received by the 
Sponsor will continue to be used as part of the overall research trial data and results. No new 
analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or the 
specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens. In this situation, the request for specimen 
destruction cannot be processed.
4
METHODOLOGY

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4.1
Entry Criteria
4.1.1
Diagnosis/Condition for Entry into the Trial
Locally advanced unresectable or metastatic (stage IV) colorectal adenocarcinoma.
4.1.2
Subject Inclusion Criteria
1. Have histologically confirmed, locally advanced unresectable or metastatic (stage IV) 
colorectal adenocarcinoma
2. Have locally confirmed MSS or pMMR CRC. MSS is defined as 0-1 allelic shifts among 
3- 5 tumor microsatellite loci using a PCR-based assay. pMMR is defined as presence of 
protein expression of 4 MMR enzymes (MLH1, MSH2, MSH6, and PMS2) by 
immunohistochemistry.
3. Have stable disease or progression on a prior regimen containing infusional 5-FU or 
capecitabine according to the interpretation of the treating provider
4. Be willing and able to provide written informed consent/assent for the trial.
5. Be 18 years of age on day of signing informed consent.
6. Have measurable disease based on RECIST 1.1.
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion (Phase II expansion cohort only).  Newly-obtained is defined as a specimen 
obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1.  Subjects for 
whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety 
concern) may submit an archived specimen only upon agreement from the Sponsor.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate 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 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels 
>1.5 X institutional ULN
Hepatic
Serum total bilirubinb
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases

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System
Laboratory Value
Albumin
≥2.5 g/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
bPatients with Gilbert's disease may be included if their direct bilirubin is ≤ 1.5 X 
ULN.
10. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
11. Female subjects of childbearing potential (Section 4.7.2
Contraception) must be 
willing to use an adequate method of contraception as outlined in Section 4.7.2 – 
Contraception, for the course of the study through 120 days after the last dose of study 
medication.
12. Male subjects of childbearing potential (Section 4.7.2) must agree to use an adequate 
method of contraception as outlined in Section 4.7.2Contraception, starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
4.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment.
2. Has a known diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.
3. Has a known history of active TB (Bacillus Tuberculosis).
4. Known hypersensitivity to pembrolizumab or any of its excipients.

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5. Known hypersensitivity/intolerance to capecitabine, infusional 5-fluorouracil, or 
bevacizumab.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent.
-
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study at the discretion of the treating provider.
-
Note:  If subject received major surgery, they must have recovered adequately, in 
the opinion of the treating provider, from the toxicity and/or complications from 
the intervention prior to starting therapy.
8. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.
10. Has 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.
11. Has known history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease.
12. Has an active infection at the time of cycle 1 day 1 requiring systemic therapy.
13. Has a 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.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial in the opinion of the treating provider.

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15. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
19. Requires therapeutic anticoagulation with warfarin at baseline.
Patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days 
prior to starting study drug, however, therapeutic or prophylactic therapy with low-
molecular weight heparin is allowed.
20. Has history of known coagulopathy that increases risk of bleeding or a known history of 
clinically significant hemorrhage within 12 months of start of study drug.
21. Known bleeding risk including serious hemorrhage or hemoptysis within the last 3 
months; major surgery within the past 8 weeks or minor surgery within the past 4 weeks.
22. Has known gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE 
Grade > 3 within 6 months of start of study drug.
23. Has greater than 1+ proteinuria on a urine dipstick or equivalent routine laboratory 
analysis will require further testing with a urine protein to creatinine ratio (UPCR).  
UPCR must be calculated as follows: UPCR = protein concentration (mg/dL)/creatinine 
(mg/dL).  If the UPCR ≥ 1, then the patient will not be eligible for study entry. However, 
if urinalysis or equivalent routine laboratory analysis shows no protein, then UPCR 
testing is not required. Patients with 1+ proteinuria are eligible even if UPCR is >/=1.
24. Has a known history of non-healing wounds or ulcers, or bone re-fractures within 3 
months of fracture.
25. Has a history of arterial thromboembolism within 12 months of start of study drug.
26. Has inadequately controlled hypertension (defined as systolic blood pressure greater than 
150 mm Hg or diastolic blood pressure greater than 95 mm Hg).  The use of 
antihypertensive medications to control blood pressure is permitted. Retesting is 
permitted.
27. Has a known history of hypertensive crisis or hypertensive encephalopathy within 6 
months prior to planned start of study drug.
28. Has had known clinically significant cardiovascular disease within 12 months of planned 
start of study drug, including myocardial infarction, unstable angina, grade 2 or greater 
peripheral vascular disease, cerebrovascular accident, transient ischemic attack, 

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congestive heart failure, or arrhythmias not controlled by outpatient medication, 
percutaneous transluminal coronary angioplasty/stent.
29. Has a known history of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 6 months prior to planned start of study drug.
30. Known reversible posterior leukoencephalopathy syndrome (RPLS).
31. Difficulty swallowing, malabsorption, known active partial or complete bowel 
obstruction, or other chronic gastrointestinal diseases or conditions that may hamper 
compliance and/or absorption of capecitabine.
32. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of study drug.  Administration of killed vaccines is allowed.
4.2
Trial Treatments
4.2.1
Dose Selection
This is a single-center, single-arm, open-label, phase II trial of pembrolizumab in combination 
with capecitabine and bevacizumab in subjects with locally advanced, unresectable, or metastatic 
MSS/pMMR CRC.  An initial safety lead-in will be performed to define the maximum tolerated 
dose (MTD)/recommended phase 2 dose (RP2D) of capecitabine when administered with 
pembrolizumab and bevacizumab.  The rationale for selection of doses to be used in this trial is 
provided in Section 4.0 – Background and Rationale.
Of note, the adverse event profiles of pembrolizumab, capecitabine, and bevacizumab do not 
appear to interact, thus the three agents are anticipated to be tolerable when co-administered. The 
dose of pembrolizumab administered during the safety lead-in will not exceed the established 
phase II dose when administered as monotherapy. The doses of capecitabine and bevacizumab 
administered during the safety lead-in will not exceed the standard of care doses, in combination, 
for CRC, or the RP2D of each drug in combination with pembrolizumab. The safety lead-in also 
incorporates a de-escalation of capecitabine dosing if unexpected dose-limiting toxicity is 
observed.
The RP2D/MTD of capecitabine administered with pembrolizumab and bevacizumab will be 
incorporated into the phase II portion of this study.  In the unlikely event that the safety lead-in 
phase of this study is unable to define an adequately safe dose of capecitabine administered with 
pembrolizumab and bevacizumab, a phase II study of pembrolizumab with bevacizumab or 
capecitabine will be performed.
Each treatment cycle will be 3 weeks. The drug doses, frequency, route of administration, and 
regimen are outlined in Table 2.
Table 2 Trial Treatment

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Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3-
week cycle
Experimental
Bevacizumab
7.5 mg/kg
Q3W
IV infusion
Day 1 of each 3-
week cycle
Standard of 
care
Capecitabine
1000 mg/m2
or MTD from 
safety run-in
BID
PO tablets
Day 1-14 of each 3-
week cycle
Standard of 
care
Trial treatment should begin on the day of registration, within 28 days of signing consent.  For 
the phase II cohort prior to interim analysis only, IV infusion of bevacizumab will begin on Day 
1 of Cycle 2.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
4.2.1.1 Safety Run-in Schedule to Establish the MTD of Capecitabine in Combination with 
Pembrolizumab and Bevacizumab
The established safety data for pembrolizumab, capecitabine, and bevacizumab, when 
administered separately, do not appear to overlap indicating that the three agents are expected to 
be tolerable when co-administered at established dose levels.  However, since there is no safety 
data available for the combination of capecitabine administered with pembrolizumab and 
bevacizumab, the first 6 patients will be considered as safety lead-in and observed in groups of 3 
for DLTs for an evaluation period of 21 days (see DLT definitions in Section 5.2.1.2 and 5.2.1.3) 
as follows:

If at Dose Level 0, ≤1 of the first 3 patients develop DLT, 3 more patients will be 
enrolled to Dose Level 0.

If at Dose Level 0, >1 of the first 3 patients or >1 of the first 6 patients develops DLT, 
cohort enrollment will be stopped immediately and re-started from the beginning with 
3+3 patients enrolled at a dosing interval of 3 weeks (Dose Level -1).

If at Dose Level -1, >1 of the first 3 patients or >1 of 6 patients develops DLT, cohort 
enrollment will be stopped immediately and re-started from the beginning with 3+3 
patients enrolled at a dosing interval of 3 weeks (Dose Level -2).

If at Dose level -2, >1 of the first 6 patients develops DLT, the safety lead-in will be 
discontinued.

If the safety lead-in is discontinued due to capecitabine toxicity, a phase II study of 
pembrolizumab plus bevacizumab will be performed.
The safety lead-in will determine the RP2D/MTD of capecitabine when administered with 
pembrolizumab and bevacizumab.  Capecitabine will be initially administered at 1000 mg/m2 
PO BID on days 1-14 of every 3-week cycle with pembrolizumab at 200 mg IV and 
bevacizumab 7.5 mg/kg IV every three weeks. Dose modification guidelines for capecitabine 
drug-related adverse events are provided in Table 6. A subject who experiences a DLT 
considered at least possibly related to capecitabine may remain in the trial and continue receiving 

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capecitabine at a lower dose (plus pembrolizumab and bevacizumab) if the investigator deems 
potential benefits outweigh the risks. If more than 2 DLTs considered at least possibly related to 
capecitabine are observed amongst the six first subjects, a de-escalation of capecitabine will 
begin at the dose levels listed in Table 3.
Table 3. Dosing of Capecitabine During the Safety Lead-in
Dose level
Dose of Capecitabine
Minimum Number of Patients
0
1000 mg/m2 PO BID
6
-1
800 mg/m2 PO BID
6
-2
600 mg/m2 PO BID
6
The dose levels of pembrolizumab and bevacizumab are fixed at levels listed in Table 2 and will 
not be modified. Criteria for holding or permanently discontinuing pembrolizumab or 
bevacizumab are provided in Table 5 and Table 7.
4.2.1.2 Definition of Dose-limiting Toxicity
Dose-limiting toxicity (DLT) will be defined as clinically-significant toxicities which are at least 
possibly treatment-related and meet the criteria listed below:
Hematologic toxicities

Grade 4 absolute neutropenia lasting >7 days

Grade ≥3 febrile neutropenia (ANC <1000 and T≥38.5°C)

Grade 4 thrombocytopenia

Grade 3 thrombocytopenia lasting >7 days, requiring dose modifications during Cycle 1, 
requiring platelet transfusion, or associated with clinically significant bleeding (defined as 
bleeding requiring hospitalization, transfusion, or an invasive procedure such as 
endoscopy).

