Conditions: High Grade Malignant Neuroendocrine Carcinoma (Diagnosis)
Keywords: NEC
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This is a pilot study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinoma

Detailed description:
PRIMARY OBJECTIVE:

1\. Evaluate the best overall response rate (ORR) of pembrolizumab or pembrolizumab plus chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (investigator-reported).

SECONDARY OBJECTIVE:

1. To determine the safety and tolerability of pembrolizumab-based therapy in this patient population.
2. To evaluate duration of response (DOR) in participants receiving pembrolizumab or pembrolizumab plus chemotherapy.
3. To evaluate progression free survival (PFS) in participants treated with pembrolizumab or pembrolizumab plus chemotherapy (median PFS and 18 wk PFS).
4. To evaluate overall survival (OS) in participants receiving pembrolizumab or pembrolizumab plus chemotherapy.

OUTLINE:

Part A: Participants are treated with pembrolizumab alone. An adaptive Simon's two-stage design was used, and the overall plan hinges on the activity of single agent pembrolizumab in the first stage of Part A. If there is sufficient activity in the first stage of Part A, the study will expand to the second stage of Part A and forgo Part B. If there is insufficient activity in the first stage of Part A, the study will proceed to the first stage of Part B (pembrolizumab plus chemotherapy).

Part B: Participants are treated with pembrolizumab plus chemotherapy (physician's choice, paclitaxel or irinotecan). Patients with stable disease (SD) or better after 9 cycles (27 weeks) of pembrolizumab-based therapy will have the option to continue with pembrolizumab alone, unless the first partial response (PR) or complete response (CR) is noted at 27 weeks.

All participants will undergo a pre-treatment tumor biopsy (unless the tumor is inaccessible and/or a biopsy is not felt to be in the participant's best interest). Participants may continue study treatment until progressive disease (PD), unacceptable adverse events, inter-current illness that prevents further administration of treatment, investigator's decision to withdraw the participant, the participant withdraws consent, pregnancy of the participant, noncompliance with trial treatment or procedure requirements, participant receives 35 treatments (approximately 2 years) of pembrolizumab, or administrative reasons requiring cessation of treatment.

Arms:
arm 1: Participants will receive 200 mg of pembrolizumab via IV over 30 minutes every 3 weeks for 24 months or 35 administrations (whichever comes first). arm 2: Participants will receive 200 mg of pembrolizumab via IV over 30 minutes every 3 weeks for 24 months or 35 administrations (whichever comes first) and chemotherapy treatment of 125 mg/m\^2 of irinotecan via IV on days 1 and 8 of each 21-day cycle or paclitaxel via IV on days 1, 8, and 15 of each 21-day cycle per physician discretion

Interventions: intervention 1: Pembrolizumab intervention 2: Irinotecan intervention 3: Paclitaxel
Intervention descriptions: intervention 1: Given Intravenously (IV) intervention 2: Given IV intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
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.
A Pilot Study of Pembrolizumab-based Therapy in 
Previously Treated High Grade Neuroendocrine 
Carcinomas
Protocol Number:  CC #169524
Investigational Product: Pembrolizumab
Version Number:  4.0
Version Date:  04/14/2021
IND Number:  Exempt
Principal Investigator
Emily Bergsland, MD 
University of California San Francisco
Co-Principal Investigators:
Jennifer Ang Chan, MD
Nitya Raj, MD
Dana Farber Cancer Institute 
Memorial Sloan Kettering Cancer Center
 
Statistician
Li Zhang, Ph.D.
Revision History
Version 1.1
03/04/2016
Version 1.2
09/27/2016
Version 1.3
11/14/2016
Version 1.4
01/02/2017
Version 1.5
02/07/2017
Version 1.6
03/03/2017
Version 1.7
04/20/2017
Version 1.8
08/10/2017
Version 1.9
03/12/2018
Version 2.0
01/02/2019
Version 2.1
03/31/2020
Version 3.0
08/14/2020
Version 3.1
02/02/2021
Version 4.0
04/14/2021
NCT# 03136055


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Protocol Signature Page
Protocol No.: 169524
Version Date: 04/14/2021
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC). 
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements. 
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date


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Protocol Signature Page – Participating Sites
Protocol No.: 169524
Version Date: 04/14/2021
Participating Site(s)
Principal Investigator Name:  
Jennifer Ang Chan, MD
Institution Name:
Dana Farber Cancer Institute
Address:  
Telephone: 
E-mail:  
Principal Investigator Name: 
Nitya Raj, MD
Institution Name:
Memorial Sloan Kettering Cancer Center
Address:  
Telephone:  
E-mail:  
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, and local regulatory 
requirements.  
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date


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Abstract
Title
A Pilot Study of Pembrolizumab-based Therapy in Previously Treated 
High Grade Neuroendocrine Carcinomas
Study Description
This is a single arm, open-label, adaptive two-stage study in biomarker 
“unselected” subjects with previously treated advanced extrapulmonary 
high-grade neuroendocrine carcinomas (excluding small cell and large 
cell lung neuroendocrine carcinoma, SCLC and Merkel cell carcinoma, 
MCC). 
There are two parts of the study. In Part A, subjects are treated with 
pembrolizumab alone and in Part B with pembrolizumab plus 
chemotherapy (physician’s choice, paclitaxel or irinotecan). All subjects 
will undergo a pretreatment tumor biopsy (unless the tumor is 
inaccessible and/or a biopsy is not felt to be in the patient’s best 
interest). 
Phase of Study
Pilot
Investigational 
Products
Pembrolizumab
Study population
Adult patients of either sex with diagnosed Advanced, poorly 
differentiated (G3) NEC (excluding SCLC and Merkel cell carcinoma) 
Primary Objective
to evaluate the best overall response rate (ORR) of pembrolizumab or 
pembrolizumab plus chemotherapy according to RECIST1.1 
(investigator-reported). 
Secondary 
Objectives
1) to determine the safety and tolerability of pembrolizumab-based
therapy in this patient population.
2) to evaluate duration of response (DOR) in patients receiving
pembrolizumab or pembrolizumab plus chemotherapy.
3) to evaluate progression free survival (PFS) in subjects treated with
pembrolizumab or pembrolizumab plus chemotherapy (median
PFS and 18 wk PFS).
4) to evaluate overall survival (OS) in subjects receiving
pembrolizumab or pembrolizumab plus chemotherapy.
Sample Size
Approximately a total of 35 subjects (all treated by pembrolizumab) or 
36-42 (first 14 treated by pembrolizumab and next 22-28 treated by
pembrolizumab plus chemotherapy) will be enrolled in the study.


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Duration of Study 
Treatment
Participants may continue study treatment until progressive disease 
(PD), unacceptable adverse events (AEs), 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, 
subject receives 35 treatments (approximately 2 years) of 
pembrolizumab, or administrative reasons requiring cessation of 
treatment.
Duration of Follow 
up
After the end of treatment, each subject will be followed for 30 days for 
AE monitoring. Serious adverse events (SAE) and events of clinical 
interest (ECI) will be collected for 90 days after the end of treatment or 
for 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.


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List of Abbreviations
Abbreviation/Term
Definition
5-FU
5-fluorouracil     
AE
Adverse Event    
ALT
Alanine Aminotransferase    
ANC
Absolute Neutrophil Count   
AP
Alkaline Phosphatase    
ASaT
All Subjects as Treated  
aPTT
Activated Partial Thromboplastin Time  
AST
Aspartate Aminotransferase    
ß-HCG
Beta Human Chorionic Gonadotropin  
CBC
Complete Blood Count   
CNS
Central Nervous System   
CPI
Checkpoint Pathway Inhibitor
CR
Complete Response    
CrCl
Calculated Creatinine Clearance   
CRF
Case Report Form   
CT
Computed Tomography    
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4   
DCR
Disease Control Rate   
DKA
Diabetic Ketoacidosis
DLT
dose limiting toxicity
DOR
Duration of Response   
ECI
Events of Clinical Interest  
ECOG
Eastern Cooperative Oncology Group  
ERC
Ethics Review Committee   
FDA
Food and Drug Administration  
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FOLFIRI
Folinic Acid - Fluorouracil - Irinotecan
GCP
Good Clinical Practice   
GI
gastrointestinal
GFR
Glomerular Filtration Rate   
HBsAg
Hepatitis B surface Antigen  
HCV
Hepatitis C Virus   
HIV
Human Immunodeficiency Virus   
IB
Investigator’s Brochure    
ICF
Informed Consent Form   
ICH
International Conference on Harmonization  
IHC
Immunohistochemistry     


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List of Abbreviations
Abbreviation/Term
Definition
IND
Investigational New Drug
INR
International Normalized Ratio   
irAEs
Immune-related Adverse Events   
irRECIST
Immune related RECIST (Modification of RECIST 1.1)
IRB
Institutional Review Board   
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif  
ITSM
Immunoreceptor Tyrosine-based Switch Motif  
IV
Intravenous     
IVRS
Interactive Voice Response System  
IWRS
Integrated Web Response System  
Kg
Kilogram     
LCNEC
Large Cell Neuroendocrine Carcinoma
LDH
Lactate Dehydrogenase    
mAb
Monoclonal Antibody    
mcL
Microliters     
MDSC
Myeloid-derived Suppressor Cell
MEL
Melanoma     
Mg
Milligram     
Mg/kg
Milligram per Kilogram   
mL
milliliter     
MRI
Magnetic Resonance Imaging   
mRNA
Messenger RNA
NA or N/A
Not Applicable  
NCI
National Cancer Institute   
NE
Neuroendocrine
NEC
Neuroendocrine carcinoma
NET
Neuroendocrine tumor
NGS
Next Generation Sequencing
NMR
Nuclear magnetic resonance
NSAID
Non-Steroidal Anti-inflammatory Drug   
NSCLC
Non-Small Cell Lung Cancer  
ORR
Overall Response Rate   
OS
Overall Survival    
OTC
Over-the-counter     
PD
Progressive Disease    
PD-L1
Programmed Death Ligand 1
PD-NEC
Poorly-differentiated neuroendocrine carcinoma
PFS
Progression Free Survival   
PK
Pharmacokinetic     


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List of Abbreviations
Abbreviation/Term
Definition
PR
Partial Response    
PT
Prothrombin Time    
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid    
RR
Response Rate    
Q9W
Every 9 Weeks   
SAE
Serious Adverse Events   
SCC
small cell carcinoma
SGOT
Serum Glutamic Oxaloacetic Transaminase  
SGPT
Serum Glutamic Pyruvic Transaminase  
SOP
Standard Operating Procedures   
TB
Bacillus Tuberculosis
TCRβ
T Cell Receptor β
TGR
Tumor Growth Rate
TIL
Tumor Infiltrating Lymphocytes   
TKI
Tyrosine Kinase Inhibitor
TSH
Thyroid Stimulating Hormone   
ULN
Upper Limit of Normal  
WBC
White Blood Cell   
WD-NET
Well-differentiated neuroendocrine tumor


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TABLE OF CONTENTS
Protocol Signature Page..........................................................................................................2
Protocol Signature Page – Participating Sites.......................................................................3
Abstract ....................................................................................................................................4
List of Abbreviations ...............................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
1
TRIAL DESIGN ........................................................................................................15
1.1
Trial Design............................................................................................................15
1.2
Trial Diagram ........................................................................................................16
2
OBJECTIVES & HYPOTHESES............................................................................17
2.1
Primary Objective & Hypothesis .........................................................................17
2.2
Secondary Objectives ............................................................................................17
2.3
Exploratory Objectives .........................................................................................17
3
BACKGROUND & RATIONALE ..........................................................................18
3.1
Background ............................................................................................................18
3.1.1
Pharmaceutical and Therapeutic Background .....................................................18
3.1.2
Preclinical and Clinical Trial Data.......................................................................19
3.1.3
Preclinical Studies................................................................................................19
3.1.4
Ongoing Clinical Trials .......................................................................................19
3.2
Rationale.................................................................................................................19
3.2.1
Rationale for the Trial and Selected Subject Population .....................................19
3.2.2
Rationale for Dose Selection/Regimen/Modification..........................................21
3.2.3
Rationale for Endpoints .......................................................................................25
4
METHODOLOGY ....................................................................................................27
4.1
Entry Criteria ........................................................................................................27


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4.1.1
Diagnosis/Condition for Entry into the Trial.......................................................27
4.1.2
Subject Inclusion Criteria ....................................................................................27
4.1.3
Subject Exclusion Criteria ...................................................................................30
4.2
Trial Treatments....................................................................................................32
4.3
Dose Selection/Modification..................................................................................32
4.3.1
Dose Selection .....................................................................................................32
4.3.2
Safety Lead-in......................................................................................................33
4.3.3
Definition of DLT for irinotecan .........................................................................33
4.3.4
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab and Combination Therapy ..............................34
4.4
Timing of Dose Administration............................................................................41
4.5
Duration of therapy...............................................................................................42
4.6
Trial Blinding/Masking.........................................................................................42
4.7
Randomization or Treatment Allocation ............................................................42
4.8
Stratification...........................................................................................................43
4.9
Concomitant Medications/Vaccinations (allowed & prohibited)......................43
4.9.1
Acceptable Concomitant Medications.................................................................43
4.9.2
Prohibited Concomitant Medications ..................................................................43
4.10
Rescue Medications & Supportive Care..............................................................44
4.10.1 Supportive Care Guidelines.................................................................................44
4.11
Diet/Activity/Other Considerations .....................................................................47
4.11.1 Diet.......................................................................................................................47
4.11.2 Contraception.......................................................................................................47
4.11.3 Use in Pregnancy .................................................................................................48
4.11.4 Use in Nursing Women........................................................................................48


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4.12
Subject Withdrawal/Discontinuation Criteria....................................................48
4.12.1 Discontinuation of Study Therapy after Complete Response (CR).....................49
4.13
Subject Replacement Strategy..............................................................................49
4.14
Stopping Rule.........................................................................................................49
4.15
Clinical Criteria for Early Trial Termination ....................................................49
5
TRIAL FLOW CHART............................................................................................51
5.1
Pembrolizumab alone............................................................................................51
5.2
Pembrolizumab plus irinotecan ...........................................................................53
5.3
Pembrolizumab plus paclitaxel ............................................................................56
6
TRIAL PROCEDURES ............................................................................................59
6.1
Trial Procedures ....................................................................................................59
6.2
Administrative Procedures ...................................................................................59
6.2.1
Informed Consent ................................................................................................59
6.2.2
General Informed Consent...................................................................................59
6.2.3
Review of Inclusion/Exclusion Criteria...............................................................59
6.2.4
Medical History ...................................................................................................59
6.2.5
Prior and Concomitant Medications Review.......................................................60
6.2.6
Disease Details and Treatments...........................................................................60
6.2.7
Assignment of Screening Number.......................................................................60
6.2.8
Assignment of Randomization Number ..............................................................60
6.2.9
Trial Compliance (Medication/Diet/Activity/Other)...........................................61
6.3
Clinical Procedures/Assessments .........................................................................61
6.3.1
Adverse Event (AE) Monitoring..........................................................................61
6.3.2
Full Physical Exam..............................................................................................61
6.3.3
Directed Physical Exam.......................................................................................61


