Conditions: Ovarian Cancer
Keywords: immunotherapy platinum-resistant ovarian cancer immune checkpoint inhibitors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
To evaluate the efficacy and safety of anti-PD-1 antibody MK-3475 (pembrolizumab) in combination with gemcitabine and cisplatin chemotherapy in women with recurrent platinum-resistant ovarian cancer.

Detailed description:
This is a single-arm, open-label, phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody MK-3475 (pembrolizumab) in combination with standard of care gemcitabine and cisplatin chemotherapy in women with recurrent platinum-resistant ovarian cancer (encompasses ovarian, peritoneal and fallopian tube cancer). Subjects will receive 2 cycles of gemcitabine and cisplatin chemotherapy followed by 4 cycles of gemcitabine and cisplatin combined with pembrolizumab in 21-day treatment cycles. Subjects will continue to receive single-agent pembrolizumab every 21 days as maintenance therapy for up to 2 year until progression or the subject meets withdrawal criteria. Tumor imaging with CT scan will occur at baseline and every 6 weeks (after each second cycle) during chemotherapy treatment and every 9 weeks thereafter. The primary endpoint is efficacy as defined overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Secondary endpoints for efficacy include progression free survival at 6 and 12 months, time to progression, duration of response and overall survival. Safety and tolerability of the regimen will be determined by assessing the frequency and intensity of adverse events as defined by the Common Terminology Criteria for Adverse Events (CTCAE v.4). Quality of life will be measured using the European Organization for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30).

Arms:
arm 1: 2 cycles of 750mg gemcitabine and 30mg cisplatin chemotherapy (standard of care) followed by 4 cycles of gemcitabine and cisplatin combined with pembrolizumab in 21-day treatment cycles followed by single-agent pembrolizumab maintenance therapy for up to 2 years of treatment (6 cycles combination treatment + 28 cycles maintenance).

Gemcitabine 750 mg/m2 every 3 weeks (Q3W) x 6 cycles IV infusion

-Day 1 and Day 8 of each 3 week cycle Standard of care

Cisplatin 30 mg/m2 Q3W x 6 cycles IV infusion

-Day 1 and Day 8 of each 3 week cycle after gemcitabine Standard of care

Pembrolizumab 200 mg Q3W starting with cycle 3 IV infusion

-Day 1 of each 3 week cycle after gemcitabine and cisplatin Experimental

Interventions: intervention 1: Pembrolizumab intervention 2: Gemcitabine intervention 3: Cisplatin
Intervention descriptions: intervention 1: Pembrolizumab IV solution intervention 2: Gemcitabine IV solution intervention 3: Cisplatin IV solution

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
Protocol Version 11: 02 Jan 2019 
A phase II study of pembrolizumab with cisplatin and gemcitabine treatment in 
patients with recurrent platinum-resistant ovarian cancer 
Principal Investigator:
Dr. Christine Walsh, MD 
Cedars-Sinai Medical Center 
8700 Beverly Blvd. 
Los Angeles, CA 90048 
310-423-5456; Fax: 310-423-0155
Christine.Walsh@cshs.org
Consenting Co-Investigator(s): 
Name 
Department/Division
Ilana Cass, MD 
Gynecologic Oncology 
Andrew Li, MD 
Gynecologic Oncology 
BJ Rimel, MD
Gynecologic Oncology 
Biostatistician: 
Andre Rogatko, PhD 
Director, Biostatistics and Bioinformatics 
Cedars Sinai Medical Center 
(310) 423-3316
Andre.Rogatko@cshs.org
Study Drug: 
Pembrolizumab, cisplatin and gemcitabine
IND Number:
N/A 
Funding Source: 
Merck 
Version: 
Version 11:  02 Jan 2019 
NCT:
NCT02608684


 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
Protocol Version 11: 02 Jan 2019 
 
 
Signature Page 
Protocol Version 11: 02Jan2019 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................. 6 
1.0 
TRIAL SUMMARY ..................................................................................................... 8 
2.0 
TRIAL DESIGN .......................................................................................................... 9 
2.1 
Trial Design ............................................................................................................ 9 
2.2 
Trial Diagram ......................................................................................................... 9 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 9 
3.1 
Primary Objective(s) & Hypothesis(es) .......................................................... 9 
3.2 
Secondary Objective(s) & Hypothesis(es) .................................................. 10 
3.3 
Exploratory Objective ....................................................................................... 10 
4.0 
BACKGROUND & RATIONALE ........................................................................... 10 
4.1 
Background ......................................................................................................... 10 
4.2 
Rationale .............................................................................................................. 11 
5.0 
METHODOLOGY ..................................................................................................... 15 
5.1 
Entry Criteria ....................................................................................................... 15 
5.2 
Trial Treatments ................................................................................................. 18 
5.3 
Randomization or Treatment Allocation ...................................................... 24 
5.4 
Stratification ........................................................................................................ 24 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ........... 24 
5.6 
Rescue Medications & Supportive Care ...................................................... 25 
5.7 
Diet/Activity/Other Considerations ............................................................... 30 
5.8 
Subject Withdrawal/Discontinuation Criteria ............................................. 31 
5.9 
Subject Replacement Strategy ....................................................................... 32 


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5.10 
Clinical Criteria for Early Trial Termination ................................................ 32 
6.0 
TRIAL FLOW CHART ............................................................................................. 33 
6.1 
Study Flow Chart ................................................................................................ 33 
7.0 
TRIAL PROCEDURES ........................................................................................... 35 
7.1 
Trial Procedures ................................................................................................. 35 
7.2 
Assessing and Recording Adverse Events ................................................ 42 
7.3 
Reporting Requirements for Adverse Events ............................................ 46 
8.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 51 
8.1 
Trial Design .......................................................................................................... 51 
8.2 
Early Stopping for Futility................................................................................ 51 
8.3 
Design Operating Characteristics ................................................................. 52 
8.4 
Early Stopping for Safety ................................................................................. 52 
8.5 
Statistical Analyses ........................................................................................... 54 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF COMMERCIAL 
SUPPLIES ................................................................................................................. 54 
9.1 
Investigational Product .................................................................................... 54 
9.2 
Packaging and Labeling Information............................................................ 55 
9.3 
Commercial Supplies Disclosure .................................................................. 55 
9.4 
Storage and Handling Requirements ........................................................... 55 
9.5 
Returns and Reconciliation ............................................................................. 55 
10.0 
STUDY MANAGEMENT ......................................................................................... 55 
10.1 
Conflict of Interest ............................................................................................. 55 
10.2 
Institutional Review Board and Consent ..................................................... 55 
10.3 
Registration Procedures .................................................................................. 56 


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11.0 
Data and Safety monitoring................................................................................. 57 
11.1 
Data Monitoring and Quality Assurance ...................................................... 57 
11.2 
Safety Monitoring ............................................................................................... 57 
11.3 
Adherence to the Protocol .............................................................................. 58 
11.4 
Amendments to the Protocol .......................................................................... 58 
11.5 
Obligations of Investigators............................................................................ 59 
11.6 
Record Retention ............................................................................................... 59 
12.0 
REFERENCES ......................................................................................................... 60 
APPENDIX A: ECOG Performance Status ................................................................... 63 
APPENDIX B: CTCAE ........................................................................................................ 64 
APPENDIX C: RECIST 1.1 ................................................................................................ 65 
APPENDIX D: Immune-Related Respone Criteria ..................................................... 68 
APPENDIX E: FACIT-TS-G Questionnaire ................................................................... 69 
APPENDIX F: FACT-G Questionnaire ........................................................................... 70 
APPENDIX G: Summary of Protocol Changes ........................................................... 72 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CA125 
Cancer Antigen 125 
CBC 
Complete Blood Count 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
CSA 
Controlled Substances Act 
CSF 
Colony-stimulating factor 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DKA 
Diabetic Ketoacidosis 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
ERC 
Ethical Review Committee 
EU 
European Union 
FACIT-TS-G 
Functional Assessment of Chronic Illness Therapy 
FACT-G 
Functional Assessment of Cancer Therapy 
FDA 
US Food and Drug Administration 
FOXP3 
Forkhead Box P3 
G-CSF 
Granulocyte colony-stimulating factor 
GFR 
Glomerular Filtration Rate 
HIV 
Human immunodeficiency virus 
Ig 
Immunoglobulin 
IMM 
Independent Medical Monitor 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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irRC 
Immune-related response criteria 
ITIM 
Immunoreceptor Tyrosine-based Inhibition Motif 
ITSM 
Immunoreceptor Tyrosine-based Switch Motif 
IV (or iv) 
Intravenously 
Ki67 
Protein marker for cellular proliferation 
LDH 
Lactate Dehydrogenase 
mAB 
Monoclonal antibody 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTC 
Over the Counter 
PD 
Progressive Disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed death-ligand 1 
PD-L2 
Programmed death-ligand 2 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PMDA 
Pharmaceutical and Medical Devices agency 
PO 
Per Os (oral) 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
Q 
Every 
QMC 
Quality Management Core 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
T1DM 
Type 1 Diabetes Mellitus 
TB 
Tuberculosis 
TIL 
Tumor Infiltrating Lymphocyte 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 
 
 
 


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1.0 TRIAL SUMMARY 
Title 
A phase II study of pembrolizumab with cisplatin and gemcitabine treatment 
in patients with recurrent platinum-resistant ovarian cancer. 
Short Title 
Pembrolizumab with cisplatin and gemcitabine in platinum-resistant 
ovarian cancer 
Protocol Number 
IIT2015-13-Walsh-PemCiGem 
Phase 
2 
Methodology 
Single-arm, open-label, phase II trial 
Study Duration 
24 months (2 years) 
Study Center(s) 
Single-center 
Objectives 
To evaluate the efficacy and safety of anti-PD-1 antibody MK-3475 
(pembrolizumab) in combination with standard of care gemcitabine and 
cisplatin chemotherapy in women with recurrent platinum-resistant ovarian 
cancer 
Number of Subjects 
25 
Diagnosis and Main 
Inclusion Criteria 
Recurrent platinum-resistant ovarian cancer (encompasses ovarian, 
peritoneal and fallopian tube cancer) 
Study Product(s), Dose, 
Route, Regimen 
Intravenous Cisplatin + Gemcitabine + Pembrolizumab 
Estimated enrollment 
period 
2/1/2016 – 2/1/2018 
Duration of administration 
2 cycles of gemcitabine and cisplatin chemotherapy followed by 4 cycles 
of gemcitabine and cisplatin combined with pembrolizumab in 21-day 
treatment cycles followed by single-agent pembrolizumab maintenance 
therapy for up to 2 years of treatment (6 cycles combination treatment + 28 
cycles maintenance).   
Duration of Participation 
Duration of participation will vary. Treatment will continue until disease 
progression or until the subject meets withdrawal criteria. 
Statistical Methodology 
Twenty-five patients would be needed to test the null hypothesis: p ≤ 0.111 
against the alternative hypothesis: p ≥ 0.300 at the 5.0% level of 
significance and with 80% power.   
 
 
 


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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single-arm, open-label, phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody 
MK-3475 (pembrolizumab) in combination with standard of care gemcitabine and cisplatin 
chemotherapy in women with recurrent platinum-resistant ovarian cancer (encompasses ovarian, 
peritoneal and fallopian tube cancer).  Subjects will receive 2 cycles of gemcitabine and cisplatin 
chemotherapy followed by 4 cycles of gemcitabine and cisplatin combined with pembrolizumab in 21-
day treatment cycles.  Subjects will continue to receive single-agent pembrolizumab every 21 days as 
maintenance therapy for up to an additional 28 cycles until progression or the subject meets withdrawal 
criteria. Altogether, the maintenance cycles in addition to the 6 combination cycles will total to 
approximately two years of study treatment. Tumor imaging with CT scan will occur at baseline and 
every 6 weeks (after each second cycle) during chemotherapy treatment and every 9 weeks during the 
maintenance phase (or earlier than every 6-9 weeks as clinically indicated per PI discretion).  The 
primary endpoint is efficacy as defined overall response rate by Response Evaluation Criteria in Solid 
Tumors (RECIST v.1.1).  Secondary endpoints for efficacy include progression free survival at 6 and 
12 months, time to progression, duration of response and overall survival.  Safety and tolerability of the 
regimen will be determined by assessing the frequency and intensity of adverse events as defined by 
the Common Terminology Criteria for Adverse Events (CTCAE v.4).  Quality of life will be measured 
using the FACIT-TS-G and FACT-G (See APPENDIX). 
2.2 
Trial Diagram 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To estimate the anti-tumor activity and durability of response (definitions in section 
4.2.3.1) to pembrolizumab with cisplatin and gemcitabine treatment in patients with recurrent, 
platinum-resistant ovarian cancer as determined by Response Evaluation Criteria in Solid Tumors 
(RECIST). 