Grade 4 anemia

Grade 3 anemia requiring transfusion
Other treatment-related toxicities:

Any treatment-related death

Any dose reduction required during Cycle 1 due to potential treatment-related toxicity

Any other treatment-related toxicity that results in >7 consecutive days of missed 
capecitabine doses or a dosing delay lasting >7 consecutive days during cycle 1

Any treatment delay of > 21 consecutive days during cycle 1 due to toxicity that fails to 
resolve to baseline or grade ≤1

Any drug-related grade ≥3 non-hematologic toxicity despite optimal supportive care 
(toxicity grade should be determined after optimal supportive care has been provided, 
when appropriate) except the following:

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o
Grade ≥3 nausea, vomiting, or diarrhea lasting ≤72 hr in the absence of maximal 
medical therapy
o
Alopecia
o
Grade 3 hypertension that recovers to grade ≤2 within 7 days of adjustment or 
addition of oral blood pressure medication(s)
o
Grade 3 fatigue, asthenia, anorexia, fever, or constipation that resolves to grade ≤2 
within 72 hr
o
Grade 3 infusion-related reaction resolving within 6 hours with medical 
management
o
Asymptomatic changes in laboratory values (including electrolytes abnormalities 
that respond to medical intervention or are clinically insignificant; elevation of 
amylase/lipase with recovery to grade ≤ 2 within 7 days; elevation of alkaline 
phosphatase)
o
Grade 3 immune-related adverse events (such as endocrinopathies, dermatitis, 
colitis, or pneumonitis) known to be associated with pembrolizumab that improve 
to grade ≤ 1 within 21 days of supportive management (Table 5)
4.2.1.3
Dose Modifications
Safety Run-In and the Phase II Study
In the event that capecitabine or bevacizumab is discontinued, the subject may still be eligible for 
continued treatment with pembrolizumab plus bevacizumab or pembrolizumab plus capecitabine, 
respectively.   If both capecitabine and bevacizumab are discontinued, or if pembrolizumab is 
discontinued, the subject will come off study. Subjects who do not complete the first on-
treatment imaging assessment may be replaced.
Refer to Table 5, Table 6, and Table 7 for dose modification guidelines for adverse events for 
pembrolizumab, capecitabine, and bevacizumab respectively.  If a subject experiences several 
toxicities and there are conflicting recommendations, follow the most conservative dose 
adjustment recommended (dose modification appropriate to the most severe toxicity).
Reduction or withholding of one agent and not the other agent is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to one of the study treatment.
If, in the opinion of the Investigator, the toxicity is related to the combination of two agents, 
capecitabine may be reduced, or both treatments may be interrupted or discontinued according to 
recommended dose modifications.  If the toxicity is related to the combination of three agents, 
capecitabine may be reduced, or all three agents held according to the recommended dose 
modifications. Exceptional circumstances to following the dose modification tables below may 
be considered after consultation with the Sponsor.
If a toxicity is not otherwise specified, investigators should refer to the label or local standard of 
care for dose adjustments. At the Investigator’s discretion, dose modification according to Table 
4 is allowed for intolerable Grade 2-3 toxicities that are not specified in the tables below.  These 
dose modification decisions must be documented in the subject records.

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The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be used 
to grade the severity of adverse events.
If appropriate, the Investigator may attribute each toxicity event to pembrolizumab, capecitabine, 
or bevacizumab alone and use stepwise capecitabine dose modifications according to Table 4.
Pembrolizumab and bevacizumab dose reductions are not permitted.  Pembrolizumab or 
bevacizumab treatment may be interrupted or discontinued due to toxicity.
Table 4. Dose Modifications for Capecitabine, Pembrolizumab, and Bevacizumab
Drug
Starting Dose
Dose Level -1
Dose Level -2
Dose Level -3
Capecitabine
1000 mg/m2
BID
800 mg/m2 BID
600 mg/m2 BID
Discontinue
Pembrolizumab
200 mg fixed-
dose
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Bevacizumab
7.5 mg/kg
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose Modifications for Pembrolizumab
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 5 below.  
Table 1 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab and combination therapy
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination 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/combination treatment, 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/combination treatment are 
provided in Table 1.

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Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event [to the combination,  to capecitabine or bevacizumab alone or to pembrolizumab 
alone, for adverse events listed in Table 1, both interventions must be held according to the 
criteria in Table 1 Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab and combination therapy.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 1

If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined in Table 1, the 
combination of  capecitabine, bevacizumab and pembrolizumab may be restarted at the 
discretion of the investigator.  In these cases where the toxicity is attributed to the 
combination or to capecitabine, pembrolizumab and bevacizumab alone, re-initiation of 
pembrolizumab as a monotherapy may be considered at the principal investigator’s 
discretion .

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Table 1 Dose Modification and toxicity management for immune-related AEs associated with pembrolizumab and 
combination therapy
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
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
Grade 2 or 3
Withhold
Diarrhea/Col
itis 
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

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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 prednisone or equivalent) 
followed by taper
  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
T1DM or 
Hyperglycem
ia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycem
ia 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
Hyperthyroidis
m
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

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidis
m
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
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
  Monitor changes of renal 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
Grade 1
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 
Dermatologi
c 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
All Other 
Persistent 
Grade 2
Withhold
  Based on severity of AE 
  Ensure adequate evaluation to confirm 

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 3
Withhold or 
discontinue 
based on the 
event e 
irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
administer corticosteroids
etiology or exclude other causes
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 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x 
ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab 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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Dose Modifications for Capecitabine
If the starting dose of capecitabine is 1000 mg/m2, subjects may have up to 2 capecitabine dose 
level reductions throughout the course of the study, as described in Table 4.  If further toxicity 
occurs or the criteria for resuming treatment are not met, capecitabine treatment may be 
discontinued.  If a dose level reduction for toxicity occurs with capecitabine, the dose may not be 
re-escalated.  Dose modifications are always based on the previous cycle.
Any toxicity associated or possibly associated with capecitabine treatment should be managed 
according to standard medical practice.  Patients who require capecitabine hold, dose reduction, 
or discontinuation are permitted to continue to receive study treatment with pembrolizumab in 
combination with bevacizumab.
Table 6. Dose Modification Guidelines for Capecitabine Drug-related Adverse Events
Toxicity
Hold 
Capecitabine 
Treatment for 
Grade
Timing for 
Restarting 
Capecitabine 
Treatment
Dose for 
Restarting 
Capecitabine 
Treatment
Discontinue 
Capecitabine 
Treatment
Hematologic
3a
Neutrophil count 
resolves to 
>1,000/mm3
No Reduction
*consider G-
CSF
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
Neutropenia
4a
Neutrophil count 
resolves to 
>1,000/mm3
Reduction by 1 
DL
*consider G-
CSF
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
3a
Toxicity 
resolves to 
Grade 0-1
Reduction by 1 
DL
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
Febrile 
Neutropenia
4a
NA
Discontinue
Permanently 
discontinue 
capecitabine
Thrombocyto 
penia
3-4a
Platelet count 
resolves to
>75,000 mm3
Reduction by 1 
DL
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
Non-hematologic
Diarrhea, 
Mucositis, or
Hand-foot 
2-3
Toxicity 
resolves to 
Grade 0-1
Reduction by 1 
DL
Toxicity does not 
resolve within 12 
weeks of last dose, 

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Toxicity
Hold 
Capecitabine 
Treatment for 
Grade
Timing for 
Restarting 
Capecitabine 
Treatment
Dose for 
Restarting 
Capecitabine 
Treatment
Discontinue 
Capecitabine 
Treatment
or >2 Dose Level 
reductions exceeded
Syndrome
4
NA
Discontinue
Permanently 
discontinue 
capecitabine
All other
Non- 
Hematologic 
Toxicitiesb
3-4a
Toxicity
resolves to 
Grade 0-1
Reduction by 1 
DL
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
Laboratory 
adverse 
events.
4
NA
Reduction by 1 
DL
Toxicity does not 
resolve within 12 
weeks of last dose, 
or >2 Dose Level 
reductions exceeded
a Permanent discontinuation should be considered for any severe or life-threatening event.
b Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician 
discretion. Permanently discontinue from agent for persistent Grade 2 adverse reactions for 
which treatment has been held and did not recover to Grade 0-1 within 12 weeks of the last 
dose.
Dose Modifications for Bevacizumab
There are no recommended dose reductions of bevacizumab.  Guidelines for bevacizumab dose 
management due to adverse events considered at least possibly related to bevacizumab are 
summarized in Table 7. If adverse events occur that require holding bevacizumab, the dose will 
remain the same once treatment resumes.  Patients who require bevacizumab hold or 
discontinuation are permitted to continue to receive study treatment with pembrolizumab in 
combination with capecitabine.
Any toxicity associated or possibly associated with bevacizumab treatment should be managed 
according to standard medical practice.  Bevacizumab has a terminal half-life of 2 to 3 weeks; 
therefore, its discontinuation results in slow elimination over several months.  There is no 
available antidote for bevacizumab.  Subjects should be assessed clinically for toxicity prior to, 
during, and after each infusion.  If unmanageable toxicity occurs because of bevacizumab at any 
time during the study, treatment with bevacizumab should be discontinued.
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed in 
Table 7.
Table 7. Dose Modification Guidelines for Bevacizumab Drug-related Adverse Events

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Toxicity/Event
Grade
Action to be taken
1-2
No dose modifications
3
If not controlled to ≤159/99 mmHg with 
medication, discontinue bevacizumab
Hypertension
4
(including RPLS - 
confirmed by MRI, 
or hypertensive 
encephalopathy)
Discontinue bevacizumab
1-2
No dose modification for grade 1 non-
CNS events
Grade ≥ 1 New CNS 
hemorrhage
Discontinue bevacizumab
Hemorrhage
Grade > 1 non- CNS 
hemorrhage
Discontinue bevacizumab
1-2
No dose modification for grade 1/2 
events
3-4 Asymptomatic
Hold study drug treatment. If the planned 
duration of full-dose anticoagulation is 2 
weeks, study drug should be held until 
the full-dose anticoagulation period is 
over. If the planned duration of full-dose 
anticoagulation is >2 weeks, study drug 
may be resumed during the period of full-
dose anticoagulation if the following 
criteria is met:
The participant must be therapeutically 
anticoagulated with an approved 
anticoagulant agent (no oral coumadin 
derivatives) according to standard 
prescribing guidelines.
Venous Thrombosis
4 Symptomatic
Discontinue bevacizumab
Arterial 
Thromboembolic event:
Any grade
Discontinue bevacizumab
Angina, Myocardial 
Infarction, Transient 
Ischemic Attack, 
Cerebrovascular 
Accident, any other 
arterial TBE event.
1-2
No dose modification
3
Hold bevacizumab until resolution to Gr 
1
CHF (LVSD)
4
Discontinue bevacizumab
Proteinuria
1-2
No dose modification