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6.3.4
Vital Signs............................................................................................................61
6.3.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...................62
6.3.6
Tumor Imaging and Assessment of Disease........................................................62
6.3.7
Baseline brain imaging ........................................................................................62
6.4
Laboratory Procedures/Assessments...................................................................62
6.4.1
Serum/Urine β-hCG.............................................................................................64
6.5
Post-study Anti-Cancer Therapy Status..............................................................64
6.6
Tumor Tissue Collection and Correlative Studies Blood Sampling .................64
6.6.1
Fresh Tumor Biopsy for Correlative Studies.......................................................65
6.6.2
Blood collections for Correlative Studies............................................................65
6.7
Other Procedures...................................................................................................66
6.7.1
Withdrawal/Discontinuation................................................................................66
6.7.2
Blinding/Unblinding............................................................................................66
6.8
Visit Requirements ................................................................................................66
6.8.1
Screening .............................................................................................................66
6.8.2
Treatment Period..................................................................................................66
6.8.3
Post-Treatment Visits ..........................................................................................66
7
ASSESSING AND RECORDING ADVERSE EVENTS.......................................67
7.1
Definition of an Adverse Event.............................................................................67
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ...........................................................................................68
7.3
Reporting of Pregnancy and Lactation to the Sponsor and to Merck..............68
7.4
Immediate Reporting of Adverse Events to the Sponsor and to Merck...........68
7.4.1
Serious Adverse Events .......................................................................................68
7.4.2
Events of Clinical Interest....................................................................................69


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7.5
Evaluating Adverse Events...................................................................................70
7.6
Sponsor Responsibility for Reporting Adverse Events......................................73
8
STATISTICAL PLAN...............................................................................................73
8.1
Statistical Analysis Plan Summary ......................................................................73
8.1.1
Primary objective.................................................................................................73
8.1.2
Other objectives...................................................................................................73
8.2
Statistical Analysis Plan ........................................................................................74
8.2.1
Analysis populations............................................................................................74
8.2.2
Primary Efficacy Objective: Overall response rate .............................................74
8.2.3
Secondary Efficacy Objectives............................................................................75
8.2.4
Statistical Methods for Safety Analyses..............................................................75
8.3
Statistical Analysis Plan Summary: Exploratory Objectives............................76
8.3.1
Molecular Characteristics of NEC.......................................................................76
8.3.2
Tumor Growth Rate (TGR) .................................................................................77
9
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................77
9.1
Investigational Product .........................................................................................77
9.2
Packaging and Labeling Information..................................................................78
9.3
Clinical Supplies Disclosure..................................................................................78
9.4
Storage and Handling Requirements...................................................................78
9.5
Returns and Reconciliation...................................................................................78
9.6
Chemotherapy........................................................................................................78
10
ADMINISTRATIVE AND REGULATORY DETAILS .......................................79
10.1
Confidentiality .......................................................................................................79
10.1.1 Confidentiality of Data ........................................................................................79


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10.1.2 Protection of Privacy ...........................................................................................79
10.2
Compliance with Financial Disclosure Requirements .......................................79
10.3
Compliance with Law, Audit and Debarment ....................................................79
10.4
Compliance with Trial Registration and Results Posting Requirements.........79
10.5
Study Management................................................................................................80
10.5.1 Pre-Study Documentation....................................................................................80
10.5.2 Institutional Review Board Approval..................................................................80
10.5.3 Informed Consent ................................................................................................80
10.5.4 Changes in the Protocol.......................................................................................80
10.5.5 Handling and Documentation of Clinical Supplies .............................................81
10.5.6 Oversight and Monitoring Plan............................................................................81
10.5.7 Multicenter Communication................................................................................81
10.5.8 Coordinating Center Documentation of Distribution ..........................................82
10.5.9 Regulatory Documentation..................................................................................82
10.6
Data Management..................................................................................................83
11
References...................................................................................................................84
APPENDIX 1: ECOG Performance Status.........................................................................90
APPENDIX 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE)......91
APPENDIX 3: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors.....................................................................92
APPENDIX 4: Immune-Related Response Criteria (irRC) for Evaluation of Immune 
Therapy Activity in Solid Tumors............................................................................93
APPENDIX 5: Data and Safety Monitoring Plan: Multicenter Phase 2 or 3 Trial with 
Safety Lead-In............................................................................................................94


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1
TRIAL DESIGN
1.1Trial Design
This is a single arm, open-label, adaptive two-stage study in biomarker “unselected” subjects 
with previously treated advanced extrapulmonary high-grade neuroendocrine carcinomas 
(excluding small cell and large cell lung neuroendocrine carcinoma, SCLC and Merkel cell 
carcinoma, MCC). In addition to positive markers of neuroendocrine differentiation, NECs are 
typically defined by having small cell or large cell NEC morphology Subjects will be required to 
have a least one measureable lesion by Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) for response assessment, and have been previously treated with at least one line of 
systemic therapy. 
There are two parts of the study. In Part A, subjects are treated with pembrolizumab alone and 
in Part B with pembrolizumab plus chemotherapy (physician’s choice, paclitaxel or irinotecan). 
All subjects will undergo a pretreatment tumor biopsy (unless the tumor is inaccessible and/or a 
biopsy is not felt to be in the patient’s best interest). Adaptive Simon’s two-stage design is used. 
The overall plan hinges on the activity of single agent pembrolizumab in the first stage of Part A. 
If there is sufficient activity in the first stage of Part A, the study will expand to the second stage 
of Part A and forgo Part B. If there is insufficient activity in the first stage of Part A, the study will 
proceed to the first stage of Part B (pembrolizumab plus chemotherapy). Approximately a total 
of 35 subjects (all treated by pembrolizumab) or 36-42 (first 14 treated by pembrolizumab and 
next 22-28 treated by pembrolizumab plus chemotherapy) will be enrolled in the study. Data 
from irinotecan and paclitaxel treated patients will be pooled.
The primary objective of this trial is to evaluate the best overall response rate (ORR) of 
pembrolizumab or pembrolizumab plus chemotherapy according to RECIST1.1 (investigator-
reported). On study, imaging assessments will be performed every 9 weeks for 6 months (27 
weeks) then every 12 weeks (Q12W) calculated from the date of allocation and independent of 
treatment delays. RECIST 1.1 will be used 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 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 or pembrolizumab plus chemotherapy 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. 
Subjects will continue to be treated with pembrolizumab or pembrolizumab plus chemotherapy 
until PD, unacceptable AEs, 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 the subject has received 35 treatments pembrolizumab (approximately 2 years). Subjects 
who discontinue treatment for reasons other than PD will have post-treatment follow-up for 
disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone for OS until death, 
withdrawal of consent, or the end of the study, whichever comes first. 
Subjects who attain confirmed CR 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.


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Adverse events 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 (Appendix 2). After the end of treatment, each subject will 
be followed for 30 days for AE monitoring. SAEs and ECIs will be collected for 90 days after the 
end of treatment or for 30 days after the end of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.
This study will be conducted in compliance with Good Clinical Practice.
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 (Section5). Details of each 
procedure are provided in the Trial Procedures (Section6). Mandatory pre-treatment biopsy is 
required in all patients (unless the tumor is inaccessible and/or a biopsy is not felt to be in the 
patient’s best interest). 
1.2Trial Diagram
 

Single arm, open-label, adaptive two-stage study in biomarker “unselected” subjects with 
previously treated advanced high-grade neuroendocrine carcinomas (excluding small cell 
lung carcinoma, SCLC, large cell NEC of lung, and Merkel cell carcinoma, MCC).

The overall plan hinges on the activity of single agent pembrolizumab in the first stage of 
Part A. If there is sufficient activity in the first stage of Part A, the study will expand to the 
second stage of Part A and forgo Part B (total N=35 pt). 

If there is insufficient activity in the first stage of part A, the study will proceed to Part B 
(pembrolizumab plus chemotherapy) after a safety lead-in (6 pt) for irinotecan plus 


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pembrolizumab (with an option to assess dose level -1 if there are safety concerns). The 
total sample size for Part B will be N=22-28.

After all 14 patients have been enrolled to stage I of part A, and while waiting for their 18-
week efficacy data, up to six patients can be accrued to the safety lead-in for Part B. This 
will help to avoid significant delays in accrual to the study, and streamline the transition to 
part B if required due to a lack of efficacy in Part A. If >2 responses occur in Part A Stage 1 
before Part B safety lead-in is completed, a decision can be made whether to complete Part 
B safety lead-in versus discontinue and proceed with Part A Stage 2 depending on analysis 
of results and toxicity at that time. 
2
OBJECTIVES & HYPOTHESES
2.1Primary Objective & Hypothesis
Objective: to evaluate the best Overall Response Rate (ORR) per RECIST 1.1 assessed by 
investigator of pembrolizumab or pembrolizumab plus chemotherapy in subjects with previously 
treated poorly differentiated neuroendocrine carcinoma.
Hypothesis: Pembrolizumab or pembrolizumab plus chemotherapy have activity in previously 
treated high-grade extrapulmonary neuroendocrine carcinoma.
2.2Secondary Objectives
1.
Objective: To determine the safety and tolerability of pembrolizumab-based therapy in 
this patient population.
2.
Objective: To evaluate duration of response (DOR) in patients receiving pembrolizumab 
or pembrolizumab plus chemotherapy.
3.
Objective: To evaluate progression free survival (PFS) in subjects treated with 
pembrolizumab or pembrolizumab plus chemotherapy (median PFS and 18 wk PFS).
4.
Objective: To evaluate overall survival (OS) in subjects receiving pembrolizumab or 
pembrolizumab plus chemotherapy.
2.3Exploratory Objectives
1.
Objective: To compare ORR, DOR, and PFS based on irRECIST with the same 
measures assessed by RECIST 1.1.
2.
Objective: To characterize  the molecular features of neuroendocrine carcinomas.
3.
Objective: To correlate clinical outcomes (ORR, DOR, PFS, OS) with molecular 
features of neuroendocrine carcinoma.  
4.
Objective: To describe the relationship between baseline tumor growth rate (TGR) and 
RECIST measurements for all patients enrolled in Part A and Part B of this study.
5.
Objective: To examine changes in TGR over time in patients treated with 
pembrolizumab alone (Part A) and pembrolizumab plus chemotherapy (Part B). 


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3
BACKGROUND & RATIONALE
3.1Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475.
3.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. 1  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.2-6 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).7, 8 The structure of 
murine PD-1 has been resolved [9].  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70, which are involved in the CD3 T-cell signaling cascade.7, 9-11 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.12, 13 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.14, 15 Expression has also been shown during thymic development 
on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.16 
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.12, 17-19 
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.12 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).20   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 been approved in the United Stated for the 


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treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. It is also approved 
in head and neck squamous cell carcinoma, and PDL1 (+) non-small cell lung cancer. 
Nivolumab (another PD1 inhibitor) is FDA approved for the treatment of non-small cell lung 
cancer, metastatic melanoma, renal cell carcinoma and Hodgkin Lymphoma. Atezolizumab is a 
PDL-1 inhibitor approved for use in non-small cell lung cancer.
3.1.2
Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
3.1.3
Preclinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection, wither as a mon-therapy or in combination with other treatment modalities. Anti-
mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a 
monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma and 
colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of INF-γ, granzyme B and perforin, indicating that the 
mechanism of action involved local infiltration and activation of effector T-cell function in vivo.21-
26 Experiments have confirmed the in vivo efficacy of PD-1 blockade as a mono-therapy as well 
as in combination with chemotherapy in syngeneic mouse tumor models (see the Investigator’s 
Brochure [IB]).
3.1.4
Ongoing Clinical Trials
Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small cell 
lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative breast 
cancer, and gastric adenocarcinoma. Pembrolizumab is now FDA approved for use in 
melanoma, head and neck squamous cell carcinoma, and non-small cell lung cancer.
Ongoing clinical trials of pembrolizumab are being conducted in multiple malignancies, including 
advanced melanoma, non-small cell lung cancer, and a number of other advanced solid tumor 
indications and hematologic malignancies. For study details please refer to the IB. Of note, 
studies are ongoing with pembrolizumab in combination with paclitaxel-based chemotherapy, as 
well as in combination with irinotecan (see https://clinicaltrials.gov).
3.2Rationale
3.2.1
Rationale for the Trial and Selected Subject Population
Neuroendocrine Neoplasms: Neuroendocrine (NE) neoplasms are a diverse group of rare 
neoplasms distinguished by site of origin, functional status, and degree of aggressiveness.27-29 
For unknown reasons, the incidence has increased five-fold over the past 30 years.27 In fact, 
taken together, gastrointestinal NE tumors (NETs) are the second most common 
gastrointestinal malignancies behind colorectal cancer. NETs are divided into three grades; with 
the low and intermediate grades (G1 and G2) being considered well-differentiated NETs (WD-
NETs) and the high-grade (G3) group consisting of poorly differentiated neuroendocrine 
carcinomas (PD-NECs). Well-differentiated NETs are relatively indolent, with a natural history 
that can evolve over years or decades. They are not associated with mutations common to the 
exocrine cancers that arise at the same organ site and are relatively genetically stable with a 
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Poorly differentiated NECS: In contrast, PD-NECs share certain microscopic features of 
neuroendocrine differentiation but are uniformly aggressive, demonstrate a high proliferative 
rate (Ki67 typically 60-70%) and are classified histologically as small cell carcinoma (SCC) or 
large cell neuroendocrine carcinoma (LCNEC).31  There are no validated markers to 
discriminate between the two types.32  Unlike WD-NETs, PD-NECs frequently (up to 40% of 
cases) occur in association with non-neuroendocrine precursor lesions or carcinomas (“mixed” 
tumors) and often share mutations with the exocrine cancers of the same organ.28 The 
prototypical PD-NEC is small cell lung cancer (SCLC), which accounts for 13% of all lung 
cancers and 95% of all SCCs, and demonstrates a high mutation rate (1-40/Mb, average 8/Mb) 
and a transient, but marked, response to platinum-based chemotherapy.31, 33 
While rare, extrapulmonary PD-NECs can arise nearly anywhere including the gastrointestinal 
tract, prostate, bladder and cervix (typically comprising <3% of malignancies in each site).28, 31 A 
recent review of UCSF data revealed that 10.6% of 262 cases of pancreatic NETs were poorly 
differentiated; 16% of 755 GI-NETs were poorly differentiated. Others have also reported that a 
sizable fraction (5-10%) of digestive NETs are high grade.34-36 Furthermore, therapy-induced 
PD-NECs have been identified in the setting of resistance to androgen deprivation in prostate 
cancer and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancers harboring 
activating mutations in EGFR.37, 38 As such, high grade NECs arising outside the lungs are not 
as uncommon as once thought. Like SCLC they are highly aggressive and often characterized 
by P53 mutations and RB loss, although some genetic alterations are site specific (e.g. 
TMPRSS2-ERG gene rearrangement in 50% of PD-NECs of the prostate).39, 40 The etiology of 
PD-NECs is unclear, although SCLC is associated with smoking, PD-NECs of the prostate are 
usually therapy-related, and Merkel cell carcinoma of the skin is associated with Merkel cell 
polyomavirus (MCPyV) infection. Interestingly, PD-NECs are not typically associated with 
inherited cancer syndromes (e.g. MEN1) and may arise though a pathway distinct from well 
differentiated tumors of the same tissue of origin.
There is no standard therapy for progressive extrapulmonary PD-NECs, which (in the absence 
of site-specific data) are typically treated with platinum-based chemotherapy according to SCLC 
guidelines.41, 42 The optimal therapy for large cell NEC of the lung is similarly unclear. NCCN 
guidelines suggest that early stage disease should be treated like NSCLC (nccn.org). However, 
chemotherapy regimens typically used for SCLC may be most appropriate when systemic 
therapy is required.43, 44 No standard therapy exists for refractory SCLC, which is typically 
associated with ORR 10-20% and short PFS (<4 months) regardless of chemotherapy regimen 
(e.g. irinotecan, paclitaxel, topotecan, temozolomide).29, 42, 45 A recent analysis of 294 patients 
with extrapulmonary PD-NECs revealed a median OS 11.8 months from first line therapy 
(typically platinum-based, 46% ORR), 7.6 months from 2nd line, and 5.9 months from third line 
palliative chemotherapy.46 Results from this and other retrospective studies suggest that 
FOLFIRI and FOLFOX also hold promise in this population.46-48 Similarly, temozolomide-based 
therapy may have activity in GI-NECs (although the benefit appears greatest in “lower risk” 
patients with somatostatin receptor scintigraphy positive tumors and Ki67 <60%).49 Additional 
treatment options are desperately needed in the face of transient responses to chemotherapy 
and a median OS of 12-15 months.46  
Immunotherapy and poorly differentiated NECs: Immunotherapy with checkpoint pathway 
inhibitors (CPI) hold promise in high grade NECs given the relatively high mutation burden and 
high-programmed death ligand-1 (PD-L1) expression in SCLC, as well as the presence of 
shared histopathological and molecular features between SCLC and extrapulmonary NECs.46, 50 
High mutation burden has been associated with response to PD1 inhibitors (non-small cell lung 
cancer, melanoma, mismatch-repair deficient tumors), which has led to their approval in 
melanoma and squamous NSCLC.33, 51, 52 Furthermore, mutational burden may correlate with a 
particular gene signature and the immunogenicity of that signature. Immunogenicity may, in 


