Conditions: Ovarian Cancer
Keywords: Ovarian platinum pembrolizumab taxane
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
Phase II single arm, open label, nonrandomized study. The aim of our study is to assess the Progression Free Survival (PFS) in suboptimally cytoreduced epithelial ovarian/ primary peritoneal/ fallopian tube cancer patients treated with the novel combination of carboplatin every 21 days (triweekly) /weekly paclitaxel IV with pembrolizumab IV followed by maintenance pembrolizumab IV.

Detailed description:
Utilization of combination standard intravenous chemotherapy with intravenous pembrolizumab (for 6 cycles) in first line treatment of patients with advanced ovarian cancer post surgery with any residual disease. This will be followed by single agent intravenous pembrolizumab (every 3 weeks) for 12 additional cycles.

Arms:
arm 1: Single arm study:

Pembrolizumab IV every 21 days (200 mg) Carboplatin IV every 21 days Paclitaxel IV infusion (80 mg/m2) every 7 days for 6 cycles Followed by 12 months pembrolizumab IV every 21 days

Interventions: intervention 1: Pembrolizumab intervention 2: Carboplatin intervention 3: Paclitaxel
Intervention descriptions: intervention 1: IV every 21 days at 200 mg intervention 2: IV every 21 days intervention 3: IV infusion (80mg/m2) every 7 days for 6 cycles

Protocol document:
Prot_000.pdf: 
PROTOCOL 3475-250 
1 | P a g e  
 
`
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL 3475-250 
 
TITLE:  PHASE II OPEN LABEL NONRANDOMIZED SINGLE ARM TRIAL OF THE 
ANTI PD 1 THERAPY PEMBROLIZUMAB IN COMBINATION WITH FIRST LINE 
PLATINUM BASED CHEMOTHERAPY FOLLOWED BY 12 MONTHS 
MAINTENANCE PEMBROLIZUMAB MONOTHERAPY FOR PATIENTS WITH 
SUBOPTIMALLY CYTOREDUCED STAGE III/IV EPITHELIAL OVARIAN CANCER. 
 
IND NUMBER:  130424 
ClinicalTrials.gov Identifier: NCT02766582 
 
Date:  December 17, 2018. Version 6.1 
 
Sponsor-Principal Investigator Coordinating Center 
Denise Uyar, MD 
Associate Professor, Department of Obstetrics and Gynecology 
Medical College of Wisconsin Cancer Center 
9200 West Wisconsin Avenue 
Milwaukee, WI 53226 
duyar@mcw.edu 
Office:  414-805-6606 
Fax 414-805-6622 
 
Sub Investigators: 
Erin Bishop, MD. erbishop@mcw.edu – 414-805-6606  
William Bradley, MD. wbradley@mcw.edu – 414-805-6606 
Janet Rader, MD. jrader@mcw.edu – 414-805-6606 
Medical College of Wisconsin Cancer Center 
9200 West Wisconsin Avenue 
Milwaukee, WI 53226 
 
Other Investigators: 
Biostatistician 
Pippa Simpson, PhD.  psimpson@mcw.edu – 414-955-4521 
Chief, Quantitative Health Sciences 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53146 
 
 
 
 


PROTOCOL 3475-250 
2 | P a g e  
 
Correlative Studies 
James Verbsky, MD, PhD.  jverbsky@mcw.edu – 414-266-6700 
Medical College of Wisconsin 
Children’s Corporate Center, Suite C465 
999 N. 92nd Street 
Wauwatosa, WI 53226. 
 