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Toxicity/Event
Grade
Action to be taken
3
Hold bevacizumab until resolution to 
≤Gr 2. If UA results with ≥2 g/dL 
protein, collect 24-hour urine protein.  
Resume treatment when 24-hour urine 
protein is <2 g/dL
4 (nephrotic 
syndrome)
Discontinue bevacizumab
GI Perforation
Any event
Discontinue bevacizumab
1
Continue patient for partial obstruction 
NOT requiring medical intervention
2
Hold bevacizumab for partial obstruction 
requiring medical intervention. Patient 
may restart upon complete resolution
Bowel Obstruction
3-4
Hold bevacizumab for complete 
obstruction. Patient may restart upon 
complete resolution. If surgery is 
necessary, patient may restart 
bevacizumab after full recovery from 
surgery, and at investigator’s discretion.
Wound dehiscencea 
requiring medical or 
surgical therapy
Discontinue bevacizumab
Infusion Related
Reaction
1-2
3-4
Slow infusion.
Discontinue bevacizumab
Other Unspecified Bev-
related AES
3
4
Hold bevacizumab until recovery to 
≤Grade 1
Discontinue bevacizumab
aBevacizumab will be temporarily suspended at least 4 weeks prior to elective surgery.
4.2.2
Timing of Dose Administration
All trial treatments will be administered in the order presented below.  All study treatments are 
anticipated to be administered on an outpatient basis; however, inpatient administration is 
permitted.
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.1). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons.
Safety lead-in:
Study treatment with pembrolizumab must be administered on Day 1 Cycle 1, followed by 
bevacizumab and capecitabine.
Phase II:

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Cycle 1 Day 1:
Study treatment with pembrolizumab must be administered on Day 1 Cycle 1, followed by 
capecitabine.  Prior to the interim analysis, bevacizumab will not be administered in Cycle 1. 
Post interim analysis, study treatment with pembrolizumab must be administered on Day 1 Cycle 
1, followed by bevacizumab and capecitabine.
Cycle 2 Onwards:
Study treatment with pembrolizumab, followed by bevacizumab and capecitabine may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle for administrative 
reasons.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study treatment (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects may restart study treatment as soon as clinically appropriate at the 
Investigator’s discretion, and not exceeding 3 weeks from the interrupted dosing.  Discussion 
with the Sponsor should occur if the Investigator determines a subject cannot restart study 
medication within 3 weeks.  The reason for interruption should be documented in the subject's 
study record.
Pembrolizumab
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.
However, given the variability of infusion pumps from site to site, a window of -5 minutes and
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). The Pharmacy 
Manual contains specific instructions for the preparation of the pembrolizumab infusion fluid 
and administration of infusion solution. Pembrolizumab will be provided to patients enrolled in 
this study by Merck Pharmaceuticals.
Capecitabine
Administration of capecitabine should begin on Day 1 of each 3-week cycle following 
administration of pembrolizumab and bevacizumab, as detailed in Table 8 and the Trial Flow 
Chart (Section 6.1).  Please refer to the product label for additional guidance on administration 
procedures for commercially available capecitabine.  Capecitabine will be
administered orally as a dose of 1000 mg/m2 twice daily from Day 1 to Day 14 of each treatment 
cycle, for a total of 28 doses over 14 days. On Day 1 of Cycle 1, the subjects will begin oral 
dosing with their evening meal. If the morning dose of capecitabine is missed on Day 1, patients 
are allowed to make up this missed dose on Day 15 to complete 28 doses.
The capecitabine dose will be based on the subject’s actual body weight, and the dose will be 
recalculated if there is a weight change of >10% from baseline. Capecitabine is supplied 
commercially and is available in 500 and 150 mg tablets. Either tablet may be prescribed per 
UCSF standard of care, treating provider’s judgment and to optimize patient management.  The 

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daily dose will be adjusted to the nearest full tablet strength.  If the nearest total daily dose is an 
odd number of tablets, do not split. Instead, dose one additional tablet in the morning or evening 
to achieve required average BID dose. Capecitabine is swallowed with water within 30 minutes 
after a meal.
Bevacizumab
Bevacizumab infusion will begin no sooner than 1 hour after completion of pembrolizumab 
infusion for the first cycle of combined therapy.  Thereafter bevacizumab may begin upon 
completion of pembrolizumab.  The bevacizumab dose (7.5 mg/kg) will be based on the 
subject’s actual body weight, and the dose will be recalculated if there is a weight change of 
>10% from baseline.  Bevacizumab will be administered as a 90-minute (+/-15 minutes) infusion 
for the first treatment; 60 minute (+/-10 minutes) infusion for the second treatment; and 30 
minute (+/-10 minutes) infusion for subsequent cycles.  The infusion rates may be adjusted based 
on tolerability and may be decreased in the setting of infusion-related reactions.
Table 8. Dose Schedule and Administration of Capecitabine, Pembrolizumab, and 
Bevacizumab
Cycle 1
Cycle ≥2
Week 1
Week 2
Week 3
Week 1
Week 2
Week 3
Capecitabine
Schedule
Dailya
Daily
Rest
Daily
Daily
Rest
Dose
1000 mg/m2 
BID PO
1000 
mg/m2 
BID PO
1000 mg/m2 
BID PO
1000 
mg/m2 
BID 
PO
Administration
With water 
within 30 mins 
after a meal
With 
water 
within 
30 mins 
after a 
meal
With water 
within 30 mins 
after a meal
With 
water 
within 
30 
mins 
after a 
meal
Pembrolizumab
Schedule
Day 1
NA
NA
Day 1
NA
NA
Dose
200 mg
200 mg
Administration
Infusion: 30 
min (-5/+10 
min)
Infusion: 30
minutes (-5 
min/+10 min)
Bevacizumab
Schedule
Day 1b
NA
NA
Day 1c
Dose
7.5 mg/kg
7.5 mg/kg
Administration
Infusion:90 
min (+/-15 
min)b
Infusion: 90 
min (+/- 15 
min) if first 

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Cycle 1
Cycle ≥2
Week 1
Week 2
Week 3
Week 1
Week 2
Week 3
infusion, 60 
min (+/-10 
min) if second, 
30 min (+/-10 
min) 
subsequent 
cycles as 
tolerated.
Comment
Start 1 hr after 
completion 
pembrolizumab 
infusion
Start 1 hr after 
completion of 
pembrolizumab 
infusion, if first 
combined 
treatment with 
pembrolizumab
a First dose of the capecitabine on Day 1 Cycle 1 begins after evening meal
b Day1 Cycle 1 infusion of bevacizumab for safety run-in cohort and for the phase II 
expansion cohort.
c First bevacizumab infusion for phase II cohort prior to interim analysis is Day 1 Cycle 2.
4.2.3
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator, and subject will know the 
treatment administered.
4.3
Randomization or Treatment Allocation
This is a single-arm non-randomized trial.
4.4
Stratification
No stratification based on age, sex, or other characteristics will be used in this trial.
4.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.
4.5.1
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 

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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.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2.
4.5.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy

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.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology, or as a premedication for 
iodinated contrast if not amenable to MRI imaging instead of contrast CT.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.
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:

Oral coumadin-derivative anticoagulants such as warfarin are prohibited

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In addition:

Monitor phenytoin levels, as the phenytoin dose may need to be reduced with taken 
concomitantly with capecitabine.

Exercise caution if CYP2C9 substrates are co-administered with capecitabine. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
4.6
Rescue Medications & Supportive Care
4.6.1
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous 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 the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1.3 for dose 
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.

Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and bowel 
perforation (such as peritoneal signs and ileus).
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 

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electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis, administer oral corticosteroids.
o
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.

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o
Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.
Table 9 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
Table 9. Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the 
opinion of the investigator.
None
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
Stop Infusion and monitor 
symptoms.
Additional appropriate 
medical therapy may include 
but is not limited to:
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:

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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
prophylactic medications 
indicated for ≤ 24 hrs

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 
one 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 
trial treatment 
administration.
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
antipyretic).
Grades 3 or 4 
Grade 3:
Prolonged (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)
Stop Infusion.
Additional appropriate 
medical therapy may include 
but is not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
No subsequent dosing.

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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated

Epinephrine
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.
Subject is permanently 
discontinued from further 
trial treatment 
administration.
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
Supportive Care Guidelines for Capecitabine and Bevacizumab
Please refer to the product label or local standards of care for additional supportive measures for 
capecitabine and bevacizumab.
4.7
Diet/Activity/Other Considerations
4.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting.
4.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has 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 hormone replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
OR

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(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.
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 (one 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 two 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 
ERCs/IRBs.  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.

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Subjects should be informed that taking the study medication 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 
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.
4.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. 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 the Sponsor and Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck, if the outcome is a serious adverse 
experience (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 the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and Merck and followed as described above and in 
Section 7.2.2
4.7.4
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.
4.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.5.1 – Other Procedures.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Appendix 11.5.
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, please 
see Section 7.1.2.7.

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
Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.5.1.

Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.6.4 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for 
reasons other than progressive disease will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming 
lost to follow-up.  After documented disease progression each subject will be followed by 
telephone for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
4.8.1
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.
4.9
Subject Replacement Strategy
Subjects who do not complete the first on-treatment imaging assessment may be replaced.
4.10
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

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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
5
TRIAL PROCEDURES
5.1
Trial Procedures
The Study Flow Charts (Section 5.1) summarize the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at additional or unscheduled time points if deemed clinically necessary by the 
investigator.
In some cases, the evaluations or testing may be potentially sensitive in nature (e.g., HIV, HBV, 
or HCV results), and thus local regulations may require that additional informed consent be 
obtained from the subject. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.