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turn, correlate with neoantigen load, which may ultimately prove to be even more predictive of 
response to CPI than mutation rate.52-54  Tumor-associated PD-L1 expression remains under 
investigation as a potential biomarker of response, but its validity has been confounded by an 
inconsistent predictive value across trials, use of variable cutoff points and definitions of positive 
expression (in tumor cells, immune cells or both), and potential dependence on tumor 
histology/microenvironment.55, 56 Other data suggest that the presence of functional tumor 
infiltrating lymphocytes (TIL), specifically antitumor cytotoxic T-lymphocytes, is a key 
determinant of CPI efficacy.57 Absent or low CTL responses (modulated by both the local and 
systemic immunosuppressive environment) must be induced or enhanced in order for CPI 
activity. An ability to quantify tumor antigen-specific T-cell recognition or expression of T-cell 
receptor activation markers may also be informative.58 In the end, both host immunologic and 
intratumoral factors likely impact sensitivity to checkpoint blockade, making identification of valid 
biomarkers a challenge.59 
Emerging data from studies of CPI in SCLC suggest promising activity and provide hope that 
extrapulmonary PD-NECs and large cell NEC of the lung will prove responsive.60 PDL-1 and 
PDL-2 are expressed in a subset of poorly differentiated NECs (in tumor infiltrating 
macrophages) arising in and outside of the lungs. Expression correlates with the presence of 
tumor infiltrating lymphocytes and suggests a role for checkpoint inhibitors in at least some 
patients. 61 In 20 patients with PD-L1 (+) platinum-refractory SCLCs treated with pembrolizumab 
alone, a 35% partial response (PR) (7/20, of which 6/7 responses evident by 8 weeks; median 
time to response 8 weeks, range 7-16 weeks) and a 40% DCR were noted.60 Of 147 evaluable 
tumors, 29% demonstrated (+) PD-L1 expression. In unselected .platinum-treated patients with 
SCLC, 40 subjects receiving nivolumab (an anti-PD-1 antibody) demonstrated an 18% PR (38% 
DCR); in 46 patients treated with nivolumab plus ipilimumab (an anti-cytotoxic T-lymphocyte–
associated antigen 4, CTLA4, antibody), a 32% RR was noted (54% DCR).62 The median time 
to response was approximately 2 months (rarely occurring after “pseudoprogression”) and 
responses were seen in platinum-sensitive and refractory patients. Furthermore, approximately 
1/3 of tumors were PD-L1 (+), but responses were evident regardless of PD-L1 status. There 
was a suggestion that combination therapy was more efficacious than monotherapy. Preliminary 
data also suggest a very high RR with single agent pembrolizumab in previously untreated 
Merkel cell carcinoma, perhaps owing to MCPyV-specific immune responses (5 confirmed and 3 
unconfirmed responses in the first 10 patients).63  In gastroenteropancreatic NETs (GEP-NETs), 
expression of PD-L1 appears to correlate with grade (restricted to G3 in one small series) and 
inversely correlates with survival.64
3.2.2
Rationale for Dose Selection/Regimen/Modification 
Pembrolizumab: An open-label Phase I trial (Keynote 001) was conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab.  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 dose levels were well tolerated, and no dose-
limiting toxicities were observed. Pembrolizumab 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 was identified.  Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity.
The PK information from KEYNOTE-001, -002 and -006 was analyzed with the population PK 
approach to characterize serum concentrations over time based on a dataset including 2188 
subjects across the melanoma and NSCLC indications (see IB). Conclusions of this analysis 
were further verified with addition of PK data in second line (2L) NSCLC from KEYNOTE-010 
and now with data including the pembrolizumab fixed dosage of 200 mg Q3W in first line (1L) 


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NSCLC from KEYNOTE-024 (see IB for details). Pharmacokinetic (PK) data analysis of 
pembrolizumab administered Q2W and Q3W showed slow systemic clearance, limited volume 
of distribution, and a long half-life.  Pharmacodynamic data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days).  The results confirm that the PK profile of 
pembrolizumab is consistent with other therapeutic mAbs with a low systemic clearance and a 
limited volume of distribution. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and supports both 
body weight normalized dosing or a fixed dose across all body weights. The data furthermore 
suggest similar efficacy and safety in melanoma at 10 mg/kg Q3W vs the 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.
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.
Support for 200 mg q3wk flat dosing. Since the anti-tumor effect of pembrolizumab is driven 
through reactivation of adaptive immune response by blocking PD-1 expressed on T cells, but 
not direct binding to cancer cells, once the PD-1 on T cells are fully saturated by pembrolizumab, 
the shape of the exposure-response relationship among indications is expected to be similar. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
supported by exposure-response analysis in multiple indications and 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 are well 
tolerated and safe. 
A flat exposure- response relationship was demonstrated between pembrolizumab exposure (or 
dose) and efficacy or safety within the dose range of 2 to 10 mg/kg or 200 mg to 10 mg/kg 
(exposure at 2 mg/kg Q3W is similar to exposure at 200 mg Q3W). The similarity in efficacy 
between the tested dose regimens is further supported by comparisons of overall response rate 
(ORR)/survival outcomes for the tested dose regimens in the melanoma and NSCLC indications. 
Available pharmacokinetic results in subjects with various indications (melanoma, NSCLC, 
HNSCC and MSI-H) support a lack of meaningful difference in PK among tumor types.
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.
Chemotherapy: 
Current data suggest that several chemotherapeutic agents can be used to treat PDNECs after 
first-line therapy. For late recurrences (>6 mo after completion of first line therapy), the initial 
regimen is typically reintroduced (per SCLC guidelines). In contrast, no standard therapy exists 
for primary refractory PD NEC, PDNEC that progresses within six months of completion of first 
line therapy, or late recurrence PDNEC that progresses after rechallenge with initial therapy. 


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Patients are typically treated according to SCLC guidelines; however, no single regimen is 
thought to be appreciably more active than another. In general, in the salvage setting, single 
agent chemotherapy is associated with <20%% ORR.65 As such, this protocol allows 
investigators to choose one of two commonly used regimens: two weeks on, 1 week off 
administration of irinotecan and weekly paclitaxel (depending on prior therapy, co-morbidities 
and patient/physician preference). 66 The data from chemotherapy-treated patients will be 
pooled in this pilot study. Temozolomide-based therapy was not considered an option due to its 
very immunosuppressive effects.
Paclitaxel dose and schedule: While a variety of regimens have been tested, emerging data 
suggest that weekly paclitaxel (60-90 mg/m2) has an improved safety and tolerability profile (+/- 
improved efficacy) compared to q 3wk regimens.66, 67 While paclitaxel can be given weekly 
without breaks, patients often require breaks or growth factors due to myelosuppression.68 One 
commonly used regimen involves paclitaxel 80 mg/m2 IV over one hour q wk x 6, out of an 8-
week cycle (23%RR in refractory SCLC). 66 However, the incidence of grade ¾ neutropenia is 
high (>50%, 64%) necessitating growth factor support or treatment holidays in a number of 
patients.66 As such, 3 weeks on/1 week off is a commonly used regimen, still others use 2 
weeks on/1 week off in practice. 69
In addition to other common chemotherapy-associated toxicities (see package insert), paclitaxel 
can be associated with hypersensitivity reactions (HSR; ranging from mild pruritis and flushing 
to anaphylaxis). As such, patients are typically premedicated with dexamethasone, ranitidine 
and diphenhydramine IV 30 min before chemotherapy.66 Given the potential complications 
stemming from weekly dexamethasone (including reducing the efficacy of CPI), there is interest 
in exploring other premedication regimens (particularly since the original schedules were 
designed for higher dose, q 3 wk paclitaxel regimens). While no official guidelines exist, several 
alternative premedication strategies appear promising including 1) dexamethasone 10 mg IV 30 
min before first dose (plus H1/H2 blockade), eliminating premedications or tapering with dose 
#2 if no HSR 2) 20 mg dexamethasone IV before 1st dose, 10 mg IV before 2nd dose, then taper 
by 2 mg increments weekly if no HSR (reaching 0 mg by 9th infusion) 3) 10 mg orally 12- and 6-
hour before 1st dose, tapered in subsequent weeks 4) 10 mg IV before doses 1-3, 4 mg IV 
before doses 4-12.70 Taken together, studies suggest 0.3% rate of grade 3 /4 HSR with reduced 
dose dexamethasone, which compares favorably with 2-4% rate with higher dexamethasone 
(largely from higher dose paclitaxel trials).70 
Irinotecan dose and schedule: Several small studies have suggested that irinotecan has modest 
activity in refractory SCLC. One study showed ORR 16% using irinotecan 125 mg/m2 per week 
(4 weeks on/2 off).71 The RR was 35% in “sensitive disease”, the RR was 4% in primary 
resistant /refractory disease. Another study suggested DCR 17.5% (PR 7%) with irinotecan 300 
mg/m3 q 3 wk.72 
Irinotecan is moderately emetogenic and often requires dexamethasone premedication. For the 
same reason as above, there is an interest in exploring steroid sparing antiemetics, such as 
using 5HT3 receptor and NK1 receptor antagonists without steroid after cycle 1. Whether to add 
back dexamethasone will be driven by patient symptoms.
Chemotherapy plus pembrolizumab: While chemotherapy has the potential to be 
immunosuppressive, an emerging body of literature suggests that the effects are pleotropic; 
depending on the drugs, doses and schedules, some agents can stimulate an immune 
response. 73 For example, when delivered below the MTD, normal responses to influenza virus 
can be seen despite concurrent chemotherapy. 
Combination studies of CPI with targeted agents or chemotherapy are also underway.74. Tumor 
cells that are killed by chemotherapy may facilitate dendritic cell activation and priming. 


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Furthermore, chemotherapy may sensitize tumor cells to T cell mediated killing by inhibiting Treg 
cells and myeloid-derived suppressor cells (MDSCs) and by increasing the expression of death 
receptors on tumor cells.74 In melanoma, the combination of CTLA4 blockade plus 
chemotherapy improves survival compared to chemotherapy alone.75 These results suggest that 
CPI in combination with chemotherapy can potentially induce synergistic anti-neoplastic effect.73
Paclitaxel plus pembrolizumab. Microtubular inhibitors like paclitaxel interfere with mitosis 
leading to an increase in chromosomal content, ER stress, and exposure of calreticulin—which 
facilitates recognition (and elimination) of malignant cells by the immune system (e.g. dendritic 
cells).73 Preclinical data suggests paclitaxel depletes MDSCs in mouse tumor models, and may 
boost T cell priming by dendritic cells. In addition, treatment may increase the relative 
abundance of circulating CTLs over TREG cells.73  The potential for a synergistic or additive effect 
of pembrolizumab and paclitaxel is supported by the fact that the immune modulator ipilimumab 
improves the efficacy of paclitaxel-based therapy in NSCLC and SCLC.76, 77 
The safety profile of pembrolizumab is not expected to change with the addition of paclitaxel. 
Mature safety and efficacy data are pending, but preliminary data suggest that pembrolizumab 
can be combined with full-dose paclitaxel (e.g. paclitaxel 200 mg/m2 and carboplatin AUC 6 in 
NSCLC-KEYNOTE-21).78  Additional combination studies are ongoing, including pembrolizumab 
plus weekly paclitaxel (NCT02440425) and pembrolizumab in combination with paclitaxel, 
carboplatin and radiation therapy (NCT02621398). In a phase II study in NSCLC, grade 3/4 
events were not different between 204 patients receiving ipilimumab or placebo with carboplatin 
and paclitaxel. 76 NCT02440425 is an ongoing phase II study in ovarian cancer assessing 
standard dose weekly paclitaxel and pembrolizumab (without a dedicated phase I component or 
safety lead-in) (R. Wenham, PI, personal communication). A preplanned analysis of toxicity after 
the first 10 patients did not reveal any unanticipated toxicities and enrollment is ongoing at full 
doses of both agents. As such, given the relatively well-documented toxicities associated with 
dose-dense paclitaxel, the lack of anticipated overlapping toxicities with pembrolizumab (MK-
3475), and the data available from ongoing studies with similar combinations, we believe it is 
reasonable to conduct a pilot trial with the combination (without a phase I component or formal 
safety lead in).
Irinotecan plus pembrolizumab. Topoisomerase inhibitors may also synergize with CPI. 
Irinotecan may stimulate MDSC accumulation in the tumor microenvironment.73 In a murine 
model of melanoma, the combination of topoisomerase inhibitors and immune-based therapies 
leads to increased sensitivity to T cell killing.79 Clinical studies of irinotecan plus pembrolizumab 
are ongoing (NCT02331251); irinotecan may need to be dose reduced when given in 
combination with pembrolizumab on a q 3 wk schedule in lung cancer (RPTD 250 mg/m2 q 3 
wk, down from 300 mg/m2).80 Preliminary evidence for activity has been seen in refractory 
SCLC.80 A nivolumab plus irinotecan (150 mg/m2 q 2 wk) study is ongoing (NCT02423954). 
Given the lack of prior experience with pembrolizumab and two weeks on, one week off 
administration ofirinotecan (125 mg/m2), the study will include a planned analysis of toxicity 
after 6 patients have been treated with standard dose irinotecan plus pembrolizumab. If 2 or 
more patients experience dose-limiting toxicity that is clearly related to irinotecan, this agent will 
be de-escalated to 100 mg/m2 and 6 additional patients will be treated. Dose modification of 
irinotecan should be undertaken per standard practice. If further, de-escalation is required, the 
irinotecan will be dropped as a chemotherapy option for Part B.
Rationale for dealers’ choice chemotherapy for Part B. Final recommendations for 
pembrolizumab/chemotherapy dose/schedule will be made if/when Part B opens, based the 
available data at that time. Since there is no standard therapy for refractory (non-SCLC) poorly 
differentiated NEC and the response to chemotherapy in this setting is uniformly low, we have 
proposed to pool patients getting either two weeks on, one week off administration of irinotecan 