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Hypothesis:  The combination of pembrolizumab with standard of care cisplatin and gemcitabine 
treatment in patients with recurrent, platinum-resistant ovarian cancer will result in durable objective 
responses. 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To determine the safety and tolerability of pembrolizumab with cisplatin and 
gemcitabine treatment in patients with recurrent, platinum-resistant ovarian cancer as assessed by 
Common Terminology Criteria for Adverse Events (CTCAE). 
Hypothesis:  The combination of pembrolizumab with standard of care cisplatin and gemcitabine 
treatment in patients with recurrent, platinum-resistant ovarian cancer will be well tolerated. 
3.3 
Exploratory Objective 
(1) 
Objective: To explore whether baseline tumor characteristics predict response to the 
combination of pembrolizumab with standard of care cisplatin and gemcitabine treatment in 
patients with recurrent, platinum-resistant ovarian cancer. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on MK-
3475. 
4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades.  Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies [1-3].  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 [4]. 
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) [5].  The structure of murine PD-1 has been resolved.  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.  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  
Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells 
as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors.  Both ligands are type I transmembrane receptors containing both IgV- 
and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 


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signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma.  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.  In September, 2014, KeytrudaTM (pembrolizumab) was approved in the United States for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. KeytrudaTM was also granted 
accelerated approval in October 2015 by the FDA to treat patients with advanced non-small cell lung 
cancer whose disease has progressed after other treatments and with tumors that express PD-L1. 
4.1.2 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 
Rationale for the Trial and Selected Subject Population 
Ovarian cancer is the most lethal of the gynecologic malignancies.  While 75% of patients with 
advanced epithelial ovarian cancer will achieve a clinical remission following surgical cytoreduction and 
platinum and taxane based chemotherapy, the vast majority will relapse and develop chemoresistant 
disease [6].  Despite aggressive surgical and chemotherapeutic treatment, fewer than 50% of patients 
with stage III or IV disease will survive longer than 5 years. There is a critical need for more effective 
therapies for this fatal malignancy. 
In solid tumors including melanoma, lung, kidney, prostate and other cancers, modulation of the 
immune system is showing promise as an effective treatment strategy [7].  This is an active area of 
research in many tumor types and the optimal immunotherapy approach for ovarian cancer patients 
has yet to be defined. 
Therapeutic blockade of immune checkpoints releases the silencing of cytotoxic T-cell responses and 
allows for effective anti-tumor immune responses.  In an earlier study, antibody treatment against PD-
L1 (BMS-936559) caused tumor regression and prolonged disease stabilization in heavily pretreated 
patients with a variety of solid tumors and also showed a milder toxicity profile compared to anti-CTLA-
4 antibody treatment [8].  However, in this trial, only 1 of 17 patients with advanced ovarian cancer 
demonstrated an objective response.  In 2015, Hamanishi and colleagues reported data on the efficacy 
and safety of an anti-PD-1 antibody (BMS-936558, nivolumab) in patients with platinum-resistant 
ovarian cancer [9, 10].   Used as a single agent, the anti-PD-1 treatment was found to be well tolerated 
and associated with a 15% best overall response rate and 45% disease control rate.  The median 
overall survival time was 20 months at study termination.  Taken together, these data suggest that 
immune checkpoint blockade may have efficacy in the treatment of ovarian cancer. 
Platinum-resistance correlates highly with resistance to other cytotoxic therapies.  When ovarian cancer 
relapses within 6 months of last chemotherapy, response rates to later-line agents range from 10-20%.  
One of the more effective treatment options in this setting has been the combination use of cisplatin 
and gemcitabine chemotherapy.  Laboratory studies demonstrate synergy between the compounds 


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and the ability of gemcitabine to reverse platinum resistance [11].  There have been three clinical trials 
testing the combination of cisplatin and gemcitabine in platinum-resistant ovarian cancer populations.  
The results are summarized below. 
1. Rose, et al.  Gynecol Oncol 2003 [12].  In this single institution study, 36 platinum-resistant ovarian 
cancer patients (multiple prior chemotherapy regimens eligible) were treated with gemcitabine 750 
mg/m2 + cisplatin 30 mg/m2 on days 1 and 8 of a 21-day cycle.  There were 4 (11%) complete 
responses, 11 (31%) partial responses, 9 (26%) stable disease and 11 (31) progressive disease.  
Among the responders, the median duration of response was 11 months.  Progression-free interval 
was 6 months and median overall survival was 12 months.  Responses were seen, even in the setting 
of prior gemcitabine exposure.  Four of six patients who failed prior gemcitabine treatment were 
responders to the regimen. 
2. Nagourney, et al. Gynecol Oncol 2003 [13].  In this single institution study, 27 patients with platinum-
resistant ovarian cancer (multiple prior chemotherapy regimens eligible) were treated with cisplatin 30 
m/gm2 and gemcitabine 600-750 mg/m2 on days 1 and 8 of a 21-day cycle.  There were 7 (26%) 
complete responses, 12 (44%) partial responses, 7 (26%) stable disease and 1 (4%) disease 
progression.  The median time to progression for objective responders was 8 months. 
3. Brewer, et al.  Gynecol Oncol 2006 [14].  In this multi-center cooperative group, GOG trial (GOG 
126-L), 59 patients with platinum-resistant ovarian cancer (eligibility limited to one prior platinum-based 
regimen) were treated with cisplatin 30 mg/m2 followed by gemcitabine 750 mg/m2.  The dose of 
gemcitabine was reduced to 600 mg/m2 due to hematologic toxicity.  There were 4 (7%) complete 
responses, 5 (9%) partial responses, 31 (54%) stable disease and 12 (21%) progressive disease.  The 
median time to progression was 5.4 months.  The median overall survival was 15 months. 
Taken together, these three studies suggest activity for the combination of cisplatin and gemcitabine in 
the platinum-resistant and gemcitabine-resistant ovarian cancer population.  The sequencing of the two 
drugs appears to impact the toxicity profile.  Gemcitabine given prior to cisplatin appears to result in 
less hematologic toxicity and better tolerability.  Despite promising response rates, the durability of 
response was limited, ranging from 5.4 to 8 months in the three trials.  The purpose of this study is to 
determine whether the addition of an anti-PD-1 monoclonal antibody to cisplatin and gemcitabine 
treatment will improve upon the responses and durability of remissions in patients with platinum-
resistant ovarian cancer. 
The body of literature addressing the combination of immunotherapy with chemotherapy is growing.  
Because chemotherapy-induced lymphodepletion is predicted to limit the ability to mount an immune 
response, the combination of chemotherapy with immunotherapy has been thought to be antagonistic.  
However, there is data to suggest that chemotherapy and immunotherapy could work synergistically 
when sequenced properly.  Established tumors employ a number of powerful immunosuppressive 
mechanisms to escape immune surveillance [5].  Chemotherapy reverses suppression by causing loss 
of suppressive T-regulatory cells and triggers a “re-booting” of the immune system that causes T-cells 
to become more susceptible to antigen-recognition [15-19].  Removal of tumor burden relieves the 
immune system from persistent antigen presentation which subsequently removes tolerance and allows 
T cells to regain anti-tumor function [20].   
Cisplatin and gemcitabine also have specific impacts on the immune system.  Cisplatin decreases T-
regulatory and myeloid derived suppressor cells (MDSC) and sensitizes tumor cells to T cell-mediated 
lysis [21, 22]. Gemcitabine downregulates MDSC and has direct immunostimulatory effects [23, 24].   
Clinical trials combining immune checkpoint inhibitors with chemotherapy have recently been reported 
and the combination demonstrates anti-tumor activity with acceptable toxicity.  A phase I study 
combining nivolumab (anti-PD-1) with platinum-based doublet chemotherapy (cisplatin/gemcitabine, 
cisplatin/pemetrexed, carboplatin/paclitaxel) in non-small cell lung cancer demonstrated antitumor 
activity, no dose-limiting toxicities during the first 6 weeks of treatment, an acceptable toxicity profile 
and encouraging 1 year overall survival (ASCO 2014, NCT01454102) [25].  Nivolumab and 


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pembrolizumab have similar toxicity profiles [26].  As the safety of anti-PD-1 inhibition with cisplatin and 
gemcitabine has been demonstrated in this prior trial (no dose limiting toxicities), we plan to study the 
combination of pembrolizumab with the cisplatin/gemcitabine platinum doublet in this trial with a phase 
II design with early stopping rules for safety.   
Additional research suggests that the phasing of immunotherapy with chemotherapy has an impact on 
efficacy of the combination.  A phase II study combining the anti-CTLA4 antibody ipilimumab with 
paclitaxel and carboplatin in first-line treatment of advanced non-small cell lung cancer showed no 
improvement in progression-free survival (PFS) when ipilimumab was administered concurrently with 
chemotherapy compared to chemotherapy alone.  However, when ipilimumab was added after two 
rounds of chemotherapy in a phased regimen that allowed for antigen release to occur prior to 
immunotherapy exposure, there was an improvement in PFS [27].   
Based on this prior experience, we will evaluate the impact of adding the anti-PD-1 antibody MK-3475 
(pembrolizumab) to standard of care cisplatin and gemcitabine chemotherapy in the treatment of 
patients with platinum-resistant ovarian cancer.  We will administer two cycles of chemotherapy to allow 
for tumor cytoreduction, tumor antigen release, decrease in suppressive T-regulatory and myeloid 
derived suppressor cells and remodeling of the tumor microenvironment.  Pembrolizumab will be added 
to cycles 3-6 of chemotherapy and then will be continued as single-agent maintenance therapy every 
3 weeks for up to one year until disease progression or subject meets withdrawal criteria.   
  
4.2.2 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) has been conducted by Merck to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of MK-3475 showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  
No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the 
dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  
Recent data from other clinical studies within the MK-3475 program has shown that a lower dose of 
MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed by Merck using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies 
and would support both body weight normalized dosing or a fixed dose across all body weights.  MK-
3475 has been found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W 
(i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 


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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors 
is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg 
Q3W in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor 
burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK 
model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose 
of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained 
with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure 
range established in melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that are well tolerated and 
safe.  
4.2.3 
Rationale for Endpoints 
We will assess the efficacy and safety of pembrolizumab with cisplatin and gemcitabine chemotherapy 
in patients with platinum-resistant ovarian cancer.  We will evaluate overall response rate as the primary 
efficacy endpoint and progression-free survival at 6 and 12 months, time to progression, duration of 
response and overall survival as secondary efficacy endpoints.  Efficacy will be determined by imaging 
at baseline and every 2 cycles during chemotherapy and every 3 cycles thereafter (or earlier as clinically 
indicated per PI discretion) until disease progression or treatment discontinuation.  Response will be 
determined by RECIST 1.1 andiRECIST.  To determine safety, we will report the frequency and 
intensity of adverse events by Common Terminology for Adverse Events (CTCAE v.4 criteria).   
4.2.3.1 
Efficacy and Safety Endpoints 
1. Overall response rate (Proportion of patients who achieve a complete or partial response per 
RECIST 1.1 criteria). 
2. Overall response rate by iRECIST[28].    
3. Progression-free survival at 6 months (Proportion of patients who have not progressed at 6 months 
with progression-free survival calculated from the start of treatment to the date of progression or death 
from any cause).   
4. Progression-free survival at 12 months (Proportion of patients who have not progressed at 12 months 
with progression-free survival calculated from the start of treatment to the date of progression or death 
from any cause). 
5. Time to progression (calculated in months from the start of treatment to disease progression as 
defined by RECIST 1.1). 
6. Duration of response (calculated in months as time from documentation of tumor response to disease 
progression). 
7. Overall survival (calculated in months from the start of treatment to the date of death from any cause). 
8. Frequency and intensity of adverse events (CTCAE v.4) as measured at each visit, during safety 
follow up (30 days after discontinuation of treatment) and during follow up (every nine weeks after 
discontinuation)  


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4.2.3.2 
Biomarker Research 
Subjects will be given the option to participate in optional biomarker research.   
Subjects will be given the option to consent for optional CT-guided biopsy prior to treatment.  Formalin-
fixed, paraffin-embedded slides will be obtained from the primary cytoreductive surgery if available as 
disclosed in the main informed consent form. 
Tissue specimens will be assessed for PD-L1 expression by immunohistochemistry.  Other biomarkers 
may also be tested including, but not limited to PD-1, CD8, CD4, FoxP3 and Ki67.  
Immunohistochemistry expression will be correlated to treatment response in an exploratory manner.  
Subjects will be given the opportunity to consent for optional blood collection.  If the patient provides 
consent, blood will be collected at baseline and every 2 cycles for storage for future correlative studies.  
4.2.3.3 
Quality of Life 
Quality of life (QOL) will be measured by the FACIT-TS-G and FACT-G questionnaires [29].  The FACT-
G questionnaire will be administered at baseline.  The FACT-G and FACIT-TS-G questionnaires will be 
administered between cycle 2 - 3 (reflecting QOL after 2 cycles of chemotherapy), between cycle 4 - 5 
(reflecting QOL after 2 cycles of chemotherapy + pembrolizumab) and at 6 (between cycle 8 and 9), 12 
months (after cycle 17) and 24 months (after cycle 34) during maintenance therapy.   
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Subject Inclusion Criteria 
5.1.1.1 
In order to be eligible for participation in this trial, the subject must: Be willing and 
able to provide written informed consent/ for the trial. 
5.1.1.2 
Be  18 years of age on day of signing informed consent. 
5.1.1.3 
Have diagnosis of recurrent epithelial ovarian, peritoneal or fallopian tube carcinoma that 
has progressed within 6 months of prior cytotoxic platinum-based chemotherapy. Histologic 
confirmation of the primary tumor by review of the pathology report is required.   Patients 
must have had at least one prior platinum-based chemotherapeutic regimen.  Initial 
treatment may have been administered as an intraperitoneal, intravenous or dose-dense 
regimen.  Progression on a non-platinum containing regimen is eligible if the patient is 
considered platinum-resistant to the last platinum-containing regimen.  Patients who have 
received prior cisplatin and gemcitabine treatment are eligible to participate. 
5.1.1.4 
Have measurable disease based on RECIST 1.1 (See Appendix C) 
5.1.1.5 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
5.1.1.6 
Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 28 days of treatment initiation.  
5.1.1.7 
Female subject of childbearing potential should have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  


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Patients who have had prior hysterectomy and/or bilateral oophorectomy are not required to 
have a pregnancy test.  
5.1.1.8 
Female subjects of childbearing potential should be willing to use 2 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 Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year.  
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 mg/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. 
5.1.2 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
5.1.2.1 
Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
 


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5.1.2.2 
Has diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
5.1.2.3 
Has a known history of active TB  (Bacillus Tuberculosis) 
5.1.2.4 
Hypersensitivity to pembrolizumab or any of its excipients.  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. 
5.1.2.5 
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 including (curative or palliative 
surgery), they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy.   
 