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5.1
Study Calendar
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 to 35 Discontinuation Safety Follow-
up
Follow Up Visits
Survival 
Follow-Up
a
At Time of 
Discontinuation
30 Days from 
Last Dose
Every 9 Weeks 
Post- 
discontinuation
Every 9 
Weeks
Scheduling Window (Days)
-28 to 0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Subject Identification Card (Optional)
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Height, Weight, and Vital Signs 
(T,P,RR,BP)
b
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X

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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 to 35 Discontinuation Safety Follow-
up
Follow Up Visits
Survival 
Follow-Up
a
At Time of 
Discontinuation
30 Days from 
Last Dose
Every 9 Weeks 
Post- 
discontinuation
Every 9 
Weeks
Scheduling Window (Days)
-28 to 0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Survival Status
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
Bevacizumab Administration, Ph II 
pre-interim analysis
X
X
X
X
X
X
X
Bevacizumab-Safety Run-in and PhII 
post interim analysis
X
X
X
X
X
X
X
X
Capecitabine
28 doses each cycle over 14 days
Laboratory Assessmentsi
Pregnancy Test - Urine or Serum \- 
hCG
Xc
X
X
X
X
X
X
X
X
X
PT/INR and aPTTe
Xd
CBC with Differentiale
Xd
X
X
X
X
X
X
X
X
X
Chemistry Panele
Xd
X
X
X
X
X
X
X
X
X
Urinalysise
Xd
X
X
X
X
X
X
X
Xe
X
X
T3, FT4, and TSHe
Xd
X
X
X
Xe
X
X
Serum Tumor Markersf
Xd
X
X
X
X
X
X
X
X
X
Tumor Tissue Collection

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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 to 35 Discontinuation Safety Follow-
up
Follow Up Visits
Survival 
Follow-Up
a
At Time of 
Discontinuation
30 Days from 
Last Dose
Every 9 Weeks 
Post- 
discontinuation
Every 9 
Weeks
Scheduling Window (Days)
-28 to 0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Archival Tumor Tissue
X
Biopsy-Fresh Tissueg (PhII cohort 
only)
X
X
Research blood - Heparinh
X
X
X
X
X
Research blood- PAXgeneh
X
X
X
X
Efficacy Measurements
Tumor Imagingk
XJ
X
k
Xl
X
a)
Subjects that experience site assessed PD or start a new anti-cancer therapy should be followed Q9W to assess for survival status.
b)
Height will be measured at Visit 1 only.
c)
For women of reproductive potential, a serum or urine pregnancy test should be performed within 72 hours prior to each dose of trial treatment and 30 days post last dose of study treatment.
d)
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
e)
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Thyroid function tests to be performed every other cycle. CBC with differential, chemistry, and 
urinalysis to be performed prior to every cycle.
f)
Serum tumor markers (CEA) should be collected at screening (baseline) and every Cycle until treatment discontinuation.
g)
Phase II cohort, pre-interim analysis cohort ONLY: CT or US-guided core needle biopsy of a metastatic site will be performed during the screening phase for immune biomarker analysis. 
An H&E will be performed at a UCSF core facility within 1 week of the pre-treatment biopsy to confirm presence of tumor cells. A second biopsy will be taken on-treatment, prior to cycle 2 in 
patients where the pre-treatment biopsy contained tumor cells and in whom repeat biopsy is feasible and not associated with excessively risk procedural risk. Phase II cohort, post interim 
analysis: If the total number of biopsies performed is <46, additional pre-treatment (but not on-treatment) biopsies will be required in post interim analysis patients until the total number of 
tumor biopsies performed reaches 46.
h)
PAXgene blood draw volume is 10 ml.  Heparin (green top) blood draw volume is 40 ml during screening, 60 ml on C1D1, and C2D1; 40 ml on C3D1 and End of Treatment.
i)
Blood will be collected from patients prior to treatment initiation during the screening phase; every 3 weeks on study therapy, including the time of disease progression.
j)
Screening tumor imaging will be performed within 28 days prior start of treatment.
k)
The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of the first dose of study drugs and will continue to be performed Q9W (63 days 
± 7 days), or earlier if clinically indicated.
l)
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment discontinuation (± 4 weeks). If previous 
tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation is not required.

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5.1.1
Administrative Procedures
5.1.1.1 Informed Consent
The treating investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
5.1.1.1.1
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form, and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations, 
and Sponsor requirements. The investigator or qualified designee will explain the Future 
Biomedical Research consent to the subject, answer all of his/her questions, and obtain written 
informed consent before performing any procedure related to the Future Biomedical Research 
sub-trial.  A copy of the informed consent will be given to the subject.
5.1.1.2 Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.
5.1.1.3 Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. Details regarding the disease for which 
the subject has enrolled in this study will be recorded separately and not listed as medical 
history.
5.1.1.4 Prior and Concomitant Medications Review
5.1.1.4.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 

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before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.
5.1.1.4.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
5.1.1.5 Disease Details and Treatments
5.1.1.5.1
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.
5.1.1.5.2
Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation, and surgeries.
5.1.1.5.3
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.
5.1.1.6 Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to registration. Each subject will be assigned only one 
screening number.  Screening numbers must not be re-used for different subjects.
Any subject who is screened multiple times will retain the original screening number assigned at 
the initial screening visit. Specific details on the screening visit requirements 
(screening/rescreening) are provided in Section 6.0.
5.1.1.7 Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation with the Sponsor-Investigator and written 
documentation of the decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff while 
the subject is in the treatment center.
5.1.2
Clinical Procedures/Assessments
5.1.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. 
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized 

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in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (termed immune-related adverse events, or irAEs); see the separate ECI guidance 
document in the administrative binder regarding the identification, evaluation, and management 
of potential irAEs.
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.
5.1.2.2 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical history. 
A full physical exam should be performed during screening.
5.1.2.3 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.
5.1.2.4 Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 
Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, 
weight, and blood pressure.  Height will be measured at screening only.
5.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 11.2) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.
5.1.2.6 Tumor Imaging and Assessment of Disease
Tumor imaging should be performed by computed tomography (CT) (preferred).  MRI or 
magnetic resonance imaging should only be used when CT is contraindicated or for imaging in 
the brain, but the same imaging technique should be used in a subject throughout the trial. CT 
imaging is the more commonly used modality and is preferred for the majority of subjects. An 
MRI can be utilized if clinically appropriate.  Imaging should include the chest, abdomen, and 
pelvis at baseline and all subsequent follow-up time points.  Imaging of the abdomen and pelvis 
should be IV-contrast enhanced.
5.1.2.6.1
Baseline Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of the first 
cycle.  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 are 

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acceptable for use as initial tumor imaging if they are of diagnostic quality, include all anatomy 
as described in the SIM, and performed within 28 days prior to the date of allocation.
5.1.2.6.2
Tumor Imaging During Trial
The first on study imaging assessment should be performed at 9 weeks (63 ±7 days from the date 
of allocation).  Subsequent tumor imaging should be performed Q9W (63 days ±7 days) or more 
frequently if clinically indicated until PD.  Imaging should not be delayed for delays in cycle 
starts or extension of pembrolizumab cycle intervals.  Per RECIST 1.1, partial or complete 
response should be confirmed by a repeat tumor imaging assessment not less than 4 weeks from 
the date the response was first documented. The tumor imaging for confirmation of response 
may be performed at the earliest 4 weeks after the first indication of response, or at the next 
scheduled tumor imaging (i.e. 9 weeks later), whichever is clinically indicated.  Subjects will 
then return to regular scheduled imaging Q9W, starting with the next scheduled imaging time 
point.  Subjects who obtain a confirmation imaging assessment do not need to undergo scheduled 
tumor imaging if it is < 4 weeks later and may wait until the next scheduled imaging time point.
Per irRECIST (Appendix 11.5), if radiologic imaging identifies PD, tumor assessment should be 
repeated on 4.2.3.1.2.1), and the subject remains on treatment while awaiting radiologic 
confirmation of progression.  Subjects who obtain confirmation tumor imaging do not need to 
undergo scheduled tumor imaging if it is < 4 weeks later and may wait until the next scheduled 
imaging time point if clinically stable. Imaging should continue to be performed until disease 
progression by RECIST 1.1 (unless the investigator chooses to manage the patient by irRECIST 
which would then be irPD), the start of new anti-cancer treatment, withdrawal of consent, death, 
or notification by the Sponsor-Investigator, whichever occurs first.  Disease progression may be 
confirmed at least 4 weeks after the first tumor imaging indicating PD disease in clinically stable 
subjects.
If the subject is clinically stable as per Appendix 11.5, it is the discretion of the PI to continue to 
treat and image the subject at least 4 weeks after the first tumor imaging indicating PD by 
RECIST
1.1 by the site.  irRECIST would then be followed by the study site to determine if the follow-up 
tumor imaging confirms PD (irPD). Subjects who have unconfirmed PD may continue on 
treatment and follow the regular imaging schedule intervals until subsequent PD (irPD) is 
confirmed by the site per irRECIST provided they have met the conditions detailed in Appendix 
11.5.
5.1.2.6.3
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time of 
treatment discontinuation (± 4-week window).  If a previous scan was obtained within 4 weeks 
prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory.  In 
subjects who discontinue trial treatment due to documented disease progression (PD or irPD for 
subjects managed under irRECIST), this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by radiologic imaging using the same 

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imaging schedule of Q9W to monitor disease status until the start of new anticancer treatment, 
disease progression, death, or the end of the study, whichever occurs first.
5.1.2.7 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (e.g., 
discontinuation of study therapy).
During the follow-up period, imaging will be repeated every Q9W (63 ±7 days) until PD. See the 
Trial Flow Charts - Section 6.0 and Section 7.1.6.4 for information about the Follow-up Visits.
5.1.2.8 Immune-related RECIST (irRECIST)
As noted above, if the site has identified PD by RECIST 1.1, subject management can shift to 
irRECIST if clinically stable.  The study site may elect to continue treatment, repeat ≥ 4 weeks 
later, and assess tumor response or confirmed progression per irRECIST (see Appendix 11.5 and 
Table 10 below).
Table 10. Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Tumor Imaging
Treatment
Tumor Imaging
Treatment
1st radiologic 
evidence of 
PD
Repeat tumor 
imaging at > 4 
weeks at site to 
confirm PD
May continue study treatment 
at the local site investigator’s 
discretion while awaiting 
confirmatory tumor imaging 
by site
Repeat tumor 
imaging at > 4 
weeks to confirm 
PD per physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging 
confirms PD
No additional 
tumor imaging 
required*
Discontinue treatment*
No additional 
tumor imaging 
required
N/A
Repeat tumor 
imaging 
shows SD, 
PR, or CR
Continue 
regularly 
scheduled tumor 
imaging 
assessments
Continue study treatment at 
the local site investigator’s 
discretion
Continue 
regularly 
scheduled tumor 
imaging 
assessments
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
local site investigator’s 
discretion
In determining whether or not the tumor burden has increased or decreased, local study site 
investigators should consider all target lesions as well as non-target lesions as per irRECIST. 
Subjects that are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation.
For a clinically stable subject with first radiologic evidence of PD (i.e., unconfirmed progression 
of disease), it is at the discretion of the site investigator to continue treating the subject with the 
assigned treatment per protocol until progression of disease is confirmed at least 28 days from 
the date of the tumor imaging first suggesting PD. If radiologic progression is confirmed by 
subsequent tumor imaging (irPD) then the subject will be discontinued from trial treatment. If 
radiologic progression is not confirmed, then the subject should resume or continue trial 
treatment and have their next tumor imaging according to the protocol schedule of Q9W (63 
days ± 7 days).