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or weekly paclitaxel in Part B. This should facilitate accrual to this pilot study, allowing the 
treating provider to select the chemotherapy agent based on prior therapies, co-morbidities, 
and/or patient preference.
3.2.3
Rationale for Endpoints
3.2.3.1 Efficacy Endpoints
Primary Endpoint: The primary efficacy objective of this study is to evaluate the anti-tumor 
activity of pembrolizumab or pembrolizumab plus chemotherapy in subjects with previously 
treated PD NEC. Best overall response per RECIST 1.1 will be used as the primary endpoint 
(investigator-reported). 
Secondary Endpoint: The secondary efficacy objectives of this study are to evaluate the DOR 
and PFS per RECIST 1.1 and OS in subjects with PD NEC treated with pembrolizumab or 
pembrolizumab plus chemotherapy.
3.2.3.2 Safety Endpoints
The safety objective of this study is to characterize the safety and tolerability of pembrolizumab 
or pembrolizumab plus chemotherapy in subjects with previously treated PD NEC. The primary 
safety analysis will be based on subjects who experienced toxicities as defined by CTCAE, v4.0 
(Appendix 2). 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).
3.2.3.3 Exploratory Endpoints
Molecular Characteristics of NEC
Blood and tissue samples will be analyzed to characterize baseline and/or changes in a variety 
of parameters- e.g. proliferation indices, metabolic profile, protein expression (candidate 
approach or large scale), gene expression (e.g. transcriptomics), genomic signature 
(mutations), immunologic profile, and other molecular features of NEC (e.g. methylome profile). 
We will explore associations between molecular characteristics and clinical outcomes (ORR, 
DOR, PFS, OS). Additional tissue- and/or blood-based biomarker research to identify factors 
important for pembrolizumab and/or NEC therapy may also be pursued (e.g. exosomes, 
microRNAs, microbiome). 
For example:
Ki67 Proliferation rate in tumor
Ki67, a tumor proliferative biomarker, is determined by immunohistochemistry (IHC) of the tumor 
tissue. Poorly differentiated (G3) NEC arising in the GI tract and pancreas are defined by having 
a Ki67 >20%, and the response to chemotherapy may depend on the proliferative rate (e.g. > or 
<55%).49   The relationship between baseline tumor proliferative index (as measured by Ki67) 
and response to immunotherapy is uncertain and will be assessed. 
Baseline expression of PD-L1 in tumor
PD-L1 expression in the pre-treatment tumor biopsy will be assessed by IHC (Qualtek) and 
correlated with ORR, PFS, DOR, OS


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Characterization and quantification of tumor-infiltrating immune cells
Baseline tumor 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). Immune cell characterization 
will be performed by the UCSF CIL.
T cell receptor (TCR) sequencing (blood and tumor biopsy)
T cell receptor (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 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.74, 75 Fong, et al. performed TCR next-generation 
sequencing (NGS) on serial blood (PBMC) samples and prostatectomy samples from 
sipuleucel-T treated patients.81 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.82 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.83 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 
(blood). 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 will be assessed by multiparameter flow cytometry on peripheral blood 
samples. T cell activation status will be characterized.
Mutation profiling (tumor)
Tumor biopsies will be assessed using a cancer gene panel for patient care (e.g. UCSF500; 
http://cancer.ucsf.edu/intranet/ccgl). The UCSF500 assay provides a platform for assessing the 
mutation status of 500 genes; selected genes are also analyzed for structural rearrangements. 
Molecular changes will be correlated with response to therapy.
Metabolic profiling


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Tumor cells often exhibit markedly abnormal metabolism, a hallmark of cancer, which has the 
potential to impact efficacy of immunotherapy and response to chemotherapy.84-89 Mass 
spectroscopy-based metabolomics may be used for large scale comparative metabolic profiling 
of baseline cell metabolism and changes over time.90 Collaborators at UCSF have extensive 
experience using high resolution nuclear magnetic resonance (NMR) spectroscopy to assess for 
the metabolic profile.91 The data can be linked to gene expression profiling (e.g., by RNAseq). A 
better understanding of aberrant cell metabolism in poorly differentiated NEC may lead to 
identification of alternative therapeutic strategies to counteract reprogramming of cellular 
metabolism.92
Gene and Protein expression
Gene expression and protein expression can be assessed using a candidate gene approach 
(e.g., PCR, immunohistochemistry) or on a larger scale using tools like RNAseq and mass 
spectroscopy.
Tumor Growth Rate (TGR) (imaging)
TGR has emerged as a potentially important endpoint in clinical trials in well differentiated 
neuroendocrine tumors (NETs). This metric derives a percentage change in tumor volume per 
month using the RECIST sums of target lesions, along with the time between tumor evaluations, 
therefore enabling dynamic and quantitative evaluation of tumor kinetics.87 In NETs, baseline 
TGR and changes on study may have prognostic and/or predictive value.88-90 As such, TGR 
may provide an early indicator of benefit (or lack thereof) of drugs in development for NETs.
The value of TGR in poorly differentiated NEC is unknown. However, the complexities inherent 
to immunotherapy confound radiologic assessment using traditional RECIST criteria. For 
example, studies evaluating checkpoint blockade in various cancer types, including limited 
cases of NEC, suggest that pseudoprogression and hyperprogression may confound 
interpretation of treatment efficacy using RECIST alone.91-95 It remains unknown if TGR at 
baseline or if changes on treatment have prognostic and/or predictive value.
4
METHODOLOGY
4.1Entry Criteria
4.1.1
Diagnosis/Condition for Entry into the Trial
Subjects with previously treated locally advanced or metastatic poorly differentiated 
neuroendocrine carcinoma, including poorly differentiated (G3) NEC of the GI tract, pancreas or 
other extrapulmonary sites (including small cell or large cell histology), or poorly differentiated 
NEC of unknown primary and/or not otherwise specified. Patients with a history of a mixed 
adenoneuroendocrine carcinoma (MANEC) are eligible provided the most recent biopsy shows 
large or small cell neuroendocrine carcinoma. (Patients with Merkel cell carcinoma or small cell 
or large cell NEC lung carcinoma are not eligible).
4.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1.
Be willing and able to provide written informed consent for the trial.
2.
Be  18 years of age on day of signing informed consent.


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3.
Have a histologically proven locally advanced or metastatic high grade (G3) poorly 
differentiated neuroendocrine carcinoma (NEC)
a.
Includes small cell and large cell neuroendocrine carcinoma of unknown primary 
or any extrapulmonary site (and poorly differentiated NEC, not otherwise 
specified)
b.
Includes neuroendocrine prostate cancer (de novo or treatment-emergent) of 
prostate if small cell or large cell histology (histologic evidence of both 
adenocarcinoma and neuroendocrine carcinoma may be present in same 
patient)
c.
Other mixed tumors, e.g. mixed neuroendocrine neoplasms (MINENs) with NEC 
plus adenocarcionoma, squamous or acinar cell component are allowed if the 
high grade (small or large cell) NEC component comprises >50% of the original 
sample or subsequent biopsy 
4.
Have progressed during or after completion of first line systemic chemotherapy 
a.
No limit to the number of prior chemotherapy regimens
b.
Early progression on/after adjuvant chemotherapy counts as first-line therapy
5.
Have at least one measurable disease based on RECIST 1.1 
6.
Patients must agree to have a biopsy of primary tumor or metastatic tissue at baseline, 
and there must be a lesion that can be biopsied with acceptable clinical risk (as judged 
by the investigator).
a.
Patients with unsuccessful baseline biopsies may undergo an additional biopsy 
attempt (at the same or a different site, determined by the investigator).
b.
For patients with an intact primary and no metastatic site that can be safely 
biopsied, biopsy of the primary is acceptable, but must be approved by the 
principal investigator. 
c.
Baseline tumor biopsy may be omitted if the tumor is inaccessible and/or a 
biopsy is not thought to post exceptionally high procedural risk due to location or 
other factors
d.
If fresh tumor tissue cannot be collected, the overall study (lead-site) PI may 
approve the use of archival tissue. The use of archival tissue in lieu of a fresh 
tumor biopsy will be evaluated on a case-by-case basis and must be approved 
by the overall study (lead-site) PI. Please see section6.6.
7.
Have a performance status of 0 or 1 on the ECOG Performance Scale.
8.
Have a life expectancy of greater than 3 months.
9.
Demonstrate adequate organ function as defined in 
10. Table 1, all screening labs should be performed within 14 days of treatment initiation.  


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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 bilirubin
≤ 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
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.
11. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 14 days 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.  
12. Female subjects of childbearing potential should be willing to use two methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference 
Section4.11.2).  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year. 
Male subjects should agree to use an adequate method of contraception 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.


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4.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1.
Has Merkel cell carcinoma, small cell lung carcinoma, or large cell NEC of lung 

Intermediate grade neuroendocrine tumors are excluded 

Well differentiated Grade 3 neuroendocrine tumors are excluded

Metastatic high-grade prostate carcinoma with evidence of focal neuroendocrine 
differentiation on prostate biopsy (e.g., positive chromogranin staining by 
immunohistochemistry) without small cell or large cell NEC morphology are 
excluded, as are neuroendocrine prostate cancers with phenotype intermediate 
between adenocarcinoma and small cell

Atypical bronchial carcinoid and well differentiated G2 GEP-NET are excluded
2.
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.
3.
Has a diagnosis of immunodeficiency 
4.
Is receiving systemic steroid therapy or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment.

Physiologic doses of steroids (e.g. ≤10 mg prednisone/day or equivalent) are 
allowed. Topical, inhaled, nasal and ophthalmic steroids are allowed.
5.
Has a known history of active TB (Bacillus Tuberculosis).
6.
History of or high suspicion of Gilbert’s disease (safety run-in, Part B only)
Hypersensitivity to pembrolizumab or any of its excipients.
7.
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.
8.
Documented progression on and/or intolerance/hypersensitivity to both paclitaxel and 
irinotecan (Part B only) 
9.
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.

Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  

Concurrent somatostatin analog therapy is allowed (for control of hormone 
excess) provided patient has been on stable dose for at least two months and 
tumor progression has been documented


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
Continuation of androgen deprivation therapy (ADT) allowed for patients with 
neuroendocrine prostate cancer (in the setting of castration-resistant prostate 
cancer, CRPC)
10. 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.
11. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with asymptomatic suspected brain metastases (or small lesions of 
uncertain significance) <1 cm that do not require focal therapy are eligible. (Follow up 
imaging will be allowed on study, and focal radiation with continuation of protocol 
therapy allowed if there is progressive disease in the brain and systemic imaging shows 
stable disease/response). 
Subjects with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least four weeks and any 
neurologic symptoms have returned to baseline), they have no evidence of new or 
enlarging brain metastases (confirmed by imaging within 28 d of the first dose of trial 
treatment), and they 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 
12. 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. 
13. Has a history of (non-infectious) pneumonitis/ interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
14. Has an active infection requiring systemic therapy.
15. 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.  
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).


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21. 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.
4.2Trial Treatments
The treatment to be used in this trial is outlined below in Table 2
Table 2 Trial Treatment
Part A
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 21 
day cycle
Experimental
Part B
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/ Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 21 
day cycle
Experimental
Irinotecan
125 
mg/m2**
QW
IV infusion
Day 1, 8 of each 21 
day cycle 
Standard of 
Care
OR
Pembrolizumab
200 mg
Q3W
IV infusion
Every 21 days
Experimental
Paclitaxel
80 
mg/m2
QW
IV infusion
Over 1 hr
Day 1,8, 15 of each 
21d cycle*
Standard of 
Care
*The weekly paclitaxel regimen will allow for treatment breaks as per standard of care 
** Starting dose for safety lead-in
4.3Dose Selection/Modification
4.3.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section3– Background 
and Rationale.  Given the ongoing clinical studies with pembrolizumab plus paclitaxel and 
pembrolizumab plus irinotecan, final recommendations for chemotherapy dose/schedule (and 
steroid premedications) will be made if/when Part B opens, based on all available data at that 
time. 
Pembrolizumab should be prepared and administered according to institutional guidelines. 
Paclitaxel: Paclitaxel will be prepared and administered per routine clinical practice using 
commercial drug supply. Standard premedications (typically dexamethasone and H1 and H2 
blockers) will be given 30-60 minutes prior to paclitaxel (and after pembrolizumab).

If there is no hypersensitivity reaction to paclitaxel, premedications may be omitted for future 
paclitaxel doses at physician’s discretion.

If a hypersensitivity reaction occurs, premedications for re-challenge include 
dexamethasone 20 mg PO given 12 hours and 6 hours prior to treatment, plus IV 
premedications given 30 minutes prior to paclitaxel: dexamethasone 10 mg, 


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diphenhydramine 25 mg, and H2 - antagonist (e.g., ranitidine 50 mg). If no hypersensitivity 
reactions occur, standard premedications (see above) will be used for subsequent paclitaxel 
doses.
o
Additional antiemetics not usually required.
Irinotecan: Irinotecan will be prepared and administered per routine clinical practice using 
commercial drug supply. The starting dose level for irinotecan will be 125 mg/m2. Safety will be 
assessed after a six-patient safety lead-in. Irinotecan will be deemed “intolerable” if ≥2 of 6 
patients meet DLT criteria in dose level -1.
Irinotecan Dose Level
Pembrolizumab
Dose level 1
125 mg/m2 d 1, 8
200 mg q 21 d
Dose level -1
100 mg/m2 d 1, 8
200 mg q 21 d
4.3.2
Safety Lead-in
The first six patients enrolled in Part B will be treated with irinotecan (Dose level 1) plus 
pembrolizumab. Dose modifications for irinotecan should occur according to the package insert 
and institutional policy.  Once the sixth patient in the irinotecan plus pembrolizumab safety lead-
in has completed one cycle of therapy (or earlier if clinically indicated), the safety data will be 
reviewed. An irinotecan dose level will be considered acceptable if no more than 1 of 6 eligible 
patients in the safety lead-in experiences a DLT (see below). Alternatively, if a DLT is observed 
in two or more of the six subjects (one-third or more of the subjects), the irinotecan dose level 
will be considered intolerable and the maximum tolerated dose (MTD) will have been exceeded. 
Dose de-escalation: If the dose for the first six patients is not tolerated, Dose Level -1 (100 
mg/m2 irinotecan) will be studied in combination with pembrolizumab.  If that dose level is 
intolerable (e.g. if ≥2 of six patients meet DLT criteria), then irinotecan will be dropped as a 
chemotherapy option for Part B.  Of note, selection of the recommended phase II dose (RPTD) 
will take into consideration safety information beyond the DLT period from all cohorts.
Once the MTD for irinotecan/pembrolizumab is established, 16 additional patients will be 
enrolled to Part B (investigators’ choice- pembrolizumab plus irinotecan or pembrolizumab plus 
paclitaxel).
4.3.3
Definition of DLT for irinotecan
The DLT window will be 21 days. Adverse events will be graded according to the NCI CTCAE, 
Version 4.0. Dose limiting toxicity (DLT) will be defined as an adverse event occurring during the 
first cycle (21 days) of study drug administration considered at least possibly related to 
irinotecan and which meets any of the following criteria:
Hematologic toxicities

Grade 4 absolute neutropenia lasting >7 days

Grade ≥3 febrile neutropenia (T≥38.5°C)

Grade 4 thrombocytopenia  

Grade ≥3 thrombocytopenia with clinically significant bleeding or any requirement for platelet 
transfusion

Grade 3 thrombocytopenia lasting >7 day

Grade 4 anemia or grade 3 anemia requiring transfusion


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Other toxicities

Any treatment-related death

Any irinotecan dose reduction required during Cycle 1 due to potential toxicity

Any other treatment toxicity that results in a missed dose of irinotecan or a dosing delay 
lasting >7 consecutive days during cycle 1

Treatment (irinotecan-related) toxicity that results in C2D1 irinotecan being delayed

Any irinotecan-related ≥grade 3 non-hematologic toxicity except the following:
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 ≤2 within 5 d
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
Isolated, asymptomatic changes in laboratory values (including electrolytes 
abnormalities that respond to medical intervention or are clinically insignificant, 
asymptomatic elevation of amylase/lipase and recovery to ≤Grade 1 or baseline in 
≤5 days. ≥3 grade elevation of alkaline phosphatase if asymptomatic)

NOTE: Grade ≥3 toxicity attributed solely to pembrolizumab and not to irinotecan (e.g. grade 
4 vasculitis or other irAE) will not be considered a DLT. Replacement of patients removed 
for an AE attributed solely to pembrolizumab during DLT window may be considered 
pending discussion with principal investigator.
A subject who experiences a DLT may remain in the trial and continue receiving irinotecan at a 
lower dose (plus pembrolizumab) if the investigator deems potential benefits outweigh the risks. 
Subjects who do not complete Cycle 1 for reasons other than drug toxicity may be replaced.
4.3.4
Dose Modification and Toxicity Management for Immune-Related 
AEs Associated with Pembrolizumab and Combination Therapy
Pembrolizumab: Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure, including coadministration with additional compounds, may represent an immunologic 
etiology.  These immune-related AEs (irAEs)  may occur shortly after the first dose or several 
months after the last dose of pembrolizumab/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    withheld for drug- Table 3 below. See 
Section 4.10.1 for Supportive Care Guidelines, including use of corticosteroids.
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 


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event to the combination, to chemotherapy, either irinotecan or paclitaxel or to pembrolizumab 
alone, for adverse events listed in Table 3, both interventions must be held according to the 
criteria in Table 3 Dose Modifications and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated with Pembrolizumab.
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 3. 