➢ Note: Patients who have hypertension as an adverse event related to prior 
angiogenesis targeted therapy may be allowed if ≤ Grade 2 and considered by 
investigator to be well-controlled on anti-hypertensive agents. 
5.1.2.6 
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. 
5.1.2.7 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least four weeks prior to the 
first dose of trial treatment and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior to trial treatment.  This exception does not include carcinomatous meningitis 
which is excluded regardless of clinical stability.   
5.1.2.8 
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.  
5.1.2.9 
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
5.1.2.10 Has an active infection requiring systemic therapy. 
5.1.2.11 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 


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duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
5.1.2.12 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
5.1.2.13 Is pregnant or breastfeeding, or expecting to conceive children within the projected duration 
of the trial, starting with screening visit through 120 days after the last dose of trial 
treatment. 
5.1.2.14 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
5.1.2.15 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or 
positive serum test for HIV as per testing at screening 
5.1.2.16 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected) as per test at screening 
5.1.2.17 Has received a live vaccine within 30 days of planned start of study therapy. 
➢ Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Gemcitabine 
750 mg/m2 
Q 3W x 6 
cycles 
IV infusion 
Day 1 and Day 8 of 
each 3-week cycle 
Standard of 
care 
Cisplatin 
30 mg/m2 
Q 3W x 6 
cycles 
IV infusion 
Day 1 and Day 8 of 
each 3-week cycle 
after gemcitabine 
Standard of 
care 
Pembrolizumab 
200 mg  
Q3W starting 
with cycle 3 
IV infusion 
Day 1 of each 3-
week cycle after 
gemcitabine and 
cisplatin 
Experimental 
 
 
5.2.1 
Dose Selection/Modification 
5.2.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the Pharmacy 
Manual.   


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5.2.1.2 
Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3A below and per Appendix G. 
See Appendix G for dose modification and toxicity management guidelines for immune-related AEs 
associated with Pembrolizumab. 
See Section 5.6.1 and Events of Clinical Interest Guidance Document for supportive care guidelines, 
including use of corticosteroids. 
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 PI. The reason for interruption should be documented 
in the patient's study record.  
A maximum of two dose level modification to chemotherapy is permitted before withdrawing the patient 
from further chemotherapy, although patient may continue on Pembrolizumab monotherapy, should 
they not tolerate the combination treatment. 
Table 3A: Dose hold and discontinuation for pembrolizumab Guidelines for Drug-Related Adverse 
Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Coliti
s 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if 
new onset) or 
Hyperglycemi
a 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically 
and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Hypothyroidis
m 
 
Therapy with pembrolizumab 
can be continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while 
treatment for the thyroid disorder is instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure 
or Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-Related 
Toxicity2 
3 or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening 
event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater 
than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug 
has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
 
Table 3B: Dose modifications for chemotherapy 
 
 
 
Gemcitabine 
 
Cisplatin 
Starting Dose 
 
750 mg/m2 
 
30 mg/m2 
1 level reduction 
600 mg/m2 
 
25 mg/m2 
2 level reduction 
450 mg/m2 
 
20 mg/m2 
 
Treatment decisions will be based upon review of adverse events and laboratory studies drawn prior 
to each cycle.   
 


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Table 3C: Guidelines for chemotherapy dose modifications 
Treatment Parameter 
Treatment Modification 
DAY 1:  ANC < 1500 cells/mm3 and/or 
platelet count < 100,000/µl 
Cycle 1 and 2: Hold cisplatin and gemcitabine 
chemotherapy.  Initiation of cycle 1 or 2 of 
chemotherapy will be delayed a maximum of three 
weeks until these threshold values are achieved.  
Subjects who fail to recover adequate counts within a 
three-week delay will not receive further chemotherapy 
in the study.   
Cycle 3 – 6: Hold cisplatin and gemcitabine 
chemotherapy and administer pembrolizumab only on 
day 1.  Re-assess for chemotherapy administration on 
day 8. 
DAY 8: ANC < 1000 cells/mm3 and/or 
platelet count < 75,000/µl 
Eliminate day 8 treatment for current cycle.  
Febrile neutropenia during prior cycle 
Dose reduce gemcitabine 1 level 
ANC < 500 cells/mm3 during prior cycle 
Dose reduce gemcitabine 1 level 
Platelet count < 50,000/µl during prior 
cycle 
Dose reduce gemcitabine 1 level 
Grade 2 or greater peripheral neuropathy 
(moderate symptoms, limiting 
instrumental activities of daily living) 
Hold cisplatin (administer gemcitabine and/or 
pembrolizumab if scheduled).  Delay subsequent 
cisplatin therapy for a maximum of 3 weeks until 
toxicity resolved to grade 1 (asymptomatic, 
paresthesia).  Dose reduce cisplatin 1 level for 
subsequent cycles.   
Grade 2 or greater renal toxicity (serum 
creatinine greater than 1.8 mg/dL or 1.5X 
baseline) 
Hold cisplatin (administer gemcitabine and/or 
pembrolizumab if scheduled).  Delay subsequent 
cisplatin therapy for a maximum of 3 weeks until 
toxicity resolved to grade 1 (serum creatinine ≤ 1.8 
mg/dL).  Dose reduce cisplatin 1 level for subsequent 
cycles.   
Grade 3 or greater liver toxicity: 
ALT > 225 U/L (5X ULN) 
AST > 175 U/L (5X ULN) 
Alkaline Phosphatase > 625 U/L (5X 
ULN) 
Total Bilirubin > 3.6 mg/dL (3X ULN) 
Dose reduce gemcitabine 1 level.  Delay subsequent 
gemcitabine therapy (but continue to administer 
cisplatin and/or pembrolizumab if scheduled) for a 
maximum of 3 weeks until toxicity resolved to grade 1 
defined below. 
ALT < 135 U/L (3X ULN) 
AST < 105 U/L (3X ULN) 
Alkaline Phosphatase < 312 U/L (2.5X ULN) 
Total Bilirubin < 1.8 mg/dL (1.5X ULN) 


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Grade 3 or greater nausea (inadequate 
oral caloric or fluid intake) 
 
Grade 3 or greater vomiting (≥ 6 
episodes separated by 5 minutes in a 24 
hour period) 
Tube feeding, TPN or hospitalization 
indicated 
Optimize antiemetic therapy.  If persistent grade 3 
toxicity despite optimal antiemetic therapy, dose 
reduce cisplatin 1 level.  
All other grade 3 or 4 toxicity attributable 
to chemotherapy 
Reduce dose, hold dose, or discontinue chemotherapy 
agent per physician discretion.  Continue to administer 
pembrolizumab if scheduled.  May restart 
chemotherapy treatment when toxicity resolved to 
grade 0-1 per physician discretion.  
Cisplatin and/or gemcitabine treatment 
delay for more than 3 weeks 
Discontinue cisplatin and/or gemcitabine 
chemotherapy and continue with single agent 
pembrolizumab 
 
Growth factor support may be administered as per the 2015 American Society of Clinical Oncology 
Clinical Practice Guideline Update [30] or per investigator discretion.   
- 
Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent 
cycles of chemotherapy is recommended in patients who have an approximately 20% or higher 
risk for febrile neutropenia based on patient-, disease-, and treatment-related factors.  In 
addition to chemotherapy regimen and type of malignancy, consider the following factors when 
estimating the patient’s overall risk of febrile neutropenia: age ≥ 65 years, advanced disease, 
previous chemotherapy or radiation therapy, preexisting neutropenia or bone marrow 
involvement with tumor, infection, open wounds or recent surgery, poor nutritional status, poor 
renal function, liver dysfunction (most notably elevated bilirubin), cardiovascular disease, 
multiple comorbid conditions.  
- 
Secondary prophylaxis with a CSF is recommended for patients who experienced a 
neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis 
was not received). 
- 
CSFs should be considered in patients with fever and neutropenia who are at high risk for 
infection-associated complications or who have prognostic factors predictive or poor clinical 
outcomes.  High-risk features include expected prolonged (> 10 days) and profound (ANC < 
100 cells/mm3) neutropenia, age > 65 years, uncontrolled primary disease, pneumonia, 
hypotension and multiorgan dysfunction (sepsis syndrome), invasive fungal infection or 
hospitalization at the time of fever development.  
- 
Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they 
become available) can be used for the prevention of treatment-related febrile neutropenia.  The 
choice of agent depends on convenience, cost, and clinical situation.   
   
For more detailed guidance on managing toxicity, see the Merck Events of Clinical Interest Guidance 
Document regarding Pembrolizumab.  


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5.2.2 
Treatment after 1st Radiologic Evidence of Disease Progression 
If a patient demonstrates progression of disease on CT prior to cycle 3 of treatment (after receiving 2 
cycles of cisplatin and gemcitabine), the patient will be considered refractory to chemotherapy.  
Cisplatin and gemcitabine will not be administered for further cycles and the patient may continue on 
the trial and receive single agent pembrolizumab.   
Immunotherapeutic agents such as pembrolizumab may produce anti-tumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an approach 
can manifest as a clinical response after an initial increase in tumor burden or even the appearance of 
new lesions.  
After the site has assessed the first radiographic evidence of progressive disease (PD) by RECIST 1.1 
after the addition of pembrolizumab to trial therapy (cycle 3 and beyond), tumor assessment may be 
repeated ≥ 4 weeks later to confirm PD by iRECIST with the option for continuing treatment while 
awaiting radiologic confirmation of disease progression.  
Subjects may continue to receive study treatment while awaiting confirmation of PD if they are clinically 
stable as defined by the following criteria: 
- 
Absence of signs and symptoms (including worsening of lab values) indicating disease 
progression 
- 
No decline in ECOG performance status 
- 
Absence of rapid progression of disease 
- 
Absence of progressive tumor at critical anatomic sites (e.g., cord compression) requiring 
urgent alternative medical intervention 
If repeat imaging shows SD, PR, or CR by iRECIST, the subject may continue on study treatment and 
undergo regularly scheduled imaging assessments.   
Note: If a subject with confirmed radiographic progression (i.e. 2 tumor images at least 28 days apart 
demonstrating progressive disease) is clinically stable or clinically improved, and there is no further 
increase in the tumor dimensions at the confirmatory tumor image, an exception may be considered to 
continue treatment upon consultation with the PI.  
 