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*NOTE: If a subject has confirmed radiographic progression (i.e. 2 tumor imaging assessments 
at least 4 weeks apart demonstrating PD per irRECIST), but the subject is achieving a clinically 
meaningful benefit, an exception to continue treatment may be considered following consultation 
with the Sponsor-Investigator. If treatment is continued beyond confirmed radiographic 
progression, tumor imaging assessments should continue to be performed Q9W.
NOTE: In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging Q9W 
(63 days ± 7 days), until; the start of new anticancer treatment, disease progression, death, or the 
end of the study, whichever occurs first.
irRECIST data will be collected in the clinical database.
5.1.3
Tumor Tissue Collection and Correlative Studies Blood Sampling
Many collateral research opportunities exist with this study. Correlative science will be 
performed in collaboration with Dr. Larry Fong and UCSF Cancer Immunotherapy Lab (UCSF 
CIL).
5.1.3.1 Tumor Tissue collection
Archival tumor samples. Where available, an archival tumor formalin-fixed paraffin-embedded 
(FFPE) tissue block will be collected.
Pre-treatment and on-treatment biopsies (phase II portion only). Pre-interim analysis: during 
the screening phase, core needle biopsy of a metastatic site will be performed for immune 
biomarker analysis. An H&E stain will be performed at a UCSF core facility to confirm presence 
of tumor cells. A second biopsy will be taken on-treatment, prior to cycle 2, in patients where the 
pre-treatment biopsy contained tumor cells and in whom repeat biopsy is feasible and not 
associated with excessively high procedural risks. Post interim analysis: If the total number of 
biopsies already performed is <46, additional pre-treatment (but not on-treatment) biopsies will 
be required in sequential post interim analysis patients until the total number of tumor biopsies 
performed reaches 46.
5.1.3.2 Blood collections for Correlative Studies.
Blood will be collected from patients prior to treatment initiation during the screening phase 
(baseline); prior to cycle 1, prior to cycle 2, prior to cycle 3 and at the time of disease 
progression or treatment discontinuation.
5.1.3.3 Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research (FBR) from 
subjects who sign the FBR component of the consent:

Leftover archival or newly obtained tumor tissue

Leftover blood

Leftover RNA, DNA, or other derivatives of the above collections

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5.1.4
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis) and 
laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 11.

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Table 11. Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
(β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)
WBC (total and 
differential)
Aspartate aminotransferase (AST)
Specific gravity
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If 
abnormal)
Total triiodothyronine (T3)
Absolute Neutrophil Count
Urine pregnancy test †
Free thyroxine (T4)
Absolute Lymphocyte 
Count
Carbon Dioxide ‡
(CO2 or bicarbonate)
Thyroid-stimulating 
hormone (TSH)
Uric Acid
PK - Blood for correlative 
studies
Calcium
Carcinoembryonic antigen 
(CEA)
Chloride
Glucose
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
Creatinine
† Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.
‡ If considered standard of care

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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior 
to dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.
5.1.5
Other Procedures
5.1.5.1 Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any adverse 
events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events. Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 5.8.1 – Discontinuation of Study Therapy after CR. After 
discontinuing treatment following assessment of CR, these subjects should return to the site for a 
Safety Follow-up Visit (described in Section 7.1.6.4) and then proceed to the Follow-Up Period 
of the study (described in Section 7.1.6.4.1).
Withdrawal from Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their specimens 
and all derivatives destroyed.  Subjects may withdraw consent at any time by contacting the 
principal investigator for the main trial. Subsequently, the subject's specimens will be removed 
from the biorepository and be destroyed. A letter will be sent from the investigator to inform the 
subject of completion of destruction. Any analyses in progress at the time of request for 
destruction or already performed prior to the request being received by the Investigator will 
continue to be used as part of the overall research trial data and results.  No new analyses would 
be generated after the request is received.
5.1.6
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
5.1.6.1 Screening
5.1.6.1.1
Screening Period
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.0. Screening 
procedures may be repeated.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment. 

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
For women of reproductive potential, a serum pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment. A urine test may be considered if serum test 
is not appropriate.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results 
from assessments performed during the initial screening period are acceptable in lieu of repeat 
screening tests if performed within the specified time frame and the inclusion/exclusion criteria 
are met.  Subjects who are rescreened will retain their original screening number.
5.1.6.2 Treatment Period
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-related 
details are provided above in the Trial Procedures (Section 7.0)
5.1.6.3 Post-Treatment Visits
5.1.6.3.1
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer 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 antineoplastic therapy, whichever occurs first. SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded.
5.1.6.4 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) by radiologic 
imaging to monitor disease status.  Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, or end of 
the study. Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated.
5.1.6.4.1
Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 9 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
5.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An adverse event 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 

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and/or intensity) of a preexisting condition that is temporally associated with the use of 
pembrolizumab, is also an adverse event.
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.
Adverse events may occur during the course of the use of pembrolizumab in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), abuse, and 
withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment must be 
reported by the investigator if they cause the subject to be excluded from the trial, or are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.
From the time of treatment allocation/randomization through 30 days following last dose of trial 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets. The reporting 
timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1.  The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Adverse events will not be collected for subjects during the screening period as long as that 
subject has not undergone any protocol-specified procedure or intervention.  If the subject 
requires a blood draw, fresh tumor biopsy, etc., the subject is first required to provide consent to 
the main study and AEs will be captured according to guidelines for standard AE reporting.
5.2.1
Definition of an Overdose for this Protocol and Reporting of Overdose to the 
Sponsor-Investigator and Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab.  Appropriate supportive treatment should be provided if clinically 
indicated.  In the event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”

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All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor-Investigator and within 2 working days hours to Merck Global Safety 
 
5.2.2
Reporting of Pregnancy and Lactation to the Sponsor-Investigator and Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of drug product, or 30 days following last dose of trial 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by 
the investigator.  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 Sponsor-Investigator and within 2 working 
days to Merck Global Safety 
5.2.3
Immediate Reporting of Adverse Events to the Sponsor-Investigator and Merck
5.2.3.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
pembrolizumab that:

Results in death;

Is life-threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is another important medical event
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per 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);

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
Is associated with an overdose.
Refer to Table 12 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until registration for treatment, 
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study (reference Section 7.2.3.1 for additional 
details) that occurs to any subject must be reported within 24 hours to the Sponsor-Investigator 
and within 2 working days to Merck Global Safety if it causes the subject 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, or a procedure.
For the time period beginning at registration for treatment through 90 days following cessation of 
treatment, or 30 days following last dose of trial treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.5 for additional details), whether or not related to pembrolizumab, must be reported 
within 24 hours to the Sponsor-Investigator and within 2 working days to Merck Global Safety.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to pembrolizumab that 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 Sponsor-Investigator and Merck Global Safety.
All subjects with serious adverse events must be followed up for outcome.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices Agency (PMDA), or other local 
regulators.  Investigators will cross-reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc.  
 
at the time of submission to FDA.
5.2.3.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor-Investigator and within 2 working days to Merck Global 
Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 

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intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a 
procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following last dose of trial treatment if the subject initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to pembrolizumab, must be reported within 24 hours to the Sponsor-Investigator and 
within 24 hours to Merck Global Safety.
Events of clinical interest for this trial include:
1. An overdose of pembrolizumab, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor-Investigator, that is not 
associated with clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* However, patients with Gilbert's disease with a 
direct bilirubin of  ≤ 1.5 X ULN will not be considered an ECI.
*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.
5.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor-Investigator and Merck, 
unless there is evidence suggesting a causal relationship between the drug and the event.  Any 
such event will be submitted to the Sponsor-Investigator within 24 hours and to Merck Global 
Safety within 2 working days either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor-Investigator will monitor aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as an SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered an 
SAE.
5.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 

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changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.

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Table 12. Evaluating Adverse Events for Pembrolizumab
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE
Grading
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
A serious adverse event is any adverse event occurring at any dose or during any use of pembrolizumab that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that 
has not worsened is not a serious adverse event. A pre-existing condition is a clinical condition that is diagnosed prior to the use of pembrolizumab and is 
documented in the patient’s medical history.); or
Seriousness
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or
An investigator who is a qualified physician, will evaluate all adverse events as to:
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor-Investigator within 24 hours and to Merck 
within 2 working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor-
Investigator and to Merck within 2 working days.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units.
Action taken
Did the adverse event cause pembrolizumab to be discontinued?
Relationship to 
Pembrolizumab
Did pembrolizumab cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of
a relationship between the test drug and the adverse event based upon the available information.

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The following components are to be used to assess the relationship between pembrolizumab and the AE; the greater the correlation 
with the components and their respective elements (in number and/or intensity), the more likely pembrolizumab caused the adverse event 
(AE):
Exposure
Is there evidence that the subject was actually exposed to pembrolizumab such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of pembrolizumab?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors.
The following components are to be used to assess the relationship between the test drug and the AE:
An investigator who is a qualified physician, will evaluate all adverse events as to:
De-challenge
Was pembrolizumab discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved 
despite continuation of the  product; or (3) the trial is a single-dose drug trial); or (4) Product(s) is/are only used one time.)
Re-challenge
Was the subject re-exposed to pembrolizumab in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY PEMBROLIZUMAB, OR IF REEXPOSURE TO PEMBROLIZUMAB POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR-INVESTIGATOR AS PER DOSE MODIFICATION GUIDELINES IN 
THE PROTOCOL.
Relationship to 
Pembrolizumab
(continued)
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding pembrolizumab or drug 
class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.

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Record one of the 
following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of pembrolizumab relationship).
An investigator who is a qualified physician will evaluate all adverse events as to:
Yes, there is a reasonable possibility of 
pembrolizumab relationship.
There is evidence of exposure to pembrolizumab. The temporal sequence of the AE onset relative to the administration of 
pembrolizumab is reasonable. The AE is more likely explained by pembrolizumab than by another cause.
No, there is not a reasonable possibility 
of pembrolizumab relationship
Subject did not receive the pembrolizumab OR temporal sequence of the AE onset relative to administration of 
pembrolizumab is not reasonable OR the AE is more likely explained by another cause than the pembrolizumab. (Also 
entered for a subject with overdose without an associated AE.)