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 3, the 
combinations of chemotherapy, either irinotecan or paclitaxel and pembrolizumab may 
be restarted at the discretion of the investigator. In these cases where the toxicity is 
attributed to the combination or to chemotherapy, either irinotecan or paclitaxel alone, 
re-initiation of pembrolizumab as a monotherapy may be considered at the principal 
investigator’s discretion.


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Table 3  Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab 
Monotherapy and IO Combination 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
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/Colitis 
Recurrent 
Grade 
3 
or 
Grade 4
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be


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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 
Hyperglycemia
New 
onset 
T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
of 
-cell failure
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Administer antihyperglycemic in 
participants with hyperglycemia
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according 
to 
increased 
creatinine
or
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function


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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 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold 
or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 
or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
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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*Part B: Chemotherapy should generally be held if pembrolizumab held for drug-related toxicity. However, 
chemotherapy may continue at the discretion of the PI in patients experiencing clinical benefit (e.g. 
patient with grade 2 pneumonitis who is clinically stable and responding to treatment should be allowed to 
continue chemotherapy while holding pembrolizumab)
Paclitaxel: Paclitaxel should be administered, held and/or dose-reduced (to as low as 50 
mg/m2) as per package insert and standard of care institutional practice (including maximal 
supportive care and growth factors). Filgrastim is not permitted within 24 hours prior to or 
following any paclitaxel infusion. Pegfilgrastim (Neulasta) is not permitted in this study.
As a general rule, in order to initiate each weekly treatment (at either full or modified dose), the 
following criteria must be met for paclitaxel:

ANC ≥ 1000 /mm3 on day 1 of C2 and beyond, and day 8 and day 15 of every cycle

Platelets ≥75,000/mm3
If these criteria are not met, treatment must be delayed until counts recover to this level. 
NOTE: eligibility criteria for laboratory parameters must be met for C1D1 treatment.
Irinotecan: Irinotecan should be administered, held and/or dose-reduced (to as low as 50 
mg/m2) as per package insert and standard of care institutional practice (including maximal 
supportive care and growth factors). Filgrastim is not permitted within 24 hours prior to or 
following any irinotecan infusion. Pegfilgrastim (Neulasta) is not permitted in this study.


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As a general rule, in order to initiate each treatment (at either full or modified dose), the 
following criteria must be met for irinotecan:

ANC ≥ 1000/mm3

Platelets ≥75,000/mm3

Diarrhea ≤Grade 1 within the preceding 24 hr
NOTE: eligibility criteria for laboratory parameters must be met for C1D1 treatment.
If chemotherapy is held for cytopenias, pembrolizumab should be administered per protocol in 
otherwise stable and afebrile patients. If a chemotherapy delay of >3 weeks is required due to 
delayed toxicity recovery, the patient must discontinue chemotherapy permanently from the 
study protocol (unless approved by the Principal Investigator). Patients with stable disease or 
better who require discontinuation of chemotherapy due to toxicity will also be allowed to 
continue on study with pembrolizumab monotherapy
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Principal Investigator. The reason 
for interruption should be documented in the patient's study record.
4.4Timing of Dose Administration
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 (Section5).  Pembrolizumab treatment 
may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons (C2 and beyond) when given as monotherapy, and up to 1 day before or 
after the scheduled Day 1 of each cycle when given in combination with chemotherapy. 
Chemotherapy treatment can be administered up to 1 day before or after each scheduled 
infusion (assuming at least 6 days between chemotherapy infusions). 
Chemotherapy should generally be held if pembrolizumab held for drug-related toxicity. If day 1 
pembrolizumab is held for toxicity, day 1 chemotherapy can also be held (for up to 3 weeks) 
shifting the start of the cycle. 
However, chemotherapy may continue while holding pembrolizumab at the discretion of the 
Principal Investigator in patients experiencing clinical benefit (e.g. patient with grade 2 
pneumonitis who is clinically stable and responding to treatment). 
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks for 24 
months or 35 administrations (whichever comes first).  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).
Pembrolizumab should be prepared and administered according to institutional guidelines. 
Pembrolizumab should be administered at least 30 minutes before premedications for 
chemotherapy.


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Paclitaxel: Paclitaxel (80 mg/m2) should be administered IV on days 1, 8, and 15 of a 21 day 
cycle as per standard practice. Treatment breaks will be allowed as per standard practice. If day 
8 or day 15 chemotherapy is held it will be omitted from the cycle if not given within the allotted 
treatment window (±1 day).  
Irinotecan: Irinotecan (125 mg/m2) should be administered IV on days 1, 8 out of every 21 day 
cycle as per standard practice. If day 8 chemotherapy is held, it will be omitted from the cycle 
(not delayed to day 15) if not given within the allotted treatment window (± 1day).  
Chemotherapy (irinotecan or paclitaxel) treatment breaks (for up to 3 wk) will be allowed per 
institutional practice.
4.5Duration of therapy
Subjects will continue to be treated with pembrolizumab or pembrolizumab plus chemotherapy 
until PD, unacceptable AEs, 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 the subject has received 35 treatments pembrolizumab (or 24 months of therapy, whichever 
comes first). 
For a clinically stable subject with first radiologic evidence of PD (e.g. unconfirmed), it is at the 
discretion of the site investigator to continue treating the subject with pembrolizumab or 
pembrolizumab plus chemotherapy 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. 
Subjects who attain confirmed CR 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.
For Part B: Patients with stable disease or better after 9 cycles (27 weeks) of pembrolizumab-
based therapy will have the option to continue with pembrolizumab alone (unless the first 
PR/CR is noted at 27 weeks, in which case it should be confirmed before stopping 
chemotherapy). Patients who elect to stop chemotherapy (either due to patient preference or 
chemotherapy related toxicity) will be required to go off protocol therapy at the time of 
radiographic disease progression.
Prior to 27 weeks, patients with stable disease or better who require discontinuation of 
chemotherapy due to toxicity will also be allowed to continue on study with pembrolizumab 
monotherapy
4.6Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
4.7Randomization or Treatment Allocation
All enrolled subjects will be allocated to receive pembrolizumab 200 mg IV Q3W in an unblinded 
fashion. Whether subjects receive additional chemotherapy depends on the part and stage of 
the study at time of allocation. For Part B patients enrolled after the run-in with irinotecan alone, 
the treating investigator may choose to use either paclitaxel or irinotecan (not both) based on 
prior therapy, co-morbidities, and patient preference.


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4.8Stratification
No stratification based on age, sex, or other characteristics will be used in this trial.
4.9Concomitant 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. 
4.9.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.4.2.
Concomitant use of bone modifying agents allowed at the discretion of the treating provider.
4.9.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 
o
Continuation of androgen deprivation therapy is allowed in patients with 
neuroendocrine castrate resistant prostate cancer
o
Concurrent somatostatin analog therapy is allowed (for control of hormone excess) 
provided patient has been on stable dose for at least two months and tumor 
progression has been documented

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 

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 unless used as a premedication for chemotherapy or to modulate 
symptoms from an event of clinical interest of suspected immunologic etiology.  The use of 


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physiologic doses of corticosteroids may be approved after consultation with the principle 
investigator.
o
Note: Inhaled steroids are allowed for the management of asthma. Topical steroids 
are also allowed, as are periodic local steroid injections (e.g. for pain).
o
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV 
contrast dye) is permitted.

Filgrastim is not permitted within 24 hours prior to or following any paclitaxel or irinotecan 
infusion. Pegfilgrastim (Neulasta) is not permitted in this study.

Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications, which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
4.10 Rescue Medications & Supportive Care
4.10.1
Supportive Care Guidelines
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 is 
instructed to follow the Events of Clinical Interest (ECI) reporting guidance but does not need to 
follow the treatment guidance. Refer to Section 4.3.4 for dose modification. 

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 of bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic subjects, infectious etiologies 
should be ruled out, and if symptoms persist, endoscopic evaluation should be considered
o
Pembrolizumab-related93:


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
Treat diarrhea promptly with appropriate supportive care, including 
loperamide. Loperamide should be implemented at the first signs of 1) poorly 
or loose stool, 2) occurrence of more bowel movements than usual in one 
day, or 3) unusually high volume of stool.  Loperamide should be taken in the 
following manner: 4 mg at first onset of diarrhea then 2 mg after every 
unformed stool (daily dose should not exceed 16 mg). Avoid loperamide if 
there is blood or mucous in the stool or if the diarrhea is accompanied by 
fever. 

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 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.

For Grade 2 diarrhea/colitis suspected to be due to pembrolizumab that 
persists greater than 3 days, administer oral corticosteroids (e.g. 0.5 
mg/kg/day or prednisone or equivalent). 

For Grade 3 or 4 diarrhea/colitis suspected to be due to pembrolizumab 
that persists > 1 week, treat with intravenous steroids (equivalent of 1-2 
mg/kg/d of prednisone) followed by high dose oral steroids.  

When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.
o
Subjects treated with irinotecan on Part B should receive loperamide as per standard 
practice.

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 
electrolytes should be substituted via IV infusion.  

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.


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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 liothyroinine, is indicated per standard of care.
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 (e.g. 
equivalent of prednisone 1-2 mg/kg/d). 
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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 4 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); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).


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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
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.
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)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
4.11 Diet/Activity/Other Considerations
4.11.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
4.11.2
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.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 


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The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
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 they must adhere to the contraception requirement (described above) for the duration of 
the study and during the follow-up period defined in section 7.3 -Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study.
4.11.3
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 to 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 to Merck and followed as described above and 
in section 7.3.
4.11.4
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.
4.12 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 Section6.7– 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 Section 4.5

Unacceptable adverse experiences as described in Section 7.5

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject


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
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.

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 5 (Protocol Flow 
Chart) and Section 6.8.3(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 6.8.3).  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.
4.12.1
Discontinuation of Study Therapy after Complete Response (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. 
4.13 Subject Replacement Strategy
All patients who receive any study therapy will be analyzed for safety and efficacy. Subjects who 
discontinue from study participation prior to receiving any study therapy may potentially be 
replaced after discussion with the principal investigator. Subjects who have received any dose 
of study therapy will not be replaced. Patients removed from study for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization of all treatment related 
AEs to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first. 
However, they will not be replaced.
4.14 Stopping Rule
A stopping rule for safety will halt accrual to the study and prompt reevaluation of 
pembrolizumab dose if unacceptable treatment-related toxicity (defined as any Grade 4 toxicity, 
any recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 4 weeks) is 
observed at a frequency of ≥33% in any treatment group. If we have a 
pembrolizumab/irinotecan cohort, then we will first recruit six patients 
for pembrolizumab/irinotecan at 125 mg/m2. If ≥2 patients experience dose-limiting toxicity, then 
6 additional patients will be treated at 100 mg/m2 plus pembrolizumab. If ≥2 patients experience 
dose-limiting toxicity at this dose level, then irinotecan will be deemed intolerable and dropped 
as a treatment option.
4.15 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


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3.
Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects
4.
Plans to modify or discontinue the development of the study drug
5.
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.


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5
TRIAL FLOW CHART
5.1Pembrolizumab alone
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening 
(Visit 2)
1
2 
3
4
5
6
7
8
Safety 
Follow-up o
Follow Up 
Visits
Survival 
Follow-Upa
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
EOT n
30 days 
post discon
Every 12 
weeks post 
discon
Every 12 
weeks 
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration b
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
Xk
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events
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
Vital Signs, Weight and Heightc
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xd
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCG
Xe
PT/INR and aPTTf
Xd
CBC with Differentialf
Xd
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panelf
Xd
X
X
X
X
X
X
X
X
X
X
LDHf
Xd
X
X
X
X
X
X
X
X
Urinalysis
Xd
T3, FT4 and TSHf
Xd
X
X
X
X
X
X
Efficacy Measurements
Tumor Imaging
Xg,gg
Xh
Xi
Xk
Brain imagingm
xm


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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening 
(Visit 2)
1
2 
3
4
5
6
7
8
Safety 
Follow-up o
Follow Up 
Visits
Survival 
Follow-Upa
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
EOT n
30 days 
post discon
Every 12 
weeks post 
discon
Every 12 
weeks 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Newly Obtained Tissue Collection 
Xl
Correlative Studies Blood Collectionj
Xp
X
X
Xjj
Archival Tissue Collection
Xp
a)
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 12 weeks 
+/- 14 d to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first (See Section6.8.3.3)
b)
The window for each visit is ±3 days unless otherwise noted.
c)
Height will be measured at Visit 2 only.
d)
ECOG Performance Status and Laboratory tests for screening are to be performed within 14 days prior to the first dose of trial treatment.
e)
For women of reproductive potential, a serum or urine pregnancy test should be performed within 14 days prior to first dose of trial treatment. Pregnancy tests (urine or serum) should be repeated if 
required by local guidelines and at the discretion of the investigator.
f)
Day 1 lab samples (all cycles) can be collected up to 72 hours prior to the scheduled time point. Thyroid function tests to be performed every other cycle.
g)
Screening tumor imaging will be performed within 28 days prior to C1D1. Acceptable studies include multiphase CT or MRI (with or without FDG-PET). Contrast required unless contraindicated due to 
allergy or renal dysfunction in which case non-contrast scan allowed if radiology has confirmed pt still has measureable disease.
gg)
When available, the imaging within 1- 12 months of screening scan will be retrospectively evaluated by local institution radiologists to assess baseline TGR.
h)
The first on-study imaging time point will be performed at 9 weeks (63 ± 7 days) calculated from C1D1 and will continue to be performed Q9W (63 ± 7 days) for 6 months (27 weeks) then Q12W (84 ± 7 
days) thereafter, or earlier if clinically indicated. Weeks are in reference to calendar week, and should not be adjusted for treatment dosing delays.
i)
In subjects who discontinue study therapy without confirmed PD per RECIST, 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.
j)
Whole blood samples for correlative studies should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment progression.  Blood will be collected in four 10mL BD Sodium 
HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-top) and sent to the Immune Monitoring Core at UCSF.  With approval of the PI, blood can be processed on site (per Biospecimen 
Collection Manual) to accommodate Friday or holiday treatment schedule at subsites (and shipped to the UCSF Immune Monitoring Core the following week).
jj)
Sample should ideally be drawn at the time of tumor progression (which may or may not be the same time as treatment discontinuation). This sample may be drawn at EOT and before progression if 
patient not likely to return for a study visit at progression.
k)
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed according to the “on treatment” study schedule by 
radiologic imaging to monitor disease status if possible (every 63 days +/- 7 days for a total of six months after enrollment, then every 12 weeks ± 14 days). Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end of the study.
l)
Baseline tumor biopsy should be performed d-28 to d-1 and may be omitted if the tumor is inaccessible and/or a biopsy is thought to be too high risk. Cycle 1 D1 study drug should be given no sooner than 
24 hours after the tumor biopsy.
m)
Baseline brain MRI with contrast is preferable; however, CT scan of brain with contrast may be substituted at discretion of investigator.
n)
End of treatment (EOT) is defined as date patient and/or treating physician decides to discontinue study drug. Patients who discontinue study treatment should not be considered withdrawn from the study. 
They should undergo EOT visit and enter the post-treatment (follow-up) period. EOT visit should occur within 30 days of last dose of study drug or the decision to discontinue study drug. If a patient 
discontinues study drug at a scheduled visit, the EOT visit can occur the same day. The EOT assessments (besides imaging) do not need to be repeated if done within the preceding14 days. Imaging 
does not need to be repeated if done in preceding 4 weeks as noted above (see “i”). The EOT visit can be combined with a safety follow-up visit.
o)
Safety follow-up should occur 30 days (+/- 7 days) after last dose of study drug and should continue at monthly intervals until resolution of toxicity to < grade 2..p. Day 1 Cycle 1 Research blood sample 
can be drawn up to 7 days prior to Day 1 as long as no prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the lab draw; and no prior anti-cancer monoclonal 
antibody (mAb) within 4 weeks prior to the lab draw.
p)
If fresh tumor tissue cannot be collected, the lead-site PI may approve the use of archival tissue. The use of archival tissue in lieu of a fresh tumor biopsy will be evaluated on a case-by-case basis and 
must be approved by the overall study (lead-site) PI. Please see section 6.6