5.2.3 
Timing 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 (Section 6.0).   
The administration of day 1 treatment may be adjusted +/- 3 days to accommodate schedule changes. 
The administration of day 8 treatment may be adjusted +/- 1 day to accommodate schedule changes. 
All trial treatments will be administered on an outpatient basis. 
Gemcitabine 750 mg/m2 and cisplatin 30 mg/m2 will be given on day 1 and day 8 of a 21-day treatment 
cycle for a total of 6 cycles.  To decrease the risk of hematologic toxicity, gemcitabine will be given prior 
to cisplatin.  Antiemetic agents may include, but are not limited to ondansetron, granisetron, Ativan, 


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metoclopramide, prochlorperazine, fosaprepitant, aloxi, sancuso and akynzeo.  Dexamethasone will 
not be administered as a premedication in the initial treatment cycle, but may be added at a dose of 10 
or 20 mg IV as a premedication if the patient experiences nausea on the regimen.  Patients will receive 
hydration with at least 1 liter of fluid prior to chemotherapy.  Hydration will then continue as clinically 
indicated.  A window of -10 minutes and +10 minutes is permitted for chemotherapy administration.  
Gemcitabine 750 mg/m2 will be administered IV over 30 minutes (+/- 10 minutes).  Cisplatin 30 mg/m2 
will be administered IV over 60 minutes (+/- 10 minutes).   
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks on day 1 after 
gemcitabine and cisplatin starting with treatment cycle 3.  After completion of cycle 6, pembrolizumab 
will be administered as a single-agent for maintenance therapy every 21 days for up to two years or 
the subject meets withdrawal criteria.   
Every effort should be made to target pembrolizumab infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min.  The Pharmacy Manual 
contains specific instructions for the preparation of the pembrolizumab infusion fluid and administration 
of infusion solution. 
5.2.4 
Trial Blinding/Masking 
This is an open-label trial; therefore, Merck, investigator, and subject will know the treatment 
administered. 
5.3 
Randomization or Treatment Allocation 
This is a single-arm study.  No randomization will occur. 
5.4 
Stratification 
Patients will be stratified based on number of prior chemotherapeutic regimens (1 versus more than 1; 
prior cis/gem versus no prior cis/gem).  
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required.  
The investigator should discuss any questions regarding this with the Merck Clinical team.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  
5.5.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date may also be included on the 
CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded.  Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined in 
Section 7.2. 


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5.5.2 
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 not specified in this protocol  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Radiation therapy  
o 
Note:  Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion.   
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  An exception can be made to allow for the 
use of decadon 10 or 20 mg IV as an antiemetic premedication prior to chemotherapy (section 
5.2.3).  Otherwise, the use of physiologic doses of corticosteroids may be approved after 
consultation with Merck. 
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. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 
Supportive Care Guidelines for pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the ECI guidance document. 
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 ECI reporting guidance but does not need to follow the treatment guidance (as outlined in 
the ECI guidance document). Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, can 
be found in the ECI guidance document. 


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5.6.2 
Suggested supportive care measures: 
5.6.2.1 
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. 
▪ 
Pembrolizumab can be restarted when toxicity resolved to grade 0 or 1. 
Pembrolizumab should be discontinued if toxicity does not resolve within 12 
weeks of last dose or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
▪ 
Permanently discontinue pembrolizumab. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
 
5.6.2.2 
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).   
 
o 
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o 
Restart pembrolizumab when grade 2 or 3 toxicity resolved to grade 0 or 1. 
o 
For grade 2 or 3 diarrhea/colitis that does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks, pembrolizumab should be discontinued.   
o 
For grade 4 diarrhea/colitis, pembrolizumab should be permanently discontinued.  
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
5.6.2.3 
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.  
▪ 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of beta cell failure. 
▪ 
Resume pembrolizumab when patients are clinically and metabolically stable.  
 


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5.6.2.4 
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. 
▪ 
Restart pembrolizumab when toxicity resolved to Grade 0 or 1.  
▪ 
If toxicity does not resolve within 12 weeks of last dose or there is inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per day 
within 12 weeks, then discontinue pembrolizumab.  
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. 
▪ 
For grade 3 toxicity, restart pembrolizumab when toxicity resolved to Grade 0 
or 1.  
▪ 
If grade 3 toxicity does not resolve within 12 weeks of last dose or there is 
inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks, then discontinue pembrolizumab.  
▪ 
For grade 4 toxicity, permanently discontinue pembrolizumab 
 
 
5.6.2.5 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o 
Grade 2 hyperthyroidism events (and Grade 3-4 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. 
▪ 
Therapy with pembrolizumab can be continued while treatment for the thyroid 
disorder is instituted. 
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. 
▪ 
For grade 3 hyperthyroidism, restart pembrolizumab when toxicity resolves to 
grade 0 or 1.  If toxicity does not resolve within 12 weeks of last dose or there 
is inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks, discontinue pembrolizumab. 
▪ 
For grade 4 hyperthyroidism, permanently discontinue pembrolizumab 
 
 
5.6.2.6 
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 
▪ 
Restart pembrolizumab when grade 2 toxicity resolves to grade 0 or 1. 
▪ 
Discontinue pembrolizumab if grade 2 toxicity does not resolve within 13 
weeks of last dose.  


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▪ 
For patients with liver metastasis who begin treatment with Grade 2 AST or 
ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week and then patients should be 
discontinued.  
o 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
▪ 
For grade 3-4 toxicity, permanently discontinue pembrolizumab. 
o 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
5.6.2.7 
Renal Failure or Nephritis: 
o 
For Grade 2 events, treat with corticosteroids. 
▪ 
Restart pembrolizumab when toxicity resolves to grade 0 or 1.  
▪ 
If toxicity does not resolve within 12 weeks of last dose or there is inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per day 
within 12 weeks, discontinue pembrolizumab. 
o 
For Grade 3-4 events, treat with systemic corticosteroids. 
▪ 
For grade 3 and 4 events, permanently discontinue pembrolizumab.  
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:  
o 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
o 
For grade 3 or 4 infusion reaction, permanently discontinue pembrolizumab. 
 
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 
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 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
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. 
 
 
 
• 
All other drug-related toxicity 
o 
Patients with intolerable or persistent grade 2 drug-related adverse event, 
pembrolizumab may be held at the physician’s discretion.  Permanently discontinue 
pembrolizumab for persistent grade 2 adverse reactions which do not recover to grade 
0 or 1 within 12 weeks of the last dose. 


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o 
For grade 3 or severe toxicity, hold pembrolizumab and restart when toxicity resolves 
to grade 0 or 1.  If toxicity does not resolve within 12 weeks of last dose or there is 
inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per day 
within 12 weeks, discontinue pembrolizumab. 
o 
For grade 4 toxicity, permanently discontinue pembrolizumab.  
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.7.2 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  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.  
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 7.2.2-Reporting of Pregnancy and Lactation to the PI 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. 
5.7.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the IRB and to Merck within 10 days of the PI becoming aware of the 
outcome.   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 PI upon learning of 
the event, will report within 2 working days to Merck.  
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 IRB. 


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5.7.4 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion 
of the investigator should any untoward effect occur.  In addition, a subject may be withdrawn by the 
investigator if enrollment into the trial is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding discontinuation or withdrawal are provided in 
Section 7.1.4 – 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 5.2.2 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 5.2.2 
• 
Unacceptable adverse experiences as described in Section 5.2.1.2 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Completed trial treatment with maintenance pembrolizumab. 
• 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and 
Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment as described in Section 7.1.5.3.1).   
Subjects who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.   
After documented disease progression each subject will be followed by telephone or at their SOC clinic 
visits for overall survival until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 


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5.8.1 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that 
have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with 
pembrolizumab beyond the date when the initial CR was declared.  Subjects who then experience 
radiographic disease progression may be eligible for up to one year of additional treatment with 
pembrolizumab via the Second Course Phase at the discretion of the investigator if no cancer treatment 
was administered since the last dose of pembrolizumab, the subject meets the safety parameters listed 
in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the same dose 
and schedule at the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.9 
Subject Replacement Strategy 
If a subject meets withdrawal criteria before receiving any pembrolizumab treatment (before cycle 3) or 
voluntarily desires to withdraw from the intervention portion of the trial, the subject may be replaced 
with another one.  The subject withdrawing from the study will be asked whether they will provide 
consent to continue with the subsequent data collection components of the trial.    
 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
5.10.1 Quality or quantity of data recording is inaccurate or incomplete 
5.10.2 Poor adherence to protocol and regulatory requirements 
5.10.3 Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
5.10.4 Plans to modify or discontinue the development of the study drug 
In the event of Merck’s 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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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
 
 
 
 
 
 
Discontinuation and Follow-Up 3 
Activity 
Screenin
g1 
C1, C3, 
C5 2 
C2, C4, 
C6 2 
C7-34 
2 
Discon-
tinuation  
Safety 
Visit 11 
Follow-
up (q9w) 
12, 13 
Survival 
(q9-12w) 
14 
Informed consent 
X  
 
 
 
 
 
 
 
Inclusion, Exclusion 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Medication Review 4 
X 
X 
X 
X 
X 
 
 
 
Adverse Event Review 4 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam 4, 5 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 4 
X 
X 
X 
X 
X 
 
 
 
CBC, CMPL, Magnesium 6 
X 
Day 1, 
Day 8 
Day 1, 
Day 8 
X 
X 
 
 
 
LDH, uric acid, phosphorus, 
direct bilirubin, urinalysis 16 
X 
X 
X 
X 
X 
 
 
 
PT, PTT, INR, TSH, T4 free, T3 
total, research blood 16 
X 
 
X 
Even 
cycles 
X 
 
 
 
CA125 16 
X 
X 
X 
X 
X 
 
X 
 
Urine or Serum HCG, HIV, 
HBsAg, HCV 15 
X 
 
 
 
 
 
 
 
Imaging of chest, abdomen, 
pelvis 7 
X 
 
10-21 
days after 
C2, C4, 
C6 7 
10-21 
days 
after 
every 
third 
cycle 
starting 
with 
C9  7 
 
 
Q9 weeks 
(every 63 
days +/- 
14 days) 7 
 
CT-guided tumor biopsy 8 
X 
 
 
 
 
 
 
 
QOL questionnaires 9 
X 
Before C3, 
C5 
 
After 
C8, 
C17, 
C34 
 
 
 
 
Gemcitabine and Cisplatin 
 
Day 1, 
Day 8  
Day 1, 
Day 8  
 
 
 
 
 
Pembrolizumab 10 
 
C3, C5 
C4, C6 
C7-34 
 
 
 
 
Post-study therapy 
 
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
X 
X 
X 
 
1 Screening within 28 days of cycle 1 day 1 treatment 
2 For cycle 1 – 6, day 1 treatment may be adjusted +/- 3 days and day 8 treatment may be adjusted +/- 
1 day for administrative reasons.  For cycle 7 – 17, day 1 treatment may be adjusted +/- 3 days for 
administrative reasons (Section 7.1.1.9).  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 for he scheduled interruption, unless otherwise discussed with the PI.  The 
reason for interruption should be documented in the patient’s study record (Section 5.2.1.2).  
3 Discontinuation and follow-up visits are required only if patient received pembrolizumab  