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5.2.5
Sponsor-Investigator Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs, and investigators in 
accordance with all applicable global laws and regulations.
6
STATISTICAL ANALYSIS PLAN
6.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with ICH 
Guideline E- 9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, along with an explanation as to when and why they occurred, will be 
listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be 
clearly identified in the CSR. No separate Statistical Analysis Plan (SAP) for the primary, 
secondary, and exploratory endpoints will be issued for this study.
6.2
Statistical Analysis Plan
Key elements of the statistical analysis plan are summarized in Table 13. The comprehensive 
plan is provided in Sections 8.2 through 8.5.7
Table 13. Key Elements of the Statistical Analysis Plan
Study Design Overview
A phase II study of pembrolizumab plus capecitabine and bevacizumab in 
metastatic or locally advanced unresectable microsatellite stable colorectal cancer.
Treatment Assignment
This is an open-label study.
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis will be evaluated by testing for RECIST 1.1 ORR greater 
than 15% using Exact method based on binomial distribution.
[95% CI for ORR will be calculated using Exact method based on binomial 
distribution.]
Statistical Methods for 
Key Safety Analyses
Count and percentage of AE will be provided.
Interim Analyses
There is one interim analysis planned in this study which will be performed after 
the first 29 patients accrued in the expansion cohort. If there are 1 or fewer 
responses in these 29 patients, the study will be stopped. Otherwise, 15 additional 
patients will be accrued. 
Multiplicity
The overall type I error is controlled at 5% (one-sided) by Simon’s two-stage 
design.
Sample Size and Power
In the initial safety lead-in phase, minimum of 6 patients and a maximum of 18 
patients are required.
For expansion cohort: Simon's two-stage design (Simon, 1989) will be used. The 
null hypothesis that the true response rate is 4% will be tested against a one-sided 
alternative. In the first stage, 29 patients will be accrued (the patients in the safety 
lead-in cohort at MTD will be included in the expansion cohort). If there are 1 or 
fewer responses in these 29 patients, the study will be stopped. Otherwise, 15 
additional patients will be accrued for a total of 44. The null hypothesis will be 
rejected if 5 or more responses are observed in 44 patients. This design yields a 
type I error rate of 0.0295 and power of 80% when the true response rate is 15%.

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In this study, approximately total 44-56 subjects (the patients in the safety lead in 
cohort at MTD will be included in the expansion cohort) with locally advanced 
unresectable or metastatic CRC will be enrolled.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the study 
affiliated biostatistician at UCSF.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and sponsor-
investigator personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule.
A DLT evaluation of the first 6 patients will be conducted to confirm the safety of administering 
pembrolizumab at 200 mg (flat dosing) every three weeks with capecitabine and bevacizumab 
and follows the principles of standard 3+3 dose escalation studies, i.e., if ≤1 of 3 patients 
develops DLT, expand to 6, and if >1 of 3 or >1 of 6 patients develop DLT, de-escalate to the 
next lower dose level.  Criteria to define DLT are described in Section 5.1.1.  The highest dose 
level associated with ≤1 of 6 patients developing a DLT will define the maximum tolerated dose 
(MTD) or recommended phase 2 dose level (RP2D) and will not exceed dose level zero 
(pembrolizumab 200 mg (flat dosing) and bevacizumab 7.5 mg/kg administered once every 3 
weeks; capecitabine 1000 mg/m2 bid administered on days 1-14). This process may require up to 
3 dose level evaluations and up to 18 patients (Section 5.1).  The MTD/RP2D will be used for 
the subsequent phase II portion of this study.  If at capecitabine 600 mg/m2 bid (minus 2 dose 
level), >1 patient develops DLT, further accrual to the safety lead-in will discontinue and the 
subsequent phase II portion of this study will be replaced with a phase II study evaluating 
pembrolizumab with either capecitabine or bevacizumab (doublet rather than triplet therapy) as 
outlined in Section 13.2.3.3. Because adverse event profiles of pembrolizumab, capecitabine, and 
bevacizumab are non- overlapping, however, this combination of agents is expected to be well 
tolerated when administered at standard dose levels; thus the safety lead-in is expected to likely 
only require the six patients treated at the initial dose level.
6.3
Analysis Endpoints
6.3.1
Efficacy Endpoints
6.3.1.1 Primary Efficacy Endpoint Overall response rate (ORR) - RECIST 1.1
Overall response rate is defined as the proportion of the subjects in the analysis population who 
have a complete response (CR) or partial response (PR).

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6.3.1.2 Secondary Efficacy Endpoints 
Disease Control Rate (DCR) - RECIST 1.1 and irRECIST
Disease control rate (DCR) is defined as the percentage of subjects who have achieved 
confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to any evidence of 
progression.
Duration of Response (DOR) - RECIST 1.1 and irRECIST
For subjects who demonstrate CR or PR, duration of response is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
Progression-free Survival (PFS) - RECIST 1.1 and irRECIST
PFS is defined as the time from first day of study treatment to the first documented disease 
progression or death due to any cause, whichever occurs first.
Overall survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause.  Subjects 
without documented death at the time of the final analysis will be censored at the date of the last 
follow-up.
6.3.1.3 Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with capecitabine and bevacizumab in subjects with metastatic 
CRC. The primary safety analysis will be based on subjects who experienced toxicities as 
defined by CTCAE, Version 4.0 criteria (Appendix 12.6).  The attribution to drug, time-of-onset, 
duration of the event, its resolution, and any concomitant medications administered will be 
recorded. AEs will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and 
laboratory changes.
Furthermore, specific immune-related adverse events (irAEs) will be collected and designated as 
immune-related events of clinical interest (ECIs) as described in Section 7.2.3.2.
6.4
Analysis Populations
6.4.1
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, PFS, 
and OS.
The ASaT population consists of all subjects who received at least one dose of study treatment. 
The analysis population for DOR consists of responders.
Details on the approach to handling missing data are provided in Section 8.5 Statistical Methods.

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6.4.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in this 
study.  The ASaT population consists of all allocated subjects who received at least one dose of 
study treatment.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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.
Details on the approach to handling missing data for safety analyses are provided in Section 8.5 
Statistical Methods.
6.5
Statistical Methods
6.5.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary objectives.
For the primary efficacy endpoint of ORR, the point estimate and 95% confidence interval, will 
be provided using exact binomial method proposed by Clopper and Pearson (1934)54. Subjects in 
the primary analysis population (ASaT) without ORR data will be counted as non-responders.
For DCR, the point estimate, 95% confidence interval will be provided using exact binomial 
method proposed by Clopper and Pearson (1934)54. Subjects in the analysis population (ASaT) 
with missing DCR are considered as disease not under control.
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided as appropriate.
Censoring rules for DOR are summarized in Table 14.
Table 14. Censoring Rules for DOR
Situation
Date of Progression of Censoring
Outcome
Neither progression nor death, no 
new anti-cancer therapy initiated
Last adequate disease assessment
Censor (nonevent)
Neither progression nor death, new 
anti-cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor (non-event)
Death or progression after ≥ 2 
consecutive missed adequate 
disease assessments
Last adequate disease assessment 
prior to ≥ 2 missed adequate disease 
assessments
Censor (non-event)
Death or progression after ≤ 1 
missed adequate disease 
assessments
PD or death
End of response (Event)
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started a 
new anti-cancer therapy, and have not been determined to be lost to follow-up.
For PFS and OS endpoints, Kaplan-Meier (KM) curves and median estimates from the KM 
curves will be provided as appropriate.
The efficacy analysis is summarized in Table 15.

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Table 15. Analysis Strategy for Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data 
Approach
Primary Endpoint and Hypothesis
ORR

RECIST 1.1

Hypotheses: ORR per RECIST 
1.1 is greater than assumed 
historical control (4%).
Exact method 
based on binomial 
distribution
ASaT
Subjects with missing 
data are considered 
non- responders
Secondary Endpoints
DCR

RECIST 1.1
Exact method 
based on binomial 
distribution
ASaT
Subjects with missing 
data are considered 
as disease not under 
control
DOR

RECIST 1.1
Summary statistics 
using Kaplan- 
Meier method
All responders
Non-responders are 
excluded from 
analysis
PFS

RECIST 1.1
Summary statistics 
using Kaplan- 
Meier method
ASaT
Censored at last 
assessment
OS
Summary statistics 
using Kaplan-
Meier method
ASaT
Censored at last 
known alive date
6.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Count and percentage of AE will be 
provided.
6.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, randomized, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables 
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables for 
all enrolled subjects.
6.5.4
Analysis of Immunocorrelative Data
Wilcoxon rank-sum test will be used to assess whether there is a relationship between any of the 
immune cell subsets and objective response and with long/short-term survivors. Cox-
proportional hazard models will be applied to assess if there is relationship between any of the 
immune cell subsets and DOR, PFS, and OS, respectively. 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 response), and between subjects who have progression at 18 weeks vs. those who have 
not progressed in each arm. Additional analyses of immunocorrelative data are detailed in 
Appendices 11.6 and 11.7.

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6.5.5
Interim Analyses
There is one interim analysis planned in this study which will be performed after the first 29 
patients are accrued in the expansion cohort.  If there are 1 or fewer responses in these 29 
patients, the study will be stopped.  Otherwise, 15 additional patients will be accrued.
6.5.6
Multiplicity
The overall type I error is controlled at 5% (one-sided) by Simon’s two-stage design.
6.5.7
Sample Size and Power Calculations
In the initial safety lead-in phase, minimum of 6 patients and a maximum of 18 patients are 
required.
For expansion cohort: Simon's two-stage design (Simon, 1989) will be used. The null hypothesis 
that the true response rate is 4% will be tested against a one-sided alternative.  In the first stage, 
29 patients will be accrued (the patients in the safety lead-in cohort at MTD will be included in 
the expansion cohort).  If there are 1 or fewer responses in these 29 patients, the study will be 
stopped. Otherwise, 15 additional patients will be accrued for a total of 44. The null hypothesis 
will be rejected if 5 or more responses are observed in 44 patients.  This design yields a type I 
error rate of 0.0295 and power of 80% when the true response rate is 15%.
In this study, approximately total 44-56 subjects (the patients in the safety lead-in cohort at MTD 
will be included in the expansion cohort) with locally advanced unresectable or metastatic CRC 
will be enrolled.
6.6
Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and plotted within 
each category of the following classification variables:

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Race (white vs. non-white)

Prior exposure to bevacizumab

Stable disease or progression with prior exposure to 5FU or capecitabine

Primary tumor location (right vs. left colon or rectum)
The consistency of the treatment effect will be assessed descriptively via summary statistics by 
category for the classification variables listed above.
6.6.1
Compliance (Medication Adherence)
Drug accountability data for pembrolizumab, capecitabine, and bevacizumab will be collected 
during the study. Capecitabine accountability will be assessed based on the patient’s drug diary, 
which the study team will provide to the patient before each cycle. The drug diary will include 
the number of tablets and the strength of each tablet taken on each day of every cycle. Any 
missed doses or deviations from expected dosing will be documented in the form of a note-to-file 
or detailed in the office note from the next visit.  Any deviation from protocol-directed 
administration will be reported.