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5.2Pembrolizumab plus irinotecan
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 cycles
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
Safety 
Follow
-upo
Follow 
Up 
Visits
Survival 
Follow-
Upa
Scheduling Window (Days)kk:
-28 to -1
± 1
± 1
± 1
± 1
± 1
± 1
± 1
EOT n
30 
days 
post 
discon
Every 
12 
weeks 
post 
discon
Every 
12 
weeks 
Administrative Procedures
Day of cycle
1
8
1
5
1
8
1
5
1
8
1
5
1
8
1
5
1
8
1
5
1
8
1
5
1
8
1
5
1
8
1
5
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration b
X
X
X
X
X
X
X
X
Irinotecan administrationk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy 
status
X
Xk
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
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
Vital Signs, Weight and Heightc
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xd
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum 
-HCG
Xe
PT/INR and aPTTf
Xd
CBC with Differentialf
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 cycles
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
Safety 
Follow
-upo
Follow 
Up 
Visits
Survival 
Follow-
Upa
Scheduling Window (Days)kk:
-28 to -1
± 1
± 1
± 1
± 1
± 1
± 1
± 1
EOT n
30 
days 
post 
discon
Every 
12 
weeks 
post 
discon
Every 
12 
weeks 
Comprehensive Serum 
Chemistry Panelf
Xd
X
X
X
X
X
X
X
X
X
X
LDHf
Xd
X
X
X
X
X
X
X
X
X
Urinalysis
Xd
T3, FT4 and TSHf
Xd
X
X
X
X
X
Efficacy Measurements
Tumor Imaging
Xg,gg
Xh
Xi
Xk
Brain imagingm
xm
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Newly Obtained Tissue 
Collection 
Xl
Correlative Studies Blood 
Collectionj
Xp
Xf
Xf
Xjj
Archival Tissue Collection
Xq
a)
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 12 weeks 
+/- 14 d to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first (See Section6.8.3.3)
b)
The window for each visit is ±1 days C2D1 and beyond unless receiving pembrolizumab monotherapy (in which case ±3 days).
c)
Height will be measured at Visit 2 only.
d)
ECOG Performance Status and Laboratory tests for screening are to be performed within 14 days prior to the first dose of trial treatment.
e)
For women of reproductive potential, a serum or urine pregnancy test should be performed within 14 days prior to first dose of trial treatment. Pregnancy tests (urine or serum) should be repeated if 
required by local guidelines and at the discretion of the investigator.
f)
Day 1 lab samples (all cycles) can be collected up to 72 hours prior to the scheduled time point. Day 8 lab samples should be drawn within 24 hours prior to the scheduled time point. Thyroid function tests 
to be performed every other cycle.
g)
Screening tumor imaging will be performed within 28 days prior to C1D1. Acceptable studies include multiphase CT or MRI (with or without FDG-PET). Contrast required unless contraindicated due to 
allergy or renal dysfunction in which case non-contrast scan allowed if radiology has confirmed pt still has measureable disease.
gg)
When available, the imaging within 1- 12 months of screening scan will be retrospectively evaluated by local institution radiologists to assess baseline TGR.
h)
The first on-study imaging time point will be performed at 9 weeks (63 ± 7 days) calculated from C1D1 and will continue to be performed Q9W (63 ± 7 days) for 6 months (27 weeks) then Q12W (84 ± 7 
days) thereafter, or earlier if clinically indicated. Weeks are in reference to calendar week, and should not be adjusted for treatment dosing delays.
i)
In subjects who discontinue study therapy without confirmed PD per RECIST, 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.
j)
Whole blood samples for correlative studies should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment progression.  Blood will be collected in four 10mL BD Sodium 
HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-top) and sent to the Immune Monitoring Core at UCSF.). With approval of the PI, blood can be processed on site (per Biospecimen 
Collection Manual) to accommodate Friday or holiday treatment schedule at subsites (and shipped to the UCSF Immune Monitoring Core the following week).
k)
Patients with stable disease or better after 8 cycles (27 weeks) of irinotecan will have the option to continue with pembrolizumab alone (unless the first PR/CR is noted at 27 weeks, in which case it should 
be confirmed before stopping chemotherapy). Patients who elect to stop irinotecan (either due to patient preference or chemotherapy related toxicity) will be required to go off protocol therapy at the time 


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of radiographic disease progression. Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed according to the “on 
treatment” study schedule by radiologic imaging to monitor disease status if possible (every 63 days +/- 7 days for a total of six months after enrollment, and then every 12 weeks ± 14 days). Every effort 
should be made to collect information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end of the study.
kk)
The window for each chemotherapy visit is ±1 day unless otherwise noted (C1D8 and beyond), provided no less than 6 days between chemotherapy administrations.
l)
Baseline tumor biopsy should be performed d-28 to d-1 and may be omitted if the tumor is inaccessible and/or a biopsy is thought to be too high risk. Cycle 1 D1 study drug should be given no sooner than 
24 hours after the tumor biopsy.
m)
Baseline brain MRI with contrast is preferable; however, CT scan of brain with contrast may be substituted at discretion of investigator.
n)
End of treatment (EOT) is defined as date patient and/or treating physician decides to discontinue study drug. Patients who discontinue study treatment should not be considered withdrawn from the study. 
They should undergo EOT visit and enter the post-treatment (follow-up) period. EOT visit should occur within 30 days of last dose of study drug or the decision to discontinue study drug. If a patient 
discontinues study drug at a scheduled visit, the EOT visit can occur the same day. The EOT assessments (besides imaging) do not need to be repeated if done within the preceding14 days. Imaging 
does not need to be repeated if done in preceding 4 weeks as noted above (see “i”). The EOT visit can be combined with a safety follow-up visit.
o)
Safety follow-up should occur 30 days (+/- 7 days) after last dose of study drug and should continue at monthly intervals until resolution of toxicity to < grade 2.
p)
Day 1 Cycle 1 Research blood sample can be drawn up to 7 days prior to Day 1 as long as no prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the lab 
draw; and no prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the lab draw.
q)
If fresh tumor tissue cannot be collected, the lead-site PI may approve the use of archival tissue. The use of archival tissue in lieu of a fresh tumor biopsy will be evaluated on a case-by-case basis and 
must be approved by the overall study (lead-site) PI. Please see section 6.6


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5.3Pembrolizumab plus paclitaxel
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 cycles
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
Safety 
Follow
-up o
Follow 
Up 
Visits
Surviva
l 
Follow-
Upa
Scheduling Window (Days)kk:
-28 to -1
± 1
± 1
± 1
± 1
± 1
± 1
± 1
EOT n
30 
days 
post 
discon
Every 
12 
weeks 
post 
discon 
Every 
12 
weeks 
Administrative Procedures
Day of cycle
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration 
b
X
X
X
X
X
X
X
X
Paclitaxel administrationk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy 
status
X
Xk
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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
Vital Signs, Weight and Heightc
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xd
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or 
Serum -HCG
Xe
PT/INR and aPTTf
Xd
CBC with Differentialf
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 cycles
Treatment Cycle/Title:
Screening 
1
2 
3
4
5
6
7
8
Safety 
Follow
-up o
Follow 
Up 
Visits
Surviva
l 
Follow-
Upa
Scheduling Window (Days)kk:
-28 to -1
± 1
± 1
± 1
± 1
± 1
± 1
± 1
EOT n
30 
days 
post 
discon
Every 
12 
weeks 
post 
discon 
Every 
12 
weeks 
Comprehensive Serum 
Chemistry Panelf
Xd
X
X
X
X
X
X
X
X
X
X
LDHf
Xd
X
X
X
X
X
X
X
X
X
Urinalysis
Xd
T3, FT4 and TSHf
Xd
X
X
X
X
X
Efficacy Measurements
Tumor Imaging
Xg,gg
Xh
Xi
Xk
Brain imagingm
xm
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Newly Obtained Tissue 
Collection 
Xl
Correlative Studies Blood 
Collectionj
Xp
Xf
Xf
Xjj
Archival Tissue Collection
Xq
a.
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 12 weeks +/- 14 d to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first (See Section 6.8.3.3)
b.
The window for each visit is ±1 days C2D1 and beyond unless receiving pembrolizumab monotherapy (in which case ±3 days).
c.
Height will be measured at Visit 2 only.
d.
ECOG Performance Status and Laboratory tests for screening are to be performed within 14 days prior to the first dose of trial treatment.
e.
For women of reproductive potential, a serum or urine pregnancy test should be performed within 14 days prior to first dose of trial treatment. Pregnancy tests (urine or serum) 
should be repeated if required by local guidelines and at the discretion of the investigator.
f.
Day 1 lab samples (all cycles) can be collected up to 72 hours prior to the scheduled time point. Day 8 and Day 15 lab samples should be drawn within 24 hours prior to the 
scheduled time point. Thyroid function tests to be performed every other cycle. 
g.
Screening tumor imaging will be performed within 28 days prior to C1D1. Acceptable studies include multiphase CT or MRI (with or without FDG-PET). Contrast required unless 
contraindicated due to allergy or renal dysfunction in which case non-contrast scan allowed if radiology has confirmed pt still has measureable disease
gg.
When available, the imaging within 1-12 months of screening scan will be retrospectively evaluated by local institution radiologists to assess baseline TGR.
h.
The first on-study imaging time point will be performed at 9 weeks (63 ± 7 days) calculated from C1D1 and will continue to be performed Q9W (63 ± 7 days) for 6 months (27 weeks) 
then Q12W (84 ± 7 days) thereafter, or earlier if clinically indicated. Weeks are in reference to calendar week, and should not be adjusted for treatment dosing delays


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i.
In subjects who discontinue study therapy without confirmed PD per RECIST, 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.
j.
Whole blood samples for correlative studies should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at disease progression.  Blood will be collected in 
four 10mL BD Sodium HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-top) and sent to the Immune Monitoring Core at UCSF. With approval of the PI, blood 
can be processed on site (per Biospecimen Collection Manual) to accommodate Friday or holiday treatment schedule at subsites (and shipped to the UCSF Immune Monitoring 
Core the following week).
jj.
Sample should ideally be drawn at the time of tumor progression (which may or may not be the same time as treatment discontinuation). This sample may be drawn at EOT and 
before progression if patient not likely to return for a study visit at progression.
k.
Patients with stable disease or better after 8 cycles (27 weeks) of paclitaxel-based therapy will have the option to continue with pembrolizumab alone (unless the first PR/CR is 
noted at 27 weeks, in which case it should be confirmed before stopping chemotherapy). Patients who elect to stop chemotherapy (either due to patient preference or chemotherapy 
related toxicity) will be required to go off protocol therapy at the time of radiographic disease progression. Subjects who discontinue trial treatment for a reason other than disease 
progression will move into the Follow-Up Phase and should be assessed according to the “on treatment” study schedule by radiologic imaging to monitor disease status if possible 
(every 63 days +/- 7 days for a total of six months after enrollment, and then every 12 weeks ± 14 days). Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, end of the study.
kk.
The window for each chemotherapy visit is ±1 day unless otherwise noted (C1D8 and beyond), provided no less than 6 days between chemotherapy administrations.
l.
Baseline tumor biopsy should be performed d-28 to d-1 and may be omitted if the tumor is inaccessible and/or a biopsy is thought to be too high risk. Cycle 1 D1 study drug should 
be given no sooner than 24 hr after the tumor biopsy.
m.
Baseline brain MRI with contrast is preferable, however CT scan of brain with contrast may be substituted at discretion of investigator
n.
End of treatment (EOT) is defined as date patient and/or treating physician decides to discontinue study drug. Patients who discontinue study treatment should not be considered 
withdrawn from the study. They should undergo EOT visit and enter the post-treatment (follow-up) period. EOT visit should occur within 30 days of last dose of study drug or the 
decision to discontinue study drug. If a patient discontinues study drug at a scheduled visit, the EOT visit can occur the same day. The EOT assessments (besides imaging) do not 
need to be repeated if done within the preceding14 days. Imaging does not need to be repeated if done in preceding 4 weeks as noted above (see “i”). The EOT visit can be 
combined with a safety follow-up visit.
o.
Safety follow-up should occur 30 days (+/- 7 days) after last dose of study drug and should continue at monthly intervals until resolution of toxicity to < grade 2
p.
Day1 Cycle 1 Research blood sample can be drawn up to 7 days prior to Day 1 as long as no prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to the lab draw; and no prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the lab draw.
q.
If fresh tumor tissue cannot be collected, the lead-site PI may approve the use of archival tissue. The use of archival tissue in lieu of a fresh tumor biopsy will be evaluated on a 
case-by-case basis and must be approved by the overall study (lead-site) PI. Please see section 6.6


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6
TRIAL PROCEDURES
6.1Trial Procedures
The Trial Flow Chart - Section 5 summarizes 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 unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), 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.
6.2Administrative Procedures
6.2.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
6.2.2
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 requirements, applicable laws and regulations and 
Sponsor requirements.
6.2.3
Review of 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. 
6.2.4
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 clinically significant by the Investigator.  Details regarding the disease (high grade 


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NEC) for which the subject has enrolled in this study will be recorded separately and not listed 
as medical history.  
6.2.5
Prior and Concomitant Medications Review
6.2.5.1 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 
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. 
6.2.5.2 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.
6.2.6
Disease Details and Treatments
6.2.6.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
6.2.6.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries.
6.2.6.3 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. 
6.2.7
Assignment of Screening Number
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements. All patients will have a unique screening 
identification number that will be used to identify the subject for all procedures that occur prior to 
randomization or treatment allocation. Each subject will be assigned only on 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.
6.2.8
Assignment of Randomization Number
All eligible subjects will be allocated to a treatment by non-random assignment (depending on 
whether Part A or Part B open to enrollment) and will receive an allocation number. The 
allocation number identifies the subject for all procedures occurring after treatment allocation. 
Once an allocation number is assigned to a subject, it can never be re-assigned to another 


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subject. The allocation number will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  
A single subject cannot be assigned more than one allocation number.
6.2.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for greater than 12 weeks between 
pembrolizumab doses due for non-drug-related or administrative reasons require consultation 
between the investigator and Principle Investigator and written documentation of the 
collaborative decision on subject management.
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered. Pembrolizumab should 
be prepared and administered according to institutional guidelines. Compliance with scheduled 
chemotherapy will also be tracked.
6.3Clinical Procedures/Assessments
6.3.1
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 (Appendix 2).  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
For subjects receiving treatment with pembrolizumab 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). 
Please refer to section Error! Reference source not found. for detailed information regarding 
the assessment and recording of AEs.  
6.3.2
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, 
6.3.3
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.  
6.3.4
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 


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Trial Flow Chart (Section5).  Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure.  Height will be measured at screening only.
6.3.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.  Screening ECOG status may be completed by telephone.
6.3.6
Tumor Imaging and Assessment of Disease
Radiographic evaluations and tumor measurements will be performed at screening (within 28 
days prior to the first dose of pembrolizumab), and then every 9 weeks (+/- 7 days) thereafter x 
6 months (27 weeks) and every 12 weeks thereafter), including the off study evaluation. Weeks 
are in reference to calendar week, and should not be adjusted for treatment dosing delays. 
When available, imaging performed within 1-12 months of the screening scan will be collected. 
In order to assess baseline tumor growth rate (TGR0), imaging within 1-6 months of the 
screening scan will be assessed first. Scans 6- 12 months prior to screening scan will be 
analyzed if additional information about baseline tumor growth rate kinetics is required to put on-
study TGR data in perspective (e.g., each patient serves as his/her own control).
Imaging should include multiphase CT chest/abdomen/pelvis with contrast (or MRI 
abdomen/pelvis with contrast and chest CT+/- contrast-at physician discretion). If FDG-PET 
imaging was performed with baseline imaging, it may be included with follow-up imaging as long 
as cross sectional imaging is contrast-enhanced multiphase scan. When possible, the same 
imaging modality should be used throughout the study in given patient. 
RECIST v1.1 will be used to determine radiographic response for primary endpoint. However, 
immune-related response criteria (irRC) will also be assessed (See Appendix 4). 
6.3.7
Baseline brain imaging
A baseline brain MRI (with contrast) will be performed on all patients at screening. CT of the 
brain (with contrast) may be substituted at the discretion of the investigator.
6.4Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.  