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4 To be performed up to 7 days prior to day 1 of treatment cycles.  Procedures do not need to be 
repeated if day 1 treatment is delayed or held.   
5 Full physical examination at screening, directed physical exam at subsequent time points.  Exam 
includes weight and vital signs 
6 Laboratory studies may be performed up to 72 hours prior to treatment (Section 7.1.2). Labs on day 
8 are required to be drawn only if patient is scheduled to receive cisplatin and gemcitabine treatment.   
7 Imaging of chest, abdomen and pelvis will be done at screening and after each even cycle of treatment 
with a window of 10-21 days after day 1 of cycle 2, cycle 4 and cycle 6.  Imaging of chest, abdomen 
and pelvis will be done approximately every 9 weeks during the maintenance and follow up phases with 
a window of 10-21 days after day 1 of every third cycle starting with C9 (C9, C12, C15, etc.).   Imaging 
may be performed earlier than defined above if clinically indicated per PI discretion.  
8 Optional tissue collection will be performed during the screening phase.  Collection of archival tissue 
is not required during the screening phase.   
9 FACT-G during screening phase.  FACT-G and FACIT-TS-G at other study time points (between 
cycles 2 – 3, between cycles 4 – 5, between cycles 8 – 9, after cycle 17, after cycle 34).  
10 Pembrolizumab will be administered starting with cycle 3 of therapy.  
11 After end of treatment, subjects will be followed for 30 days for adverse event monitoring.  Serious 
adverse events will be collected for 90 days after the end of treatment (Section 5.8).  Subjects with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first (Section 7.1.5.3.1).  If a subject initiates new anti-
cancer therapy within 30 days after the last dose of trial treatment, the 30-day safely 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 (Section 7.1.1.5.3).   
12 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 2 treatments with 
pembrolizumab beyond the date when initial CR was declared.  Subjects who then experience 
radiographic progression are eligible for up to one year of additional treatment with pembrolizumab via 
the Second Course Phase at the discretion of the investigator if no cancer treatment was administered 
since the last dose of pembrolizumab, the subject meets the safety parameters listed in the 
Inclusion/Exclusion criteria and the trial is open (Section 5.8.1, Section 7.1.5.5).   Laboratory tests for 
screening or entry into the Second Course Phase should be performed within 10 days prior to the first 
dose of treatment. 
13 After study discontinuation for reasons other than progressive disease, subjects will be followed every 
9 weeks for disease status until progression, initiation of non-study cancer treatment, withdrawal of 
consent or becoming lost to follow-up (section 5.8, Section 7.1.5.4).  
14 After study discontinuation for progression, subjects will be followed by telephone or at clinic visits 
every 9 – 12 weeks for overall survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first (Section 5.8, Section 7.1.5.4.1).  
15 Patients who have had prior hysterectomy and/or bilateral oophorectomy are not required to have a 
pregnancy test (Urine or Serum HCG). 
16 Laboratory studies may be performed up to 72 hours prior to treatment (Section 7.1.2).   Labs do not 
need to be repeated if day 1 treatment is delayed or held unless clinically indicated per PI.   
 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 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. 
7.1.1 
Administrative Procedures 
7.1.1.1 
Informed Consent 
Subjects will be asked to sign and date the Informed Consent and HIPAA Authorization form after 
receiving a complete explanation of the research study including risks, benefits, and alternatives to 
participation. Eligible subjects must have the ability to understand and the willingness to sign a written 
informed consent document.  
7.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the subject qualifies for the trial.  
7.1.1.3 
Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will include 
all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator.  Details regarding the disease for which the subject has enrolled 
in this study will be recorded separately and not listed as medical history.   
7.1.1.4 
Prior and Concomitant Medications Review 
7.1.1.4.1 
Prior Medications 
The investigator or qualified designee will review prior medication use 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.  
7.1.1.4.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the 
trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 
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7.1.1.5 
Disease Details and Treatments 
7.1.1.5.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
7.1.1.5.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the last dose 
of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.  
7.1.1.6 
Assignment of Subject Number 
7.1.1.7 
Subjects will be assigned a sequential screening number S001, S002, etc.  This 
screening ID number will no longer be used after screening is complete.  
7.1.1.8 
Once a screening subject has been determined to meet eligibility criteria and has 
signed the appropriate consents, the subject will be assigned a 3-digit numeric 
subject ID that follows the standard SOCCI format (001, 002, 003, etc.). 
7.1.1.9 
Trial Compliance (Medication/Diet/Activity/Other) 
Trial medications will be administered in a chemotherapy infusion area.  Day 1 treatments will be 
scheduled every 21 days +/- 3 days. Day 8 treatments will be schedule with an accommodation of +/- 
1 day for schedule changes. 
7.1.2 
Clinical Procedures/Assessments 
During the screening phase, subjects will sign consent and undergo evaluations for inclusion and 
exclusion criteria, demographics, medical history, medication review, adverse event review, physical 
examination, vital signs and weight, ECOG performance status, laboratory evaluations (CBC with 
differential, comprehensive metabolic panel, LDH, uric acid, phosphorus, magnesium, direct bilirubin, 
urinalysis, coagulation studies, thyroid studies, CA125, urine or serum pregnancy test (if indicated), 
optional blood for correlative studies), CT scan of the chest, abdomen and pelvis and optional CT-
guided biopsy of tumor if possible.  Pathology reports from the original surgery will be reviewed to 
confirm diagnosis of epithelial ovarian, peritoneal or fallopian tube cancer.   
During the treatment phase, subjects will be monitored with history and physical examination, vital 
signs, weight, assessment of adverse events and mediation review prior to each treatment cycle.  
These assessments may occur during a clinic visit in between cycles that is distinct from a treatment 
day.  Laboratory studies can be performed up to 72 hours prior to treatment.  Assessment of thyroid 
function and blood collection for correlative studies will be performed prior to every even cycle (cycles 
2, 4, 6).  CT scan of the chest, abdomen and pelvis will be performed after every second cycle during 
chemotherapy (window of 10-21 days after day 1 of cycles 2, 4, 6) and every 9 weeks thereafter or as 
clinically indicated (window of 10-21 days after day 1 of cycles 9, 12, 15, etc.).  Similar assessments 


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will occur prior to each cycle of treatment when the subject enters the maintenance phase.  Clinically 
significant labs will be repeated within 3 days.   
7.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized 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); see the 
separate ECI guidance document regarding the identification, evaluation and management of potential 
irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full physical 
exam should be performed during screening.  
7.1.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration either on the date of treatment or during a clinic visit preceding the date of treatment.   
7.1.2.4 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
7.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.   
7.1.2.6 
Tumor Imaging and Assessment of Disease 
A baseline CT scan of the chest, abdomen and pelvis will be performed within 28 days of initiating 
treatment and RECIST 1.1 criteria (See Appendix C) will be used to verify eligibility with measurable 
disease.  Patients with allergy to IV contrast will undergo imaging with MRI of the abdomen and pelvis 
with gadolinium and CT scan of the chest without contrast.  Imaging will be performed after every even 
cycle (10-21 days after day 1 of cycles 2, 4, 6) during chemotherapy and every 3 cycles (10-21 days 
after day 1 of cycles 9, 12, 15, etc.) thereafter, or earlier if clinically indicated to assess for response.   


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7.1.2.7 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
If subject provides optional consent for biopsy, CT-guided biopsy of recurrent tumor will be obtained 
prior to initiating treatment.  Attempts will be made to obtain archival formalin-fixed, paraffin-embedded 
specimens from the original cytoreductive surgery.  Collection of archival tissue is not required during 
the screening phase. Qualtek will provide tissue shipping instructions. 
If subject provides optional consent for blood collection, blood will be collected at baseline and 
thereafter prior to every even cycle of treatment and will be stored for future correlative studies.  
7.1.3 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
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 thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies (optional) 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† 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 or entry into the Second Course Phase should be performed within 10 
days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory procedures can be 
conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to each dose of trial treatment. If review is found to be 
acceptable, the investigator or qualified designee will enter an order to release treatment (no other 
specific documentation will be required).  
7.1.3.1 
Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.1.1 
Blood Collection for Serum Pembrolizumab 
7.1.3.1.2 
Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection and storage instructions for blood samples will be provided in a separate document 
and will follow institutional guidelines. 
7.1.4 
Other Procedures 
7.1.4.1 Quality of Life Questionnaires 
 
FACT-G and FACIT-TS-G are patient self-administered questionnaires.  FACT-G will be collected at 
Screening.  FACT-G and FACIT-TS-G will be collected between Cycle 2 - 3, between Cycle 4- 5, and 
if applicable between cycle 8 - 9 (approximately and 6 months since Cycle 1 Day 1) after cycle 17 
(approximately 12 months after Cycle 1 Day 1) and after cycle 34 (approximately 24 months after 
Cycle 1 Day 1).  
7.1.4.2 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation.  Any adverse events which are 
present at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.  Subjects who a) 
attain a CR or b) complete 12 months of treatment with pembrolizumab may discontinue treatment with 
the option of restarting treatment if they meet the criteria specified in Section 7.1.5.5.  After 
discontinuing treatment following assessment of CR, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.4.3 
Blinding/Unblinding 
Not applicable. 
7.1.5 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 
Screening 
7.1.5.1.1 
Screening Period 
Screening procedures are indicated in the trial flow chart (6.0) and should occur within 28 days of 
initiating treatment. 


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7.1.5.2 
Treatment Period 
Subjects will receive six cycles of chemotherapy (or less than 6 if indicated to be held or discontinued 
per protocol).  Pembrolizumab will be added during cycle 3 and will be administered as maintenance 
therapy every 21 days after the completion of chemotherapy.  Maintenance therapy will continue for up 
to an additional 28 cycles until disease progression or the subject meets withdrawal criteria. 
7.1.5.3 
Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose 
of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 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.  Subjects who are 
eligible for retreatment with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety 
follow-up visits, one after the Treatment Period and one after the Second Course Phase. 
The safety follow-up visit is only required if subjects received the study agent, pembrolizumab. 
7.1.5.4 
Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 9 weeks (63 ± 14 days) or as clinically indicated by 
radiologic imaging to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end 
of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 7.1.5.5.  
Information regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria in Section 
7.1.5.5 will move from the follow-up phase to the Second Course Phase when they experience disease 
progression.  Details are provided in Section 6.2 – Trial Flow Chart for Retreatment.    
Follow-up visits are only required if subjects received the study agent, pembrolizumab. 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be assessed (in clinic or contacted by 
telephone) every 9-12 weeks to assess for survival status until death, withdrawal of consent, or the end 
of the study, whichever occurs first.  
7.1.5.5 
Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD, PR or CR may be eligible for up to one year of additional 
pembrolizumab therapy if they progress after stopping study treatment.  This retreatment is termed the 
Second Course Phase of this study and is only available if the study remains open and the subject 
meets the following conditions: 
• 
Either  
o 
Stopped initial treatment with pembrolizumab after attaining an investigator-determined 
confirmed CR according to RECIST 1.1, and 


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▪ 
Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy 
▪ 
Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared 
 
 
OR 
o 
Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study therapy 
for reasons other than disease progression or intolerability 
AND 
• 
Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function as detailed in Section 5.1.2 
• 
Female subject of childbearing potential should have a negative serum or urine pregnancy test 
within 72 hours prior to receiving retreatment with study medication.   
• 
Female subject of childbearing potential should be willing to use 2 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 Section 5.7.2).  Subjects of child 
bearing potential are those who have not been surgically sterilized or have been free from 
menses for > 1 year.  
• 
Does not have a history or current evidence of any condition, therapy, or laboratory abnormality 
that might 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. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when they last 
received pembrolizumab.  Treatment will be administered for up to one additional year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
7.2 
Assessing and Recording Adverse Events 
7.2.1 
Definition of 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 Merck’s product, is also an adverse event. 


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Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events.  Examples of this may include, 
but are not limited to, teething, typical crying in infants and children and onset of menses or menopause 
occurring at a physiologically appropriate time. 
Merck’s product includes any pharmaceutical product, biological product, device, diagnostic agent or 
protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human 
use. 
Adverse events may occur during the course of the use of Merck’s 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. 
Progression of the cancer under study is not considered an adverse event unless it is considered to be 
drug related by the investigator. 
All adverse events with the exception of grade 1 or 2 laboratory abnormalities 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 7.2.3.1. 
7.2.2 
Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly 
affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 
7.2.3 
Definition of an Overdose for This Protocol and Reporting of Overdose to the IRB 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 


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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.” 
As per institutional policies, an overdose is considered an SAE and must be reported (See section 
7.2.5) 
All reports of overdose with and without an adverse event must be reported within 2 working days to 
Merck Global Safety. See section on SAE reporting for further information regarding institutional policy 
for reporting SAEs. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
7.2.4 
Reporting of Pregnancy and Lactation to the IRB 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), 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 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 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
7.2.5 
Immediate Reporting of Adverse Events to the IRB and to Merck 
7.2.5.1.1 
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; 
• 
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. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
that occurs to any subject from the time the consent is signed through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck’s product, must be reported within 2 working days to Merck Global Safety upon the PI becoming 
aware of the event.  


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Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the 
same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to 
be related to Merck’s product that is brought to the attention of the investigator at any time outside of 
the time period specified in the previous paragraph also must be reported immediately to the IRB and 
to Merck. 
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. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
7.2.5.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 
2 working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220).  Events 
of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the IRB, that is not associated with clinical symptoms or 
abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and 
an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  The trial site guidance for assessment and follow up of these 
criteria can be found in the Investigator Trial File Binder (or equivalent).3. 
Additional adverse 
events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest Guidance 
Document” (previously entitled, “Event of Clinical Interest and Immune-Related Adverse Event 
Guidance Document”).  This document provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document from the 
date of first dose through 90 days following cessation of treatment, or 30 days after the initiation of 
a new anticancer therapy, whichever is earlier, need to be reported within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to 
study treatment, consistent with standard SAE reporting guidelines. 


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Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated 
and subjects should be asked for signs and symptoms suggestive of an immune-related event.  
Subjects who develop an ECI thought to be immune-related should have additional testing to rule 
out other etiologic causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes.  If no other cause is found, 
then it is assumed to be immune-related. 
 
7.2.6 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 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. 
Grade 1 and 2 lab abnormalities will not be collected. The study will only collect grade 3 and 4 lab 
abnormalities as adverse events. 
7.3 
Reporting Requirements for Adverse Events 
7.3.1 
Expedited reporting 
The Principal Investigator must be notified by study staff within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the last 
administration of the study drug.  
 
Phone number for expedited reporting: Christine Walsh, Phone number: 310-423-5456 
 
7.3.2 
Reporting to the Institutional Review Board (IRB) 
The CSMC IRB requires that investigators report all adverse events that may represent an 
unanticipated problem involving risks to subjects or others as defined below. All adverse events (those 
involving subjects who were enrolled at CSMC), that have a reasonable possibility of relationship to the 
study AND meet the following criteria must be reported to the IRB: 
 • Unanticipated (regardless of severity); OR  
• Anticipated and serious  
All reportable events should be submitted in Webridge to the Office of Research Compliance and 
Quality Improvement as soon as possible, but no more than 10 days from the investigator’s 
awareness of the event. The report must contain at least:  
• Identification of the PI, study coordinator (if applicable), contact information, study title, and IRB 
number.  
• A detailed summary of the problem, including all relevant details and the PI’s assessment of the 
events leading up to the problem, to assist the IRB in its evaluation.  
• A description of any action taken to address or remedy the problem, including a description of the 
resolution, if any, or current status.  


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• An assessment as to whether any changes are required in the conduct of the research to resolve the 
problem or prevent further problems. 