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Patients should take 28 doses of capecitabine over 14 days per cycle. If patients miss their 
morning dose on Day 1, they are allowed to make up this missed dose on Day 15 to complete 28 
doses.
Patients in the safety lead-in cohort need to take >75% of prescribed capecitabine tables to be 
considered “evaluable” during Cycle 1 for DLT determination.
6.6.2
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives the 
study medication infusion. Summary statistics will be provided on Extent of Exposure for ASaT 
population.
7
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
7.1
Pembrolizumab
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by Merck as summarized in Table 16.
Table 16. Product Description
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
7.1.1
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
7.1.2
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-Investigator, 
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.
7.1.3
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
7.1.4
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the trial.

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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.
7.2
Bevacizumab
7.2.1
Form
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate 
for solution for intravenous (IV) infusion.  Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and sterile water for injection (SWFI), USP. Vials contain no preservative and 
are suitable for single use only.  This agent is commercially available and manufactured by 
Genentech.
7.2.2
Storage and Stability
According to guidelines specified in the package insert.
7.2.3
Preparation
According to guidelines specified in the package insert.
7.2.4
Administration
Bevacizumab is to be administered according to institutional standards.
The dose of bevacizumab is 7.5 mg/kg IV on Day 1 of each three-week cycle.  A window of + 
3/- 1 day for bevacizumab dosing is acceptable but bevacizumab doses must be at least 10 days 
apart.
7.2.5
Accountability
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of bevacizumab which are to include start time of infusion, stop time of 
infusion, total volume.
7.3
Capecitabine
7.3.1
Form
Capecitabine supplied as biconvex, oblong film-coated tablets for oral administration. Each light 
peach-colored tablet contains 150 mg of capecitabine, and each peach-colored tablet contains 
500 mg of capecitabine. This agent is commercially available and manufactured by Genentech.
7.3.2
Storage and Stability
According to guidelines specified in the package insert.
7.3.3
Preparation
According to guidelines specified in the package insert.
7.3.4
Administration
Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Do 
not crush or cut capecitabine tablets. Capecitabine dose is calculated according to body surface 

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area. The dose of capecitabine is 1000 mg/m2 PO on Day 1-14 of each three-week cycle.  A 
window of
+ 3/- 1 day for capecitabine dosing each cycle is acceptable.  Do not make up missed doses 
within a cycle.
7.3.5
Accountability
Capecitabine accountability will be assessed based off of the patient’s drug diary, which the 
study team will provide to the patient before each cycle. The drug diary will include the number 
of tablets and the strength of each tablet taken on each day of the cycle. Any missed doses or 
deviations from expected dosing will be documented in the form of a note-to-file signed by the 
clinician or detailed in the office note from the next visit.
8
ADMINISTRATIVE AND REGULATORY DETAILS
8.1
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 Principal Investigator (PI) will have written and dated approval 
from the UCSF IRB 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 Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.
 All investigators 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.
8.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB (Institutional Review Board). Prior to obtaining IRB approval, the 
protocol must be approved by the Helen Diller Family Comprehensive Cancer Center GI 
Oncology 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.
8.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. 

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The original signed copy of the consent document must be retained in the medical record or 
research file.
8.4
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 Investigator 
and approved by PRC and the IRB prior to implementation.
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after 
implementation.
8.5
Handling and Documentation of Clinical Supplies
The UCSF PI 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 patients to whom study drug has been dispensed by patient number and 
initials will be included. The UCSF PI or Pharmacy designee 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 patients. Furthermore, the PI will not allow the investigational drug to be used in any 
manner other than that specified in this protocol.
8.6
Case Report Forms (CRFs)
The PI and/or qualified designees will prepare and maintain adequate and accurate participant 
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 (see Section 6.0), using single data entry with a secure access account. 
The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon 
completion of the study visit; the Investigator 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 patient’s medical records maintained by 
UCSF personnel. All source documentation should be kept in separate research folders for each 
patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI or another qualified 
investigator will approve all completed CRFs to attest that the information contained on the 
CRFs is true and accurate.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.

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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, the Trial Statistician, and the Protocol Project Manager.
8.7
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 11.1 Data and Safety Monitoring Plan for a Safety Lead-In and Phase 2 
Institutional Study, for additional information.
8.8
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the study 
drugs, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.
The Principal Investigator 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 including, for example, progress notes of the 
physician, 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, 
Study Chair-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient 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 study shall retain records for a period of 2 years 
following the date 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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9
REFERENCES
1. American Cancer Society Colorectal Cancer Facts & Figures 2014-2016 Atlanta: American 
Cancer Society 2014.
2. Venook A, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of 
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3. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus 
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4. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
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6. Diaz L, Le D, Yoshino T, et al. KEYNOTE-177: First-line, open-label, randomized, phase 3 
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7. Oh DY, Venook AP, Fong L. On the Verge: Immunotherapy for Colorectal Carcinoma. 
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10. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing 
bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with 
metastatic colorectal cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2003;21:60-5.
11. Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined 
analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves 
survival for patients with metastatic colorectal cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2005;23:3706-12.
12. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, 
and leucovorin for metastatic colorectal cancer. The New England journal of medicine 
2004;350:2335-42.
13. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin- based 
chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III 

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study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2008;26:2013-9.
14. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, 
fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: 
results from the Eastern Cooperative Oncology Group Study E3200. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2007;25:1539-44.
15. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is 
associated with prolonged overall survival in metastatic colorectal cancer: results from a 
large observational cohort study (BRiTE). Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2008;26:5326-34.
16. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus 
fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI 
Treatment Referral Center Trial TRC-0301. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2006;24:3354-60.
17. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in 
metastatic colorectal cancer (ML18147): a randomised phase 3 trial. The lancet oncology 
2013;14:29-37.
18. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with 
FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the 
BEAT study. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO 2009;20:1842-7.
19. Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus 
capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer 
(AVEX): an open-label, randomised phase 3 trial. The lancet oncology 2013;14:1077-85.
20. Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and 
bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled 
trial of the Dutch Colorectal Cancer Group. Lancet 2015;385:1843-52.
21. Arnold D, Graeven U, Lerchenmuller C. Maintenance strategy with fluoropyrimidines (FP) 
plus Bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of 
FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal 
cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207). . J Clin Oncol, 32 (suppl), 
p  5s (abstr 3503) 2014.
22. Diaz-Rubio E, Gomez-Espana A, Massuti B, et al. First-line XELOX plus bevacizumab 
followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy 
in patients with metastatic colorectal cancer: the phase III MACRO TTD study. The 
oncologist 2012;17:15-25.
23. Fuchs C, AE D, J T. Multicohort phase II KEYNOTE-059 study of pembrolizumab (MK- 
3475) for recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. 
. J Clin Oncol 33, (suppl; abstr TPS4135) 2015.
24. Tabernero J, Bang Y-J, Fuchs C. KEYNOTE-062: Phase III study of pembrolizumab (MK- 
3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line 
therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin 
Oncol,  Vol 34, No 4_suppl (February 1 Supplement) 2016.

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25. Sznol M, McDermott D, Jones S, et al. Phase Ib evaluation of MPDL3280A (anti-PDL1) in 
combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma 
(mRCC). . J Clin Oncol 33, 2015 (suppl 7; abstr 410) 2015.
26. Dudek A, Sica R, Sidani A, et al. Phase Ib study of pembrolizumab in combination with 
bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research 
Consortium BTCRC-GU14-003. J Clin Oncol 34, (suppl 2S; abstr 559) 2016.
27. Reardon D, De Groot J, Colman H, et al. Safety of pembrolizumab in combination with 
bevacizumab in recurrent glioblastoma (rGBM). . J Clin Oncol 34, (suppl; abstr 2010) 2016.
28. Hochster H, Bendell J, Cleary J, et al. Efficacy and safety of atezolizumab (atezo) and 
bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic 
colorectal cancer (mCRC). J Clin Oncol 35, 2017 (suppl 4S; abstract 673).
29. McDermott DF, Huseni MA, Atkins MB, et al. Publisher Correction: Clinical activity and 
molecular correlates of response to atezolizumab alone or in combination with bevacizumab 
versus sunitinib in renal cell carcinoma. In: Nat Med. Vol 24. United States2018:1941.
30. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, 
placebo-controlled, phase 3 trial. Lancet 2013;381:303-12.
31. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. The New England journal of medicine 2015;372:1909-19.
32. Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated 
myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor 
immunity. Cancer research 2010;70:3052-61.
33. Kanterman J, Sade-Feldman M, Biton M, et al. Adverse immunoregulatory effects of 5FU 
and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer 
outcomes. Cancer research 2014;74:6022-35.
34. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of 
Conventional Chemotherapy and Targeted Anticancer Agents. Cancer cell 2015;28:690-714.
35. Wang B, Xu D, Yu X, et al. Association of intra-tumoral infiltrating macrophages and 
regulatory T cells is an independent prognostic factor in gastric cancer after radical resection. 
Annals of surgical oncology 2011;18:2585-93.
36. Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance 
the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. 
British journal of cancer 2010;102:115-23.
37. Pinheiro E, Hinton M, Mangadu R, et al. Preclinical Combination Strategies to Enhance the 
Efficacy of the Anti-PD1 Antibody Pembrolizumab. . Cancer Res 76(14 Suppl):Abstract nr 
543 2016.
38. Griffioen AW. Anti-angiogenesis: making the tumor vulnerable to the immune system. 
Cancer Immunol Immunother 2008;57:1553-8.
39. Johnson BF, Clay TM, Hobeika AC, Lyerly HK, Morse MA. Vascular endothelial growth 
factor and immunosuppression in cancer: current knowledge and potential for new therapy. 
Expert Opin Biol Ther 2007;7:449-60.
40. Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. Immunol 
Res 2001;23:263-72.