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Table 5 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 thriiodothyronine (T3)
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Free tyroxine (T4)
Absolute Lymphocyte Count
  (CO2 or biocarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Calcium
Chloride
Blood for correlative studies
Creatinine
Glucose
 
Phosphorus
 
Potassium  
 
Sodium
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.  
‡ If considered standard of care in your region.


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Laboratory tests for screening should be performed within 14 days prior to the first dose of 
treatment.  Pre-dose laboratory procedures (Day 1, all cycles) 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. 
Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do 
not need to be repeated after the end of the treatment if labs are within normal range. 
6.4.1
Serum/Urine β-hCG
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, will be tested for pregnancy within 14 days of receiving the first 
dose of study medication, and must be excluded in the event of a positive or borderline-positive 
test result. If a urine test is positive or borderline, a serum β-hCG test will be required. 
Pregnancy tests (urine or serum) should be repeated per local guidelines and at the discretion 
of the investigator. The results of the pregnancy testing will not be recorded. 
6.5Post-study Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer 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 the new anti-cancer therapy has been initiated, the subject will move into survival follow-
up.
6.6Tumor Tissue Collection and Correlative Studies Blood Sampling
All efforts should be made to collect a fresh tumor tissue biopsy at screening/ pre-treatment to 
determine patient eligibility. However, if fresh tumor tissue cannot be collected, the overall study 
(lead-site) PI may approve the use of archival tissue. The use of archival tissue in lieu of a fresh 
tumor biopsy will be evaluated on a case-by-case basis and must be approved by the overall 
study (lead-site) PI.
If archival tissue is to be used, the tissue sample must meet all following criteria;
1.
Collected within 6 months prior to the start of study treatment,
2.
Collected after the patient’s last line of therapy (with no treatment intervention between 
time of collection and start of study treatment), 
3.
Collected from either primary tumor or metastatic site in the context of routine clinical 
care (samples taken for prior research study are not allowed),
4.
Minimum sample requirements:
a.
Core needle biopsy (or larger sample, e.g. excisional biopsy or surgical Tru-Cut® 
biopsy)
b.
# of slides: 10 unstained cut 5um slides OR minimum of one x 1cm core needle 
biopsy
c.
Formalin-fixed paraffin-embedded (FFPE) (with fresh frozen if available)


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*For further details of archival sample shipment and processing requirements please 
reference the study lab/procedure manual.
6.6.1
Fresh Tumor Biopsy for Correlative Studies
Subjects will undergo biopsy of metastatic lesion (or primary site if safer and/or more 
accessible) at the time of screening (d-28 to d-1) which will be processed and banked for future 
correlative studies as outlined in Section 3.2.3.3. 
Ideally, at least four core tumor biopsies (and a minimum of two core biopsies) will be obtained 
(via up to 4 passes; multiple core biopsies may be acquired with each pass): 
a. Fresh frozen: Freshly harvested tissues should be flash frozen in liquid nitrogen or an 
ethanol/dry ice bath. Flash freezing the sample immediately helps to prevent sample 
degradation. Tissues should be stored at – 80°C or in liquid nitrogen until ready for shipping.
b. Formalin fixed paraffin embedded (FFPE): Fresh tissue sample will be placed into a 60 mL 
pre-filled polypropylene container that contains 30 mL of 10% neutral buffered formalin (NBF) 
WITHIN 1 MINUTE of collection. After 16-24 hours, sample will be processed and paraffin-
embedded. 
Additional biomarker research to identify factors important for pembrolizumab therapy may also 
be pursued. Samples will be sent to the Cancer Immunotherapy Lab (CIL) at UCSF (See 
Biospecimen Collection Manual):
Cancer Immunotherapy Lab
University of California, San Francisco
Additional details regarding tissue processing are provided in the accompanying Biospecimen 
Collection Manual (including shipping and handling information related to samples for analysis).
6.6.2
Blood collections for Correlative Studies
Research blood samples will be collected at four time points. Each time, four 10mL BD Sodium 
HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-top) will be collected and 
sent to the UCSF CIL (See Biospecimen Collection Manual for details).
Cancer Immunotherapy Lab
University of California, San Francisco
Correlative studies will be performed as outlined in Section 3.2.3.3. 
Additional details are provided in the Biospecimen Collection Manual.


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6.7Other Procedures
6.7.1
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 Error! Reference source not 
found.- Assessing and Recording Adverse Events. After discontinuing treatment following 
assessment of CR, these subjects should return to the site for a Safety Follow-up Visit and then 
proceed to the Follow-Up Period of the study (described in Section6.8.3).
6.7.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
6.8Visit Requirements
Visit requirements are outlined in Section 5- Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 6- Trial Procedures.
6.8.1
Screening
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. 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 and ECOG PS are to be performed within 14 days prior to the first dose of 
trial treatment.

For women of reproductive potential, a serum pregnancy test will be performed within 14 
days prior to the first dose of trial treatment. A urine test may be considered if serum test is 
not appropriate. 
Subjects may be rescreened ad infinitum after failing to meet the inclusion/ exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu of 
repeat screening test if performed within the specified time frame and the inclusion/ exclusion 
criteria is met. Subjects who are rescreened will retain their original screening number. 
6.8.2
 Treatment Period
Visit requirements are outlined in the Trial Flow Chart (Section 5). Specific procedure related 
details are provided above in the Trial Procedures (Section 6).
6.8.3
Post-Treatment Visits
6.8.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (+/- 7d) 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 


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with an AE of Grade > 1 will be followed monthly (+/- 7d) until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-neoplastic 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.
6.8.3.2 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 according to the “on treatment” study 
schedule by radiologic imaging to monitor disease status if possible (every 63 days +/- 7 days 
for a total of six months, and every 12 weeks ± 14 days). 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.
6.8.3.3 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 
12 weeks +/- 14 d to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
7
ASSESSING AND RECORDING ADVERSE EVENTS
7.1Definition of an Adverse Event
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 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, 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.
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use.
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.


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Progression of the cancer under study is not considered an adverse event unless it is 
considered drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and 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 6.8.3.1.
7.2Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to 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 a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met.
If a dose of Merck’s product 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.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. 
 
7.3Reporting of Pregnancy and Lactation to the Sponsor and to 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), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant 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 and within 2 working days to 
Merck Global Safety. 
7.4Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.4.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that:

Results in death;


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
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 a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event 
Refer to Table 6 for additional details regarding each of the above criteria.
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 that occurs to any subject from the time 
of the first screening biopsy or first dose of treatment, whichever is earlier, through 90 days 
following cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220
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.
All subjects with serious adverse events must be followed up for outcome.
7.4.2
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 and within 2 working days to Merck 
Global Safety. 
For the time period beginning  at the first screening biopsy or first dose of treatment, whichever 
is earlier, through 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 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, placebo treatment or a procedure.
For the time period beginning at the first screening biopsy or first dose of treatment, whichever 
is earlier, through 90 days following cessation of treatment, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow 
up to an ECI, whether or not related to Merck product, must be reported within 24 hours to the 
Sponsor and within 24 hours to Merck Global Safety.
Events of clinical interest for this trial include:


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1) an overdose of Merck product, as defined in Section 7.2- Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2) an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
7.5Evaluating 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 
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 6 Evaluating Adverse Events
An investigator, who is a qualified provider, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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.
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 the Merck product to be discontinued?
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the 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. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product 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 the Merck product? 
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


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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Merck 
product
(continued) 
Dechallenge
Was the Merck product 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 Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck product 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) Merck 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 THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency with 
Trial Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product 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.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship).
Yes, there is a reasonable possibility 
of Merck product relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck 
product is reasonable.  The AE is more likely explained by the Merck product than by another cause.
No, there is not a reasonable 
possibility Merck product relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)


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7.6Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/ERCs and investigators in 
accordance with all applicable global laws and regulations.
8
STATISTICAL PLAN
8.1Statistical Analysis Plan Summary
This study is an open-label adaptive pilot study of pembrolizumab-based therapy in previously 
treated PD-NECs. Given the rarity of this disease, PD-NECs of all sites (excluding SCLC and 
MCC) will be included (and pooled); since no standard therapy exists for refractory disease and 
treatment algorithms, (e.g. NCCN guidelines) typically recommend treating according to SCLC 
guidelines. 
The study is designed in two parts. Part A is for pembrolizumab-only treated patients, Part B is 
for patients treated with pembrolizumab plus chemotherapy (physician’s choice, irinotecan or 
paclitaxel). Part A is based on Simon’s two-stage design, and enrollment to Part B will only 
occur if Part A fails after the first stage.
The analysis will include all subjects treated (ITT) and the primary efficacy endpoint will be 
radiographic response by RECIST1.1 (investigator reported). Count and percentage of AE will 
be also provided. The total sample size needed to attain 80% power will be either 35 
(all treated by pembrolizumab) or 36-42 (first 14 treated by pembrolizumab and next 22-28 
treated by pembrolizumab/chemotherapy) with overall type I error of 0.1. 
8.1.1
Primary objective
Objectives and hypotheses of the study are stated in Section2. 
The primary efficacy endpoint will be best Overall Response Rate (ORR) by RECIST 1.1 
(investigator reported). ORR is defined as the proportion of the subjects in the analysis 
population who have a radiographic response according to RECIST 1.1 as assessed by 
investigator.
For subjects who demonstrated CR or PR, response duration is defined as the time from the 
date of first response (CR or PR) until the date of disease progression or death.
8.1.2
Other objectives

Progression free Survival (PFS) – RECIST 1.1 assessed by investigator
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.

Safety and Tolerability
The safety objective of this trial is to characterize the safety and tolerability of pembrolizumab-
based therapy in subjects with previously treated poorly differentiated NEC. The safety analysis 


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will be based on subjects who experienced toxicities as defined by CTCAE, version 4.0 criteria 
(Appendix 2). 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 Section7.4.2.
8.2Statistical Analysis Plan
8.2.1
Analysis populations
Efficacy:  The All Subjects as Treated (ASaT, ITT) population will be used for the analysis of 
ORR, PFS and OS. The ASaT population consists of all subjects who received at least one 
dose of the study treatment. If the final study consists of both Part A and Part B, the analysis will 
be done separately for each part.
The analysis population for DOR consists of responders.
Safety: 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.
8.2.2
Primary Efficacy Objective: Overall response rate
The point estimate and 95% confidence interval of overall response rate will be obtained for Part 
A and B (if available) separately. 
The sample size calculation is based on the adaptive Simon's two-stage design.94  
Part A: We will first recruit patients for pembrolizumab only (Part A). The null hypothesis that the 
true response rate is 0.10 will be tested against a one-sided alternative (26% RR). In the first 
stage, 14 patients will be accrued. 
1) If >2 responses (confirmed or unconfirmed) in the first 14 patients by 18 week scan, 21 
additional patients will be accrued (stage 2) for a total of 35 patients treated 
with pembrolizumab alone (Part A). The null hypothesis will be rejected if 7 or more 
responses are observed in 35 patients. This yields a type I error rate of 0.05 and power 
of 80% when the true response rate is 26%. 
2) If there are 2 or fewer responses in the first 14 patients by 18 weeks, the single 
treatment will be replaced by pembrolizumab/chemotherapy (Part B). Investigator may 
choose either two weeks on, one week off administration of irinotecan or weekly 
paclitaxel. We will now first recruit another 6 patients for pembrolizumab/irinotecan 
(safety lead-in, Part B) at 125 mg/m2. If more than 2 patients experiencing dose-limiting 
toxicity, then 6 additional patients will be treated at 100 mg/m2 plus pembrolizumab. 
After the safety lead-in, 16 additional patients will be accrued for a total of 22 patients 
treated with pembrolizumab/chemotherapy (Part B), which will provide 80% of power 
based on one-side binomial at a type I error rate of 0.05 to test the true response rate of 
31% against of null hypothesis of 10%.


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The total sample size needed to attain 80% power will be either 35 
(all treated by pembrolizumab) or 36-42 (first 14 treated by pembrolizumab and next 22-28 
treated by pembrolizumab/chemotherapy) with overall type I error of 0.1.
After all 14 patients have been enrolled to stage I of part A, and while waiting for their 18-week 
efficacy data, up to six patients can be accrued to the safety lead-in for Part B. This will help to 
avoid significant delays in accrual to the study, and streamline the transition to part B if required 
due to a lack of efficacy in Part A. If >2 responses occur in Part A Stage 1 before Part B safety 
lead-in is completed, a decision can be made whether to complete Part B safety lead-in versus 
discontinue and proceed with Part A Stage 2 depending on analysis of results and toxicity at 
that time. 
8.2.3
Secondary Efficacy Objectives
DOR: Duration of Response is defined as the time from the date of first response (CR or PR) 
until the date of disease progression or death. Kaplan-Meier method will be used to summarize 
DOR. Median DOR and its 95% confidence interval will be obtained for Part A and B (if 
available) separately. 
PFS: Progression free survival is defined as the time from the first day of study treatment with 
protocol therapy to the date of documented tumor progression or death due to any cause, 
whichever occurs first, as determined by irRC for irPFS and RECIST v1.1 for PFS. Subjects 
who did not progress or die will be censored on the date of their last evaluable tumor 
assessment. Kaplan-Meier method will be used to summarize progression free survival; median 
irPFS and PFS will be estimated with 95% confidence interval for Part A and B (if available) 
separately. 
OS: Overall survival is defined as the time from the first day of study treatment with protocol 
therapy to the date of death due to any cause. Kaplan-Meier method will be used to summarize 
OS. Median OS and its 95% confidence interval will be obtained for Part A and B (if available) 
separately. 
8.2.4
Statistical Methods for Safety Analyses
All subjects will be evaluated for toxicity from the time of the first treatment with pembrolizumab. 
Adverse events occurring from the start of treatment until 30 days after the end of treatment will 
be summarized by maximum toxicity grade. Safety and tolerability will be assessed by clinical 
review of all relevant parameters including adverse experiences (AEs), laboratory tests, and 
vital signs. The toxicity grade for laboratory data will be calculated using CTCAE v4.0 and the 
lab data will be summarized according to the subjects’ baseline grade and maximum grade for 
each cycle of therapy. All treatment related adverse events will be graded using NCI CTCAE 
v4.0.
Verbatim description of treatment-related adverse events will be mapped to thesaurus terms. 
Adverse events assessed as related to study drug and serious adverse events will be 
summarized similarly. Adverse events leading to treatment discontinuation will also be 
summarized.  Safety analysis will include a tabulation of all toxicities by grade.  The frequency 
of toxicities will be tabulated separately for each cohort. Count and percentage of AE will be 
provided.
In Part B of the study, there will be a safety lead-in of six patients if needed, with de-escalation if 
DLT is encountered.   The need for a safety lead-in will be determined at the time Part B begins 
based on the available clinical data at that time.