Product:  MK-3475 
48 
Protocol/Amendment No.:   
 
 
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Table 6 Evaluating Adverse Events 
An investigator, who is a qualified physician, 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 Sponsor 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 2 business days to Merck. 
 
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 Sponsor product to be discontinued? 
Relationship 
to test drug  
Did the Sponsor product cause the adverse event? The determination of the likelihood that the Sponsor product caused the 
adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the 


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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 Sponsor product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the 
Sponsor product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Sponsor 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 Sponsor 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 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Sponsor 
product 
(continued)  
Dechallenge 
Was the Sponsor 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 Sponsor product; or (3) the trial is a single-dose drug trial); or (4) 
Sponsor product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Sponsor 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) Sponsor 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 SPONSOR PRODUCT, OR IF REEXPOSURE TO THE SPONSOR 
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE 


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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 Sponsor 
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 
Sponsor product relationship). 
Yes, there is a reasonable 
possibility of Sponsor 
product relationship. 
There is evidence of exposure to the Sponsor product.  The temporal sequence of the AE onset relative to the 
administration of the Sponsor product is reasonable.  The AE is more likely explained by the Sponsor product 
than by another cause. 
No, there is not a 
reasonable possibility of 
Sponsor product 
relationship 
Subject did not receive the Sponsor product OR temporal sequence of the AE onset relative to administration of 
the Sponsor 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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7.3.3 
Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and to Merck in accordance with 
all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Trial Design 
The design for this one-arm phase II trial follows the classical two-stage design proposed by 
Simon (1989) [31].  
The primary efficacy endpoint is overall response rate (ORR) defined as the proportion of 
patients who achieve a complete or partial response per RECIST 1.1 criteria [32, 33].  
- 
Complete response (CR): disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
- 
Partial response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
- 
Stable disease (SD): Neither insufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD (see below), taking as reference the smallest sum diameters 
while on study.  
- 
Progressive disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  The appearance of one 
or more new lesions is also considered progression.   
 
Response will be assessed at each time point and the best overall response rate will be 
determined accounting for response at subsequent time points through the first 6 cycles of 
therapy [33].   
A proportion of patients with a favorable response of less than 11.1% will be of no interest.  The 
new treatment would be of interest if the proportion of patients with response is at least 30.0%.  
Twenty-five patients would be needed to test the null hypothesis: p ≤ 0.111 against the alternative 
hypothesis: p ≥ 0.300 at the 5.0% level of significance and with 80% power.  If the trial progresses 
until 25 patients are evaluated and 6 or more patients with favorable response are observed then 
the null hypothesis is rejected. 
8.2 
Early Stopping for Futility 
The early stopping point is 18 patients.  If 2 or fewer patients with favorable response are 
observed when 18 patients are accrued, then the null hypothesis is accepted and the trial is 
terminated.  The probability of early stopping under the null is 0.68 and under the alternative is 
0.06.  


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8.3 
Design Operating Characteristics 
Hypothesis: H0: p = 0.110669 and H1: p = 0.3 
Total sample size = 25 and interim analysis at N=18 
 
P (accept H0 early| H0) =  0.6793 
P (accept H0 early| H1) =  0.0600 
P (reject H0 early| H0) =  0.0000 
P (reject H0 early| H1) =  0.0000 
P (accept H0 at end| H0) =  0.2708 
P (accept H0 at end| H1) =  0.1397 
P (reject H0 at end| H0) =  0.0499 
P (reject H0 at end| H1) =  0.8004 
P (early stop| H0) =  0.6793 
P (early stop| H1) =  0.0600 
 
Overall type I error: 0.0499 
Overall power: 0.8004 
 
Average Sample Number (under H0): 20.2451 
Average Sample Number (under H1): 24.5803 
 
8.4 
Early Stopping for Safety 
An undesirable event is defined as a grade 3 or 4 pembrolizumab attributable toxicity that 
results in permanent discontinuation of the drug (see table 3 and section 5.6.1).   Let Pt be the 
true probability of an undesirable event. The trial will stop if there is statistical evidence that Pt 
exceeds 0.4. We will use a Bayesian sequential design by checking whether Pt exceeds this 
threshold value after each patient is evaluable for this event. The decision rule is to stop the 
trial if the posterior probability that Pt exceeds the threshold is 0.95; for example, P (Pt > 0.4 | 
data) > 0.95. A noninformative prior distribution for Pt will be used. Tables 7A and 7B give the 
stopping rules for the design at each look and column 2 gives the maximum number of patients 
with undesirable events in order for the trial to proceed. For example, in Table 7A, if 13 or more 
undesirable events are observed after enrolling 18 patients, the trial stops. The third column 
gives the probability of stopping the trial when in fact, the true Pt = 0.40. This is the equivalent 
of the Bayesian type I error probability. The target type I error probability was set at 0.05. 
Table 7B gives the design operating characteristics under selected values of the true probability 
Pt. It gives the probability of stopping the trial under the alternative hypothesis, the expected 
sample size, and the average sample size given that the trial stopped. For example, if the true 
value of Pt is 0.7, then there is an 81% chance that the trial is stopped early and the average 
sample size is about 11.  


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Table 7A. Rate of toxicities: Testing rate Pt > 0.4. 
Number of  
Patients 
Number to 
Continue 
Probability to  
Stop 
Cumulative Probability 
to Stop 
1 
1 
0 
0 
2 
2 
0 
0 
3 
3 
0 
0 
4 
3 
0.0256 
0.0256 
5 
4 
0 
0.0256 
6 
5 
0 
0.0256 
7 
5 
0.00983 
0.03543 
8 
6 
0 
0.03543 
9 
7 
0 
0.03543 
10 
7 
0.00425 
0.03968 
11 
8 
0 
0.03968 
12 
9 
0 
0.03968 
13 
9 
0.00199 
0.04167 
14 
10 
0 
0.04167 
15 
10 
0.00247 
0.04414 
16 
11 
0 
0.04414 
17 
11 
0.0026 
0.04674 
18 
12 
0 
0.04674 
19 
12 
0.00257 
0.04932 
20 
13 
0 
0.04932 
21 
14 
0 
0.04932 
22 
14 
0.00099 
0.0503 
23 
15 
0 
0.0503 


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24 
15 
0.00117 
0.05147 
25 
16 
0 
0.05147 
 
Table 7B. 
True Value 
of Pt 
Probability to  
Stop 
Expected 
N 
Expected 
N given that we Stopped 
0.1 
0.0001 
25 
4.11 
0.2 
0.0018 
24.96 
4.51 
0.3 
0.0115 
24.78 
5.69 
0.4 
0.0515 
24.13 
8.15 
0.5 
0.1843 
22.34 
10.59 
0.6 
0.4726 
18.65 
11.57 
0.7 
0.8092 
13.46 
10.74 
 
8.5 
Statistical Analyses 
Distributions of time-to-event data will be estimated with the nonparametric Kaplan-Meier estimator. 
Median progression-free survival at 6 and 12 months, time to progression, duration of response, and 
overall survival will be estimated from these distributions. 
Although a phase II trial is unlikely to definitively establish whether a marker can be used to predict 
clinical benefit, we may identify an association that can then be further explored in definitive phase III 
trials [34, 35].  Therefore, the following analyses are of exploratory nature. Depending on the distribution 
of the expression levels of the selected biomarkers (PD-1, PD-L1, CD8, CD4, FoxP3 and Ki67), 
Pearson’s and Spearman’s rank correlation coefficients will be used to assess the pairwise association 
between them. Univariate analysis based on log-rank test will be used to evaluate the association 
between biomarkers measured as categorical variables and time-to-event outcomes. Univariate Cox 
proportional hazards regression models will be used to assess which biomarkers measured as 
continuous variables are predictive of patient time-to-event outcomes. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF COMMERCIAL SUPPLIES 
9.1 
Investigational 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. 


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Commercial Supplies will be provided by Merck as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Commercial supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Commercial Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, Merck, the Investigator and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Commercial 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. 
Commercial supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the commercial 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. 
10.0   STUDY MANAGEMENT 
10.1 Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in the Informed 
Consent Form.  
10.2 Institutional Review Board and Consent 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. 


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In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the patient and the investigator is assured that the 
patient understands the implications of participating in the study, the patient will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
 
10.3 Registration Procedures 
All subjects that sign informed consent will be assigned a subject number sequentially by their date of 
consent.  Those subjects that do not pass the screening phase will be listed as screen failures on the 
master list of consented subjects.  Eligible subjects, as determined by screening procedures and 
verified by a treating investigator, will be registered on study at Cedars Sinai Medical Center by the 
Study Coordinator.   
Issues that would cause treatment delays after registration should be discussed with the Principal 
Investigator (PI). If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of cancellations 
as soon as possible. 
The study team will track all subjects who sign consent on a subject screening/enrollment log using a 
unique screening ID (S001, S002, etc.).  Subjects found to be ineligible will be recorded as screen 
failures.  Subjects found to be eligible will be registered. Please see section 7.1.1.6 for more information 
on subject ID assignment. 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the SOCCI Clinical Research 
Office (CRO). The following documents will be completed and provided for review: 
 
o 
Registration form (or equivalent) 
o 
Copy of required laboratory tests 
o 
Copy of required imaging reports 
o 
Eligibility checklist (signed by investigator) 
o 
Signed patient consent form and Subject’s Bill of Rights 
o 
HIPAA authorization form 
 
B) 
Registration 
 
After eligibility is verified, registration is completed as follows: 


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o 
Assign a patient study number 
o 
Enter the patient in OnCore 
o 
Notify the investigational pharmacy and treating physicians that a subject has gone on study 
and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire registration process 
 
11.0  DATA AND SAFETY MONITORING 
11.1 Data Monitoring and Quality Assurance 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be monitored by 
the PI during the course of the study through routine Disease Research Group (DRG) meetings or 
equivalent. In addition, the SOCCI CRO Quality Management Core (QMC) will conduct the following:  
 
• 
Audit preparations (AP) prior to audit conducted by any external auditing agency (i.e. NCI or 
FDA). The purpose an AP is to ensure adequate source documentation to support protocol compliance 
and data integrity are present and organized and to identify and correct any major findings prior to the 
external audit 
• 
A thorough review of selected subject cases, regulatory files, and IP accountability records (if 
applicable) within 2-3 months after the first subject is enrolled and annually thereafter while subjects 
are receiving investigational intervention.   
• 
Central eligibility verification for all subjects enrolled as described in protocol section 10.3.   
• 
Central review of all eligibility waiver requests by a SOCCI Medical Reviewer to assess 
appropriateness and risk to ensure quality data and ensure subject safety protections for investigator-
initiated research 
 
For any protocol, QMC has the authority to request more frequent reviews or closer safety monitoring 
if it is deemed appropriate for any reason. 
 
11.2 Safety Monitoring 
Oversight of the progress and safety of the study will be provided by the PI. The PI will maintain 
continuous safety monitoring for the duration of the study by reviewing subject/study data. Adverse 
events and unanticipated problems are not expected, but if they occur they will be documented and 
reported according to CSMC IRB policies and procedures. If the PI becomes aware of any new safety 
information that may place subjects at increased risk than what was previously known the IRB will be 
promptly notified and if warranted, enrollment may be held until the PI determines whether a 
modification to the study is necessary and/or the informed consent documents are updated accordingly. 
 
In addition, this protocol will utilize oversight by a Safety Committee On Early Phase Studies 
(SCOEPS). Committee membership includes experts in the field of oncology and early phase studies 
and biostatistics. SCOEPS’ responsibilities are governed by the committee charter or equivalent.   
 
The SCOEPS will provide routine monitoring of safety and enrollment for all early phase investigator-
initiated trials (IITs). The committee meets routinely and is responsible for reviewing and adjudicating 
all dose-limiting toxicities, dose escalations and appropriateness of the escalation, cohort expansion, 
subject replacements, select AEs, SAEs, and confirmation of attainment of maximum tolerated dose. 
 
The SCOEPS findings and recommendations will be reported in writing to the Principal Investigator. A 
summary report will be forwarded by the Principal Investigator or his/her designee to the Cedars-Sinai 
Medical Center IRB. 


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11.3 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study patient requires alternative treatment, or a protocol exception request approved by the 
SOCCI Medical Director and CSMC IRB, the study shall be conducted exactly as described in the 
approved protocol.  
 
11.3.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval. For any such emergency modification 
implemented, the IRB must be notified as soon as possible, but no more than 10 days from the 
investigator’s awareness of the event.  
 
11.3.2 Protocol Exceptions and Eligibility Waivers 
An exception is a type of planned deviation to the protocol, such as an eligibility waiver to enroll a 
subject who does not meet the approved inclusion/exclusion criteria. Unlike an amendment, a protocol 
exception most often involves a single subject and is not a permanent revision to the research protocol. 
The PI or her/his designee is responsible for submitting a protocol exception to the SOCCI Medical 
Director for review of the request and its supporting documentation to make a determination for further 
action. If the determination is an approval, then the request must be submitted in Webridge to the 
CSMC IRB. If the request is acknowledged by the IRB, then the   protocol exception/eligibility waiver 
may be implemented. 
Logistical deviations from the protocol (e.g., minor changes to the study schedule for an individual 
subject) do not require prior IRB approval unless the deviation has the potential to affect the subject’s 
safety. Such planned deviations that do not affect the subject’s safety should be noted in the subject’s 
research record.  Planned exceptions to the protocol that are more than logistical and/or have the 
potential to affect the subject’s safety or study integrity may not be implemented without prior approval 
from the SOCCI Medical Director and IRB. 
 