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41. Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the 
development of dendritic cells and dramatically affects the differentiation of multiple 
hematopoietic lineages in vivo. Blood 1998;92:4150-66.
42. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor 
by human tumors inhibits the functional maturation of dendritic cells. Nature medicine 
1996;2:1096-103.
43. Mulligan JK, Day TA, Gillespie MB, Rosenzweig SA, Young MR. Secretion of vascular 
endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to 
suppress T-cell functions. Hum Immunol 2009;70:375-82.
44. Ohm JE, Gabrilovich DI, Sempowski GD, et al. VEGF inhibits T-cell development and may 
contribute to tumor-induced immune suppression. Blood 2003;101:4878-86.
45. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell 
maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic 
progenitor cells. J Immunol 1998;160:1224-32.
46. Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor vasculature as 
antitumor immune modulators: the role of vascular endothelial growth factor and endothelin. 
Current topics in microbiology and immunology 2011;344:129-48.
47. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with 
metastatic melanoma. Cancer Immunol Res 2014;2:632-42.
48. Huang X, Raskovalova T, Lokshin A, et al. Combined antiangiogenic and immune therapy of 
prostate cancer. Angiogenesis 2005;8:13-23.
49. Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment 
reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. 
Proceedings of the National Academy of Sciences of the United States of America 
2012;109:17561-6.
50. Miyazaki J, Tsuzuki Y, Matsuzaki K, et al. Combination therapy with tumor-lysate pulsed 
dendritic cells and antiangiogenic drug TNP-470 for mouse pancreatic cancer. International 
journal of cancer Journal international du cancer 2005;117:499-505.
51. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic 
agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of 
adoptive immunotherapy of cancer. Cancer research 2010;70:6171-80.
52. Li B, Lalani AS, Harding TC, et al. Vascular endothelial growth factor blockade reduces 
intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer 
immunotherapy. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2006;12:6808-16.
53. Manning EA, Ullman JG, Leatherman JM, et al. A vascular endothelial growth factor 
receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research 2007;13:3951-9.
54. Clopper C, Pearson E. he use of confidence or fiducial limits illustrated in the case of 
binomial. . Biometrika 1934;26(4):404-13.

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APPENDIX A: Data and Safety Monitoring Plan: Institutional (Single Site) Phase II Trial 
with Safety Lead-In Phase
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 trials.  A summary of DSMC activities for this trial 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 trials with a safety lead-in are designated with a high-risk assessment 
during the safety lead-in phase and a moderate risk assessment for the remainder of the trial.  
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).  Additionally, the assigned 
DSMC Monitor/Auditor will review no more than a total of 10 participant charts through five 
cycles of treatment 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.  An 
abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA 
logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a full 
regulatory review will occur on a biennially basis by the DSMC for regulatory compliance.
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 

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reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.  
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 
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.

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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 
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.

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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 B: ECOG Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction.
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).
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.
3
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self- 
care.  Totally confined to bed or chair.
5
Dead.
*As published in Am.  J. Clin.  Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.

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APPENDIX C: Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)

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APPENDIX D: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.
* As 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.

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APPENDIX E: Response Evaluation by Immune-related RECISE (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. RECIST may not provide an accurate response 
assessment of immunotherapeutic agents such as pembrolizumab. Immune-related RECIST 
(irRECIST) is RECIST 1.1 adapted as described below to account for the unique tumor response 
seen with immunotherapeutics. Following site identification of PD, irRECIST will be used by 
site investigators to assess tumor response and progression and make treatment decisions.

If radiologic imaging by the site identifies PD by RECIST 1.1, subject management and 
tumor assessment will shift to irRECIST. Imaging should be repeated ≥4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.

If repeat imaging shows < 20% tumor burden compared to nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved non -target 
disease (if identified as cause for initial PD), PD is not confirmed. Treatment may 
continue and subsequently follow regular imaging schedule.

If repeat imaging confirms PD (irPD) due to any of the scenarios listed below, subjects 
will be discontinued from study therapy (exception noted in Section 7.1.4.1.5.1). In 
determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
In subjects who have initial evidence of radiological PD by the site, it is at the discretion of the 
site investigator whether to continue a subject on study treatment until repeat imaging is obtained 
(irRECIST subject management). This clinical judgment decision should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Subjects may receive study treatment while waiting for confirmation of PD if 
they are clinically stable as defined by the following criteria:

Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

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
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of PD.

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APPENDIX F: Immunocorrelative Biomarker Specimen Guidance
Background and Overview
Blood and tumor specimens will be processed and banked for use in immunocorrelative research 
including but not limited to that described below.
Characterization and quantification of tumor-infiltrating immune cells and other potentially 
predictive biomarkers: Baseline tumor and on-treatment immune profile will be assessed by 
quantifying the number of infiltrating T cells subsets, including cytotoxic CD8+, helper 
CD4+FOXP3-, and regulatory CD4+FOXP3+ T cells. The proportion of activated T cells (e.g. 
PD1+ and Ki67+) will also be analyzed, as will myeloid-derived suppressor cells (e.g. M2 
CD68/Arg-1, M1 CD68/iNOS). 
T cell receptor (TCR) sequencing (blood and tumor biopsy): TCR sequencing can also be used to 
track immunotherapy induced changes in T cell repertoire and T cell clonotypes in the blood and 
tumor tissue. T cells see antigen through their TCR, which is comprised of two subunits, α and β. 
Each is generated by a variable diversity joining (VDJ) recombination event resulting in a broad 
range of T cell clones with different specificities. The β subunit has greater clonal diversity. 
Next- generation sequencing (NGS) of the T cell receptor β chain (TCRβ) has been used to 
define the diversity and frequency of T cell clones in the blood and tumor tissue of cancer 
patients after immunotherapy treatment and has been shown to associate with clinical response 
and OS (Vanneman, Nat. Rev. Cancer 2012; Robert, NEJM 2011). Fong, et al. performed TCR 
next- generation sequencing (NGS) on serial blood (PBMC) samples and prostatectomy samples 
from sipuleucel-T treated patients (Fong, JNCI 2014). Changes in TCR sequence frequency and 
diversity showed that sipuleucel-T treatment narrows the TCR repertoire in the blood while 
increasing the TCR diversity in prostate tissue. The increase in common TCR sequences 
(clonotypes) between tumor and blood supports the notion of treatment-induced T cell migration 
into prostate tissue.
CTLA-4 blockade also induces global remodeling of the T cell repertoire (Cha Sci Transl Med, 
2014). Anti-CTLA-4 administration promotes active turnover in the T cell repertoire, which 
increases with sequential treatments and leads to increased repertoire diversity. These changes 
occurred both in naïve and non-naïve T cells, the latter of which includes the antigen-
experienced, effector T cell population. Interestingly, maintenance of pre-existing, high-
frequency clonotypes (greater than 1 in 1000) is associated with clinical response and improved 
overall survival following ipilimumab. Importantly, recent data suggest that immune repertoire 
diversity following immune checkpoint blockade can be detrimental as well as beneficial (Oh, 
Procl AACR 2016). Patients with immune related adverse events also demonstrate a more 
diverse T cell repertoire with an increase in T cell clonotypes, and greater degree of change in 
clonal frequencies of CD8+ T cells.
Using established techniques (UCSF CIL), NGS will be used to quantify the T cell immune 
response induced by pembrolizumab. TCR clonotypes will be characterized at baseline (blood 
and pre- treatment tumor biopsy), as will changes in the T cell immune response over time 

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-30-2021
Protocol CC#: 174517
Phase II -- Pembrolizumab
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(blood; on-treatment biopsy). The data may inform optimal use of therapies in the patient 
population under study and identify candidate biomarkers of response, resistance or toxicity.
Characterization of peripheral immune cell subsets (blood): Circulating immune cells may be 
assessed by multiparameter flow cytometry on peripheral blood samples. T cell activation status 
may be characterized.
Specimen Collection Procedures 
Archival Tumor
A minimum of 1 formalin-fixed paraffin-embedded (FFPE) archival tumor tissue block 
(preferred) or a minimum of 15 FFPE unstained sections from most recent pre-registration 
biopsy/surgery are to be collected, if available, together with the corresponding pathology report, 
within 60 days of registration.
Specimens will be transported to the UCSF CIL for storage and processing. 
Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container in order to avoid slides breaking during shipping and handling process.
UCSF Cancer Immunotherapy Lab (CIL) 
Fresh Tumor Biopsies
All patients in the Phase II portion of the study prior to the interim analysis will undergo a 
mandatory core needle biopsy of a metastatic tumor prior to cycle 1 day 1, as well as prior to 
cycle 2, day 1 (pre-treatment and on-treatment biopsies).
Six 18-gauge cores, 1 cm depth (or equivalent) should be obtained at each time point with the 
prioritization below. A fine needle aspirate is not acceptable.
If it is not feasible to use an 18-gauge needle, a 20-gauge needle may be used with sponsor-
investigator approval, in which case all six cores should be processed as FFPE.
Core #
Processing Method
1
FFPE
2
Flash Frozen
3
FFPE
4-6
Fresh

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-30-2021
Protocol CC#: 174517
Phase II -- Pembrolizumab
Page 66 of 102
FFPE and flash frozen cores should be processed per UCSF Biospecimen Resources (BIOS) 
standard operating procedures. Fresh Cores for UCSF CIL should be placed on a sterile gauze, 
wet with DPBS, placed in sterile container(s) appropriately labeled with patient and sample 
information, placed on ice, and delivered directly to the Fong lab (UCSF CIL) within 4 hours of 
tissue acquisition. All patient identifiers will be blacked out or scratched off before disposal of 
the container.
An H&E stained FFPE section of the pre-treatment biopsy and will be reviewed by a pathologist 
for tumor content. If no tumor cells are identified on the H&E, an on-treatment biopsy will not 
be performed (the pre-treatment biopsy will also not be repeated).  The total number of biopsies 
performed will be tallied at the time of interim analysis. If the total number of biopsies is <46, 
additional pre-treatment (but not on-treatment) biopsies will be required in post interim analysis 
patients until the total number of tumor biopsies performed reaches 46.
Research Blood Collection
All patients will have green top (heparin-treated) and PAXgene tubes of blood specimens 
collected following the schedule below.
Time point
# of green top tubes 
(heparin treated). Up to:
# of PAXgene tube
Screening (Day -28 to -1)
4 (40 mL)
1 (10 mL)
Day 1 of cycle 1
6 (60mL total)
0
Day 1 of cycle 2
6 (60mL total)
1 (10 mL)
Day 1 of cycle 3
4 (40mL total)
1 (10 mL)
Progression or treatment discontinuation
4 (40mL total)
1 (10 mL)
These specimens will be transported at room temperature to UCSF CIL within 12 hours of blood 
collection.
The study CRC will notify appropriate personnel in the UCSF CIL of anticipated tissue and 
blood arrival with at least 24-hour notice.