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8.3Statistical Analysis Plan Summary: Exploratory Objectives
8.3.1
Molecular Characteristics of NEC
Blood and tissue samples will be analyzed to characterize baseline and/or changes in a variety 
of parameters- e.g. proliferation indices, metabolic profile, protein expression (candidate 
approach or large scale), gene expression (e.g., transcriptomics), genomic signature 
(mutations), immunologic profile, and other molecular features of NEC (e.g., methylome profile). 
We will explore associations between molecular characteristics and clinical outcomes (ORR, 
DOR, PFS, OS). Additional tissue- and/or blood-based biomarker research to identify factors 
important for pembrolizumab and/or NEC therapy may also be pursued (e.g., exosomes, 
microRNAs, microbiome).  Sample analysis plans are noted in the below.
8.3.1.1 Immune Infiltration 
Immune cell subsets and localization will be assessed by immunohistochemistry (IHC) in 
baseline tissue biopsy samples. Markers will include CD3, CD8 and FoxP3. 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. Furthermore, 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.
8.3.1.2 PD-L1 staining and Ki67 staining
PD-L1 IHC will be performed by Qualtek (CLIA-certified) on baseline tumor biopsies using 
Merck’s 22C3 antibody. Descriptive statistics will be used to summarize PD-L1 scores. Wilcoxon 
rank-sum test will be used to assess whether there is a relationship between PD-L1 score and 
objective response, and with long/short-term survivors. Furthermore, Cox-proportional hazard 
models will be applied to assess if there is relationship between PD-L1 score and DOR, PFS 
and OS, respectively. 
Ki67 proliferative index will be assessed using commercially available techniques. Descriptive 
statistics will be used to summarize KI67 proliferative index. Wilcoxon rank-sum test will be used 
to assess whether there is a relationship between Ki67 proliferative index and objective 
response, and with long/short-term survivors. Furthermore, Cox-proportional hazard models will 
be applied to assess if there is relationship between a Ki67 proliferative index and DOR, PFS 
and OS, respectively.
8.3.1.3 T Cell Receptor (TCR) Repertories
TCR clonotypes will be characterized at baseline (blood and pre-treatment tumor biopsy), as will 
changes in the T cell immune response over time (blood). For each subject, a baseline tumor 
biopsy will be obtained and blood will be collected at screening, C2D1, C3D1 and at 
progression. T cell repertoire before, during and after treatment will be assessed by next-
generation sequencing. Besides the number of unique clonotypes and read depth, the TCR 
repertoire diversity will be assessed by clonality diversity index and clonality. Repertoire overlap 
will be measured by Baroni-Urbani and Buser index, and changes in clonotypes counts between 
sequencing experiments will be measured using Morisita’s distance. The diversity index will be 
compared by paired-Wilcoxon rank-sum test between baseline and the post-treatment time 
point. Wilcoxon rank-sum test will also be used to assess whether the 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.


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8.3.1.4 Mutational Profile and Mutation Burden 
Mutation profile will be performed in baseline biopsy tissues. The mutation profile and average 
number of somatic mutations per tumor will be assessed by Wilcoxon rank-sum test between 
responders vs. non-responders (defined by objective response, complete and partial), and 
between subjects who have progression at 18 weeks vs. those who have not progressed. 
8.3.1.5 Circulating Immune Cells
For each subject, blood will be collected at screening, C2D1, C3D1 and at progression. Flow 
cytometry will be performed to assess changes in circulating immune cell subsets with 
treatment, including effector T cells, regulatory T cells, and myeloid cells. The Wilcoxon rank-
sum test will be used to assess differences in immune subsets in responders vs. non-
responders (defined by objective response), and between subjects who have progression at 18 
weeks vs. those who have not progressed within each group. Changes in immune cell subsets 
in individual subjects with treatment will be assessed using paired Wilcoxon Signed-rank test.
Objective (if proceed to Part B): To explore changes in circulating TCR profiles and circulating 
immune cells in patients treated with pembrolizumab alone compared to patients treated with 
pembrolizumab plus chemotherapy.
8.3.2
Tumor Growth Rate (TGR)
TGR studies will include assessment of clinical outcomes (ORR, DOR, PFS, OS) and 
correlation with TGR and RECIST classification of disease response in patients enrolled at all 
sites. This will involve retrospective review of at least one scan performed one to twelve months 
prior to baseline imaging. RECIST measurements of pre-baseline scans will be performed by 
local institution radiologists. 
TGR will be determined from two scans as the percentage change in tumor volume per month. 
Specifically, tumor growth is assumed to be exponential, so TGR = 100 * (e^(TG) - 1), where TG 
= 3 * log (D2 / D1) / time.87 D1 and D2 represent tumor sizes (using the sum of longest 
diameters of target non-nodal lesions and shortest diameters of target nodal lesions, excluding 
non-target and new lesions) at dates 1 and 2, while time (in months) = (date 2 - date 1 + 1) / 
30.44. Baseline TGR will be determined from the change between 2 pre-treatment scans, while 
experimental TGR(s) will be determined from changes following treatment initiation (e.g., at any 
on-study scans and at the time of progression or off-study for any reason). Descriptive statistics 
will be used to summarize these metrics in comparison to changes in RECIST (and to identify 
patients exhibiting hyper-progressive disease). Clinical outcomes will be compared between 
groups (e.g., hyper-progression patients, responding patients and the remainder of the 
population) by logrank test for DOR, PFS and OS; and Chi-square test (or Fisher’s exact test) 
for response. Chi-square test (or Fisher's exact test) and t-test will be applied to evaluate 
associations between categorical and continuous clinicopathologic variables, respectively.  
9
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1Investigational Product 
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 7.


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Table 7 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
All other supplies not indicated in Table 7 above will be provided locally by the trial site. For any 
commercially available product that is provided by the trial site. The trial site is responsible to 
record the lot number, manufacturer and expiry date for any locally purchased product as per 
local guidelines unless otherwise instructed by the Sponsor. 
9.2Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
9.3Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 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.
9.4Storage 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.
9.5Returns 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. 
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.
9.6Chemotherapy
Irinotecan: commercial drug supply will be used.
Paclitaxel: commercial drug supply will be used.


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10  ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
10.1.1
Confidentiality of Data
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR/IRB mechanism and the process of informed consent. 
The CHR/IRB reviews all proposed studies involving human experimentation and ensures that 
the subject’s rights and welfare are protected and that the potential benefits and/or the 
importance of the knowledge to be gained outweigh the risks to the individual. The CHR/IRB 
also reviews the informed consent document associated with each study in order to ensure that 
the consent document accurately and clearly communicates the nature of the research to be 
done and its associated risks and benefits. 
Data generated by this trial will be considered confidential by the investigator, except to the 
extent that it is included in a publication as provided in the Publications section of this protocol.
10.1.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.
10.2 Compliance with Financial Disclosure Requirements
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, Financial 
Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff 
Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) will be provided as 
required. 
10.3 Compliance with Law, Audit and Debarment
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 11.5 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for 
additional information.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will 
allow subjects to identify potentially appropriate trials for their disease conditions and pursue 


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participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.    
10.5 Study Management
10.5.1
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 Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator 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.
10.5.2
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 CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.  
10.5.3
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 CHR-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.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
10.5.4
Changes in the Protocol
Once the protocol has been approved by the UCSF CHR, 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 CHR 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 CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites.


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10.5.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
10.5.6
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 11.5 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for 
additional information.
10.5.7
Multicenter Communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed 
to discuss risk assessment.  The following issues will be discussed as appropriate:

Enrollment information

Adverse events (i.e., new adverse events and updates on unresolved adverse events and 
new safety information)

Protocol violations

Other issues affecting the conduct of the study
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  
The 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.


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Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR 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 investigator 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.
10.5.8
Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
10.5.9
  Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 

Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.


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10.6 Data Management
The Principal Investigator and/or his/her designee 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, 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 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.
The Principal Investigator 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 Study Chair, the Trial Statistician, and the 
Protocol Project Manager.


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Lynch T, Bondarenko I, Luft A, et al. Ipilimumab in combination with paxlitaxel and 
carboplatin as first line treatment in stage IIIB/IV non-small cell lung cancer: results from a 
randomized, double blind multicenter phase II study. J Clin Oncol. 2012;30:2046-2054. 
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Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and 
carboplatin as first line therapy in extensive disease small cell lung cancer: results from a 
randomized, double-blind multicenter phase 2 trial. Ann Oncol. 2013;24:75-83. 
78.
Papadimitrakopoulou V, Patnaik A, Borghaei H, et al. Pembrolizumab (MK-3475) plus 
platinum doublet therapy as front-line therapy for advanced non-small cell lung cancer 
(NSCLC): KEYNOTE-021 cohorts A and C. J Clin Oncol. 2015;33:abstr# 8031. 
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McKenzie J, Mbofung R, Malu S, Hwu P. Increasing the antitumor efficacy of 
immunotherapy in melanoma by using topoisomerase I inhibitors. Cancer Immunology 
Research. 2016;4 (1 Suppl):abstr#B152. 
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Weiss G, Pierog M, Blaydorn L, et al. Phase Ib/II study of pembrolizumab plus 
chemotherapy: Initial results of metastatic cancer patients. Mol Cancer Ther. 2015;14:A50. 


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81.
Fong L, Cham J, Zhang L, et al. Changes in circulating and intratumoral T cell 
clonotypes in sipuleucel-T-treated prostate cancer patients. J Clin Oncol. 2015;33(suppl):abstr# 
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anti-CTLA4 treatment in cancer patients. Sci Transl Med. 2014;28:238. 
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Oh D-Y, Cham J, Zhang L, et al. T cell repertoire diversification is associated with 
immune related toxicities following immune checkpoint inhibition in metastatic cancer patients. 
Proc AACR. 2016:Abstr#4362. 
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2011;144(5)doi:10.1016/j.cell.2011.02.013
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Sriram R, Criekinge MV, Santos JD, et al. Elevated Tumor Lactate and Efflux in High-
grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy 
of Prostate Tissue Slice Cultures. Article. Cancers. 2020-02-26 2020;12(3):537. 
doi:10.3390/cancers12030537
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LE J, A E, JJ P, et al. Metabolic Profiling of IDH Mutation and Malignant Progression in 
Infiltrating Glioma. Scientific reports. 03/22/2017 2017;7doi:10.1038/srep44792
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Resistance to Anticancer Treatment. Review. Biology. 2020-12-16 2020;9(12):474. 
doi:10.3390/biology9120474
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Wang W, Bai L, Li W, Cui J. The lipid metabolic landscape of cancers and new 
therapeutic perspectives. Frontiers in Oncology. 2020;10
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APPENDIX 1: 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 2: 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 3: 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.
In addition, volumetric analysis will be explored by review for response assessment.


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APPENDIX 4: Immune-Related Response Criteria (irRC) for Evaluation of Immune 
Therapy Activity in Solid Tumors
Immune-related response criteria (irRC)* will also be used in this study for assessment for tumor 
response. 
* As published in Clinical Cancer Research:
J.D. Wolchok, A. Hoos, S. O’Day, J.S. Weber, O. Hamid, C. Lebbe, M. Maio, M. Binder, O. 
Bohnsack, G Nichol, R Humphrey, S.F. Hodi . Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec;15(23): 
7412-7420.


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APPENDIX 5: Data and Safety Monitoring Plan: Multicenter Phase 2 or 3 Trial with 
Safety Lead-In 
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes:

Review of all participant data in safety lead-in phase.

Approval to enroll past safety lead-in phase by DSMC Chair or Vice Chair.

Semiannual auditing after safety lead-in phase (depending on accrual).

Review of serious adverse events.

Minimum of a biennial regulatory auditing visit.
2.
Monitoring and Reporting Guidelines
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  The 
Study Chair is responsible for the overall conduct of the study and for auditing its safety and 
progress at all participating sites.  The Study Chair will conduct continuous review of data and 
participant safety at monthly UCSF Site Committee meetings.  The discussions are documented 
in the UCSF Site Committee meeting minutes.
All institutional Phase II or III therapeutic studies with a lead-in are designated with a high-risk 
assessment during the safety lead-in phase and a moderate risk assessment. 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 Study Chair 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 by a DSMC Monitor/Auditor on a semiannual basis with a random selection of twenty 
percent of the participants (or at least three participants if the calculated value is less than three). 
The DSMC Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants 
selected for review or until the selected participants discontinue study participation or the trial is 
closed with the IRB. Additionally, the assigned DSMC Monitor/Auditor will review no more than 
10 total participant charts during the course of auditing this trial.  DSMC Monitor/Auditors will send 
a follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business days. 
Additionally, a regulatory audit will occur on a biennial basis to review all regulatory documents 
for the trial.
The participating site’s source documents are audited remotely via either review of redacted 


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source documents downloaded by the site into the PC console of OnCore or via access to the 
site’s electronic medical records.  The DSMC Monitor/Auditor will audit no more than three 
participant charts at each participating site during the course of auditing this trial.
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters.
Multicenter communication
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites. The 
following issues will be discussed as appropriate:

Enrollment information.

Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol Violations.

Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites. The data (i.e., copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the remote 
monitoring visits in order for the DSMC to monitor the participating site’s compliance with the 
protocol and applicable FDA regulations.
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.


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
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 Site Committee meetings.  All adverse events entered into OnCore® will be reviewed on a 
monthly basis at the UCSF Coordinating Center Site Committee meetings.  All grade 3-5 adverse 
events must be reported to the UCSF Coordinating Center by the participating sites within 10 
business days of becoming aware of the event or during the next scheduled monthly conference 
call, whichever is sooner.  The UCSF Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution assignment from the UCSF Coordinating Center and the 
participating sites. 
3.2
Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be reported to the UCSF 
Coordinating Center within one business days of becoming aware of the event.  The SAEs are 
reviewed and audited by the UCSF Data and Safety Monitoring Committee on an ongoing basis 


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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 a death 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 Study Chair at the 
UCSF Coordinating Center or the assigned designee must be notified within 1 business day from 
the participating site(s) and the Study Chair must then notify the DSMC Chair (or Vice Chair) and 
the DSMC Director within 1 business day of this notification.
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 Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC Chair (or Vice Chair) and the DSMC 
Director at the time the increased rate is identified via a report. 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 Study Chair stops enrollment or stops the study due to safety issues, the DSMC 
Chair (or Vice Chair) and the DSMC Director must be notified within one business day and the 
IRB must be notified within their reporting guidelines.
Data and Safety Monitoring Committee Contacts:
  
 (DSMC Chair) 
  
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
 
 
 
 (DSMC Director)  
 
 
UCSF HDFCCC 
San Francisco, CA 94143