11.3.3 Other Protocol Deviations/Violations 
Unintentional deviations from the protocol that might affect subject safety or study integrity should be 
reported to the IRB within 10 days from when the investigator becomes aware that such a deviation 
has occurred. In this case, a Protocol Deviation report must be submitted in Webridge.  All submissions 
should include a description of the plan to avoid similar deviations in the future.   
11.4 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented 
by the Principal Investigator. It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent form might be 
required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation.  
Repeat exceptions or deviations to the protocol may suggest a protocol amendment is needed. 


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11.5 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms and into the HIPAA-compliant study 
database. Periodically, monitoring visits will be conducted and the Principal Investigator will provide 
access to his/her original records to permit verification of proper entry of data. At the completion of the 
study, all case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
11.6 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. Study documents should be kept on file until 
three years after the completion and final study report of this investigational study or as required by 
institutional guidelines. 
 


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12.0 REFERENCES 
 
1. 
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Ohtani H: Focus on TILs: prognostic significance of tumor infiltrating 
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Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW: The prognostic 
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Chen DS, Mellman I: Oncology meets immunology: the cancer-immunity cycle. 
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McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-
Pearson DL, Davidson M: Cyclophosphamide and cisplatin compared with 
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Homet Moreno B, Ribas A: Anti-programmed cell death protein-1/ligand-1 therapy 
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Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, 
Camacho LH, Kauh J, Odunsi K et al: Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med 2012, 366(26):2455-2465. 
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Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Matsumura N, Abiko K, 
Baba T, Yamaguchi K, Ueda A et al: Efficacy and safety of anti-PD-1 antibody 
(Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant 
ovarian cancer. In. J Clin Oncol 32:5s, 2014 (suppl; abstr 5511); 2014. 
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Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, 
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Clin Oncol 2015. 
11. 
Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis 
BJ: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 
1995, 22(4 Suppl 11):72-79. 
12. 
Rose PG, Mossbruger K, Fusco N, Smrekar M, Eaton S, Rodriguez M: Gemcitabine 
reverses cisplatin resistance: demonstration of activity in platinum- and 
multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol 2003, 
88(1):17-21. 
13. 
Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, Minor 
DR, DiSaia PJ: Phase II trial of gemcitabine plus cisplatin repeating doublet 
therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 
2003, 88(1):35-39. 


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14. 
Brewer CA, Blessing JA, Nagourney RA, Morgan M, Hanjani P: Cisplatin plus 
gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a 
phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2006, 
103(2):446-450. 
15. 
Emens LA: Chemoimmunotherapy. Cancer journal 2010, 16(4):295-303. 
16. 
van der Most RG, Robinson BW, Lake RA: Combining immunotherapy with 
chemotherapy to treat cancer. Discovery medicine 2005, 5(27):265-270. 
17. 
Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: moving beyond 
current vaccines. Nat Med 2004, 10(9):909-915. 
18. 
Cho BK, Rao VP, Ge Q, Eisen HN, Chen J: Homeostasis-stimulated proliferation 
drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000, 
192(4):549-556. 
19. 
Goldrath AW, Bogatzki LY, Bevan MJ: Naive T cells transiently acquire a memory-
like phenotype during homeostasis-driven proliferation. J Exp Med 2000, 
192(4):557-564. 
20. 
Drake CG: Combination immunotherapy approaches. Ann Oncol 2012, 23 Suppl 
8:viii41-46. 
21. 
Tseng CW, Hung CF, Alvarez RD, Trimble C, Huh WK, Kim D, Chuang CM, Lin CT, 
Tsai YC, He L et al: Pretreatment with cisplatin enhances E7-specific CD8+ T-
Cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res 
2008, 14(10):3185-3192. 
22. 
Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis 
E, Gabrilovich DI: Chemotherapy enhances tumor cell susceptibility to CTL-
mediated killing during cancer immunotherapy in mice. J Clin Invest 2010, 
120(4):1111-1124. 
23. 
Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM: Gemcitabine selectively 
eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing 
animals and enhances antitumor immune activity. Clin Cancer Res 2005, 
11(18):6713-6721. 
24. 
Duffy AG, Greten TF: Immunological off-target effects of standard treatments in 
gastrointestinal cancers. Ann Oncol 2014, 25(1):24-32. 
25. 
Antonia SJ, Brahmer JR, Gettinger SN, Quan Man Chow L, Juergens RA, Shepherd 
FA, Laurie SA, Gerber DE, Goldman JW, Shen Y et al: Nivolumab (anti-PD-1; BMS-
936558, ONO-4538) in combination with platinum-based doublet chemotherapy 
(PT-DC) in advanced non-small cell lung cancer (NSCLC). In. J Clin Oncol 32:5s, 
2014 (suppl; abstr 8113); 2014. 
26. 
Weber JS, Yang JC, Atkins MB, Disis ML: Toxicities of Immunotherapy for the 
Practitioner. J Clin Oncol 2015, 33(18):2092-2099. 
27. 
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, 
Neal J, Lu H, Cuillerot JM et al: Ipilimumab in combination with paclitaxel 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(17):2046-2054. 
28. 
 Seymour, L, Bogaerts J, Perrone A, Ford R, et al: iRECIST: guidelines for response 
criteria 
for 
use 
in 
trials 
testing 
immunotherapeutics. 
 
Lancet 
Oncol 
2017 Mar;18(3):e143-e152.  


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29. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JC et al: The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use 
in international clinical trials in oncology. J Natl Cancer Inst 1993, 85(5):365-376. 
30. 
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL et al: Recommendations for the Use of 
WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol 2015, 33(28):3199-3212. 
31. 
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989, 10(1):1-10. 
32. 
Pazdur R: Endpoints for assessing drug activity in clinical trials. Oncologist 2008, 
13 Suppl 2:19-21. 
33. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-
247. 
34. 
McShane LM, Hunsberger S, Adjei AA: Effective incorporation of biomarkers into 
phase II trials. Clin Cancer Res 2009, 15(6):1898-1905. 
35. 
Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, 
Parchment R, Ratain MJ, Shankar LK, Stadler WM et al: Guidelines for the 
development and incorporation of biomarker studies in early clinical trials of 
novel agents. Clin Cancer Res 2010, 16(6):1745-1755. 
 
 
 
 


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APPENDICES 
APPENDIX A: 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 B: CTCAE 
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 C: RECIST 1.1 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
C1. Measurability of tumor at baseline 
Measurable disease.  
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
- 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
- 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
- 
20 mm by chest x-ray 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node must 
be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed.   
 
Non-measurable disease. All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions). 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural/pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques.  
C2. Methods of Measurements 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should always 
be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.   
C3. Baseline Documentation of ‘target’ and ‘non-target’ lesions 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline and at the specified interval during treatment. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated measurements.  A sum 
of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as 
reference by which to characterize the objective tumor response. 
Non-target lesions. All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not required and these 
lesions should be followed as ‘present’, ‘absent’ or in rare cases ‘unequivocal progression’. 


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C4. Tumor Response Evaluation 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm.   
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest sum on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  Note: the appearance of one or more new lesions is also considered progression.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum of diameters while on study. 
Special note on assessment of lymph nodes: When lymph nodes are included as target lesion, the 
‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph node 
is defined as having a short axis < 10 mm.  In order to qualify ofr CR, each node must achieve a short 
axis of < 10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions.   
Target lesions that become ‘too small to measure’: If the radiologist believes the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If a lesion is believed to be present but 
is too small to measure, a default value of 5 mm should be assigned.  If the radiologist is able to provide 
an actual measure, that should be recorded, even if it is below 5 mm.   
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest diameters 
of the fragmented portions should be added together to calculate the target lesion sum.  As lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurement of each individual lesion.  If the lesions have truly coalesced such that the are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest diameter 
for the ‘coalesced lesion’.  
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis).  
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or maintenance of tumor marker 
level above the normal limits, 
Progressive Disease (PD): unequivocal progression of existing non-target lesions or the appearance 
of one or more lesions.  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease or progressive disease.   
 


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C5. Evaluation of Response 
 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in the following table:  
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
 
 
The best overall response is the best response recorded from the start of the treatment until the end of 
treatment taking into account any requirement for confirmation.  To be assigned a status of PR or CR, 
changes in tumor measurements with responding tumors should be confirmed by repeat imaging 
performed at least 4 weeks after the criteria for response are first met.  In the case of SD, follow-up 
measurement must have met the SD criteria at least once after study entry at a minimum interval of 6 
weeks.   
 
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 [33] 
 
 
 


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APPENDIX D: IMMUNE-RELATED RESPONE CRITERIA 
iRECIST Guidelines [28]  
Immunotherapeutic agents can sometimes cause an initial increase in tumor burden or the appearance 
of new lesions.  The iRECIST criteria were developed as an adaptation to RECIST criteria to account 
for this observation, iRECIST will be assessed secondarily following the addition of pembrolizumab to 
treatment.  iRECIST utilizes the following adaptations to RECIST 1.1. 
 
 
 


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APPENDIX E: FACIT-TS-G QUESTIONNAIRE 
 
 
 


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APPENDIX F: FACT-G QUESTIONNAIRE 
 
 
 


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


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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 


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All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
 
 
 
 
 
 


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APPENDIX H: Summary of Protocol Changes 
IIT2015-13-Walsh-PemCiGem Summary of Changes 
Amending Version 1 dated 8DEC2015 received IRB approval on February 4, 2016. 
Amendment 1: The following changes were made primarily to accommodate the use of new Quality of 
Life questionnaires (FACIT-TS-G/FACT-G) and delete reference to EORTC QLQ. 
1. Title page  
A. Version date updated 
2. Table of Contents – Updated to include new Quality of Life questionnaires (FACIT-TS-
G/FACT-G) to replace EORTC QLQ 
3. List of Abbreviations – Updated to include new Quality of Life questionnaires (FACIT-TS-
G/FACT-G) to replace EORTC QLQ 
4. Section 2.1 – Updated to include new Quality of Life questionnaires (FACIT-TS-G/FACT-G) 
to replace EORTC QLQ 
5. Section 4.2.3.3 – Updated to include new Quality of Life questionnaires (FACIT-TS-G/FACT-
G) to replace EORTC QLQ 
6. Section 6.1 – Updated to include new Quality of Life questionnaires (FACIT-TS-G/FACT-G) 
to replace EORTC QLQ 
7. Section 7.0 
A. Section 7.1.2.7 – Added line that shipping instructions will come from Qualtek, the 
outside lab processing the tissue samples. 
B. Section 7.1.3.1 – Deleted reference to Qualtek, as they will not be processing the blood 
samples. 
8. Section 12 – Updated to include new Quality of Life questionnaires (FACIT-TS-G/FACT-G) 
reference 
9. Appendices – Added Appendix E and F, new Quality of Life questionnaires (FACIT-
TS-G/FACT-G) to replace EORTC QLQ (formerly Appendix E) 
--------------------------------------------------------------------------------------------------------------------------------------- 
Amending Protocol Version 2 dated 05FEB2016 received IRB approval on February 11, 2016. 
Amendment 2: The following changes were made primarily to accommodate the use of pre-
medications sooner than previously written. Other protocol clarifications and edits are included in the 
list below. 
1. Title page – Version date updated 
2. List of Abbreviations – CSF (colony-stimulating factor) added 
3. Section 4.2.3.2 – Updated to clarify biomarker endpoints.  
4. Section 5.1.1.3 – Added “platinum-based” for internal consistency in defining platinum-
resistant ovarian cancer. 
5. Section 5.1.1.5 – Added ECOG performance status of 2 as eligible as this is more inclusive of 
individuals with platinum-resistant ovarian cancer.  
6. Section 5.2.1.2 – The text regarding parameters for chemotherapy dose adjustments was re-
formatted into a new table, Table 3C: Guidelines for chemotherapy dose modifications for 
increased clarity.  Toxicities resulting in dose modifications were specifically defined to also 
increase clarity.  For example, “grade 4 thrombocytopenia” was replaced with “platelet count 
< 25,000/microliter”.   


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7. Section 5.2.1.2 – A section was added to allow for growth factor support as recommended by 
the 2015 American Society of Clinical Oncology Clinical Practice Guideline.  The prior 
language that restricted growth factor support use to after a second episode of febrile 
neutropenia was removed as this was too restrictive, posed a safety concern, and did not 
reflect current guidelines for standard of care growth factor support use.  A protocol exception 
was approved by Dr. Sandler and the IRB on 3/10/2016 to allow for growth factor support to a 
patient who experienced febrile neutropenia during cycle 1 of chemotherapy in this study.   
8. Section 5.2.3 – the language surrounding antiemetic and hydration regimens was modified to 
be less restrictive and more reflective of current standard of care.  A statement was added to 
allow for the addition of decadron 10 mg IV as an antiemetic premedication.  This was 
approved by Merck on 2/29/2016.  A protocol exception was approved by the IRB on 
3/1/2016 to allow a subject to receive decadron as an antiemetic premedication during cycle 
2 of chemotherapy in this study.   
9. Section 5.5.2 – this language was updated to allow for use of decadron 10 mg IV as an 
antiemetic premedication.   
10. Section 6.0 – days were removed from the first row of the study flow chart as these were 
potentially inaccurate given the administrative leeway allowing for +/-3 days on day 1 and +/- 
1 day on day 8 of therapy.  “+21” was added to cycles 2-6 and maintenance to reflect the fact 
that these are 21 day cycles.  
11. Section 7.1.1.6 – clarification was provided on the assignment of patient numbers.  
12. Section 7.1.1.9 – a return carriage was added to indicate that this is a new section.  
13. Section 7.1.2 – the language was updated to clarify the timing of assessments.  Exam, vital 
signs, weight, assessment of adverse events and medication review may be performed 
during a clinic visit in between cycles.  Laboratory studies can be performed up to 72 hours 
prior to treatment (this is internally consistent with existing language on page 43 of the 
protocol).  
14. Section 7.1.2.3 – the language was updated to clarify the allowed timing of directed physical 
exam.  
15. Section 7.1.2.6 – the language was updated to clarify alternative imaging assessment for 
patients with allergy to IV contrast.  
16. Section 10.3 – add a line referencing section 7.1.1.6 for more information on subject 
registration. 
17. Section 11.1 – the Data and Quality Assurance language was updated to reflect current 
SOCCI practice. 
18. Section 11.2 – subsection title was updated to delete the word data. This section only 
addresses current SOCCI practice for safety review of IITs, the Safety Committee On Early 
Phase Studies. 
19. Section 11.2.1 – the original section was duplicative of the text in subsection 11.1 and is now 
deleted. 
20. Section 11.2.2 – this section was deleted as it is no longer relevant. IMM was replaced by 
SCOEPS. 
21. Section 11.3 – a line was added to clarify that an approved protocol exception is an instance 
when the protocol is not adhered to in addition to an emergency modification. 
22. Section 11.3.1 – some text was deleted and is now included in the following sections 11.3.2 
and 11.3.3. 
23. Section 11.3.2 – new section was added to clarify when an exception or an eligibility waiver 
may be implemented. 
24. Section 11.3.3 – formerly section 11.3.2 was edited to only address protocol deviations. 


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25. Section 11.4 – a line was added to clarify that a protocol amendment may be necessary if 
there are repeated exceptions or deviations. 
26. Section 11.5 – added a line to include data entry into a HIPAA-compliant database is also a 
study obligation of the PI. 
 
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Amending Protocol Version 3 dated 18MAR2016 received IRB approval on March 30, 2016. 
Amendment 3: Changes were made to correct discrepancies within the protocol that required 
reporting serious events within 24 hours to the IRB. CSMC IRB policy requires reporting of 
unanticipated or serious events to the IRB occur within 10 days of discovering the event. Other 
protocol clarifications and edits are included in the list below.  
1. Title page 
Version number and date updated  
Independent Medical Monitor deleted – safety monitoring section was updated in Version 3 
2. Table of Contents: added Appendix G Summary of Changes 
3. Section 2.1: clarified that maintenance cycles are for up to an additional 11 cycles, totaling 
approximately 1 year for study treatment, not an additional 1 year of maintenance cycles 
4. Section 4.2.3.2: clarified that biopsy and blood collections are optional, but donation of 
archival tissue is not if research biopsy is not performed 
5. Section 5.1 
Subsection 5.1.1.5: deleted ECOG 2, subjects with an ECOG status of 0 or 1 will be enrolled 
Subsection 5.1.1.9: added inclusion criterion that subjects must donate archival tissue if they 
opt out of a biopsy for a fresh sample 
6. Section 5.2.1.2: added a treatment parameter for grade 3 or 4 toxicity to Dose Modification 
Table 3C 
7. Section 5.7.3: reference to “reporting within 24 hours to the IRB” deleted 
8. Section 6.0: Clarifications made to cycle header, questionnaire time points, and magnesium 
was combined with other SOC blood draws that occur on Day 1 and Day 8 of treatment  
Footnote clarification added: the discontinuation visit and all follow-up are only necessary if a 
subject was administered pembrolizumab 
Footnote clarification added: Medication review, Adverse Event review, and the Physical 
Exam, can take place up to 7 days prior to treatment 
Footnote clarification added: Only FACT-G questionnaire will be administered at the 
baseline/screening visit. The FACIT-TS-G is not applicable prior to treatment 


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Footnote added: CBC with diff, CMPL and magnesium are done on day 1 and day 8 
9. Section 7.1.3: PK was deleted from Table 5  
10. Section 7.1.4.1: added description of questionnaires 
11. Section 7.1.5:  
7.1.5.2: clarified that the maintenance phase is up to an additional 11 cycles, totaling 
approximately one year of study treatment  
7.1.5.3.1 and 7.1.5.4 sentence added to two subsections to clarify that follow-up visits are 
only required if subjects received pembrolizumab 
12. Section 7.2: all references to “reporting within 24 hours to the IRB” were deleted 
13. Section 7.3.1: clarified that study staff must report an SAE to the PI  
14. Section 7.3.3: deleted section that required reporting SAEs to the FDA. This study is IND 
exempt. 
15. Table 6: clarified that an overdose should be reported to Merck within 2 business days 
16. Appendices: appended Summary of Changes – Appendix G  
 
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Amending Protocol Version 4 dated 13MAY2016 received IRB approval on May 25, 2016. 
Amendment 4: See changes below.  
1. Title page: Version number and date updated 
2. Eligibility Criteria: 
Section 5.1.1.3 – histologically confirmed deleted, as stated in Administrative Memo #3 
Section 5.1.2.9 – criterion regarding pneumonitis was updated to match sponsor’s current 
safety language. See Dear Investigator Letter for Pembrolizumab MISP - Action Requested 
date July 25, 2016 submitted with this amendment. 
3. Section 7.2.6: Added line that the study will only collect lab abnormalities if they are graded a 
3 or 4, as stated in Administrative Memo #4. 
Protocol Version 6, dated 16FEB2017, amends Protocol Version 5. IRB approval on 15 March 2017 
Amendment 5: See changes below: 
1. Exclusion criteria expands exclusion criteria 5.1.2.5 to include the note: Patients who have 
hypertension as an adverse event related to prior angiogenesis targeted therapy may be 
allowed if ≤ Grade 2 and considered by investigator to be well-controlled on anti-hypertensive 
agents. 
2. “Clinical Supplies” changed to “Commercial Supplies” throughout the protocol.  


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Protocol Version 7, dated 11July2017, amends Protocol Version 6. IRB approval on 01OCT2017 
 
Amendment 6: See changes below: 
 
1. Changes to CT Scan window to allow for out of window CT Scans based on clinical 
indication.  
 
2. Clarification changes to section 6.0 (study events table)  
 
3. Clarifications made throughout document  
 
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Protocol Version 8, dated 10OCT2017, amends Protocol Version 7. IRB approval on 
21NOV2017 
 
Amendment 7: See changes below:  
 
1. Section 4.2.3.2  
• 
Edits to language throughout this section to clarify biomarker research. 
• 
6-week intervals clarified to every two cycles  
 
2. Section 4.2.3.3 
• 
Edits to language to clarify QOL questionnaire time points.  
 
3. Section 5.1.1.7 
• 
Clarification that patients who have had prior hysterectomy and/or bilateral oophorectomy 
are not required to have a pregnancy test. 
 
4. Section 5.2.1 (Table 3C) 
• 
Changes to dose modification to specify that only the drug(s) related to specific drug toxicity 
will be held instead of entire treatment: 
 
o Continued administration of pembrolizumab/hold of cisplatin and gemcitabine 
chemo if “DAY 1:  ANC < 1500 cells/mm3 and/or platelet count < 100,000/µl” 
treatment to be modified as follows: “Cycle 1 and 2: Hold cisplatin and gemcitabine 
chemotherapy.  Initiation of cycle 1 or 2 of chemotherapy will be delayed a 
maximum of three weeks until these threshold values are achieved.  Subjects who 
fail to recover adequate counts within a three-week delay will not receive further 
chemotherapy in the study.” Protocol previously indicated hold of pembrolizumab in 
addition to chemotherapy.  
 
o Clarification of continued administration of gemcitabine and/or pembrolizumab, 
hold cisplatin if scheduled if “Grade 2 or greater peripheral neuropathy (moderate 
symptoms, limiting instrumental activities of daily living)” or “Grade 2 or greater 
renal toxicity (serum creatinine greater than 1.8 mg/dL or 1.5X baseline)” 


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o Continued administration of cisplatin and/or pembrolizumab if scheduled, delayed 
gemcitabine if subject experiences Grade 3 or greater liver toxicity, until toxicity 
resolved to Grade 1.  
 
o Continued administration of pembrolizumab/hold of cisplatin and gemcitabine 
chemo if “Grade 3 or 4 toxicity attributable to chemotherapy.” Protocol previously 
indicated hold of pembrolizumab in addition to chemotherapy.  
 
5. Section 5.2.3  
• 
 Addition of +/- 10 minutes to chemotherapy administration window.  
 
6. Section 6.1 (Study flowchart) 
• 
Addition of CT imaging SOC time points to study flowchart to clarify CT window.  
• 
Clarification that labs on day 8 are only required if patient is scheduled to receive cisplatin 
and gemcitabine treatment.  
• 
Clarification that archival tissue will not be required during screening phase. 
• 
Clarification that patients who have had prior hysterectomy and/or bilateral oophorectomy 
are not required to have a pregnancy test. 
• 
Clarification that Laboratory studies may be performed up to 72 hours prior to treatment 
(Section 7.1.2).   Labs do not need to be repeated if day 1 treatment is delayed or held 
unless clinically indicated per PI.   
 
7. Section 7.1.2.7 
• 
Clarification that Collection of archival tissue is not required during the screening phase 
 
8. Section 7.1.3 
 
• 
Clarification to laboratory testing review: “If review is found to be acceptable, the investigator 
or qualified designee will enter an order to release treatment (no other specific documentation 
will be required).” 
 
9. Section (Appendix C) 
• 
Update of RESIST to match Version 1.1 
 
 
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Protocol Version 9, dated 30NOV2017, amends Protocol Version 8. IRB approval on XX XXX 
XXXX 
 
Amendment 8: See changes below:  
 
• 
Addition of Appendix G: Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab  
 
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Protocol Version 11:  02 Jan 2019 
  
 
 
Protocol Version 10, dated 01FEB2018, amends Protocol Version 9 
 
Amendment 9: See changes below:  
 
1. Drug administration changed from 1 year to 2 year period (6 cycles of combined treatment + 28 
cycles of maintenance)  
 
2. Section 4.2.3.3 Quality of Life Questionnaires 
• 
(FACT-G and FACIT-TS-G) additional time point at 24 months (after cycle 34) 
 
3. Section 6.1 Study Flow Chart 
• 
Revised Maintenance cycles to include up to Cycle 34 
• 
Imaging revised to every third cycle starting with Cycle 9 
• 
QOL questionnaires additional time point at Cycle 34 
• 
Pembro administration extended through Cycle 34 
 
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Protocol Version 11, dated 02Jan2019, amends Protocol Version 10 
 
Amendment 10: See changes below:  
 
1. Removal of Co-Investigator: Beth Karlan, MD 
• 
Title page updated 
 
2. Protocol updated to include additional the allowance for decadron at 10 or 20 mg IV doses per 
Merck Approval 
• 
Section 5.2.3 Timing of Dose Administration 
• 
Section 5.5.2 Prohibited Concomitant Medications 
 
3. Protocol clarified to indicate iRECIST will be used rather than irRC or irRECIST 
• 
Sections 4.2.3 and 4.2.3.1 – “irRC” changed to “iRECIST” 
• 
Section 5.2.2 – “irRECIST” changed to “iRECIST” 
• 
Section 12.0 – reference replaced 
• 
Appendix D corrected to reflect iRECIST criteria 
 
4. Subject replacement strategy updated 
• 
Section 5.9 – “will” changed to “may” 
 
5. Protocol clarified for consistency regarding grade 1 and 2 laboratory abnormalities 
• 
Section 7.2.1 – “with the exception of grade 1 or 2 laboratory abnormalities” added 
• 
Section 7.2.6 – typo grade “3” corrected to “2” 
 
6. Section 7.1.5.2 – correction regarding the duration of maintenance therapy as approved in 
Amendment 9, protocol version 10 dated 01FEB2018 
 
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