Jill Gershan, PhD. jgershan@mcw.edu - 414 955 4251 
Assistant Professor 
Department of Pediatrics 
Hematology/Oncology 
Medical College of Wisconsin 
 
Liang Wang, PhD.  liwang@mcw.edu - 414-955-2574 
TBRC Building-C4970 
Medical College of Wisconsin 
8701 Watertown Plank Rd 
Milwaukee, WI 53226 
 
Pathologist 
Alexander C. Mackinnon, MD.  amackinnon@mcw.edu - 414-805-1526 
Director, Clinical and Translational Research Core Lab 
Associate Professor, Department of Pathology 
Medical College of Wisconsin 
Room 1176 FMLH West 
9200 W Wisconsin Ave 
Milwaukee, WI 53226 
 
Cleveland Foundation Clinics (Site 02) – Principal Investigator 
Chad Michener, MD 
Associate Professor, Department of Obstetrics and Gynecology 
The Cleveland Clinic Foundation 
Obstetrics and Gynecology and Women’s Health Institute/A81 
9500 Euclid Avenue 
Cleveland, OH 44195. 
(216) 445-0226 (Office) 
(216) 444-8551 (Fax) 
E-mail: michenc@ccf.org 
 
This is an investigator-initiated study.  Denise Uyar is the principal investigator and may also be 
referred to as the sponsor-investigator. Dr. Uyar is conducting the study, holds the IND, and is 
acting as the sponsor.  Therefore, the legal/ethical obligations of the principal investigator include 
both those of a sponsor and those of an investigator. 
The sub-Investigators listed above would act on behalf of the Dr. Denise Uyar in her absence. 
 
 


PROTOCOL 3475-250 
3 | P a g e  
 
CONTENTS 
1.0 
TRIAL SUMMARY .................................................................................................. 11 
2.0 
TRIAL DESIGN ........................................................................................................ 12 
2.1 
Trial Diagram ........................................................................................................ 12 
3.0 
OBJECTIVEs & HYPOTHESES ............................................................................ 14 
3.1 
Primary Objective & Hypothesis ......................................................................... 14 
3.2 
Secondary Objectives & Hypotheses ................................................................... 14 
3.3 
Exploratory Objectives: ........................................................................................ 14 
4.0 
BACKGROUND & RATIONALE .......................................................................... 15 
4.1 
Background ............................................................................................................ 15 
4.1.1 Pharmaceutical and Therapeutic Background ..................................................... 15 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 16 
4.2 
Rationale ................................................................................................................ 17 
4.2.1 Rationale for this Trial and Selected Subject Population .................................... 17 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 20 
4.2.3 Rationale for Endpoints ....................................................................................... 21 
5.0 
Study design ............................................................................................................... 25 
5.1 
Overview of the study ........................................................................................... 25 
5.1.1 Rationale for single arm ...................................................................................... 25 
5.2 
Diagnosis/condition for Entry into the Trial ....................................................... 25 
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. ............................................................. 28 
5.3 
Trial Treatments ................................................................................................... 29 
5.3.1 Dose Selection/Modification ............................................................................... 29 
5.3.2 Timing of Dose Administration ........................................................................... 34 


PROTOCOL 3475-250 
4 | P a g e  
 
5.3.3 Sequence .............................................................................................................. 38 
5.3.4 Paclitaxel Ancillary Medications ........................................................................ 39 
5.3.5 Trial Blinding/Masking ....................................................................................... 39 
5.3.6 Randomization or Treatment Allocation ............................................................. 39 
5.3.7 Stratification ........................................................................................................ 39 
5.3.8 Concomitant Medications/Vaccinations (allowed & prohibited) ........................ 39 
5.3.9 Rescue Medications & Supportive Care .............................................................. 40 
5.3.10 Diet/Activity/Other Considerations ..................................................................... 47 
5.3.11 Use in Pregnancy ................................................................................................. 47 
5.3.12 Subject Withdrawal/Discontinuation Criteria ..................................................... 48 
5.4 
Discontinuation of Study Therapy after CR ....................................................... 48 
5.5 
Subject Replacement Strategy.  None ................................................................. 49 
5.6 
Clinical Criteria for Early Trial Termination .................................................... 49 
6.0 
TRIAL FLOW CHART ............................................................................................ 50 
6.1 
Study Flow Chart .................................................................................................. 50 
7.0 
TRIAL PROCEDURES ............................................................................................ 54 
7.1 
Trial Procedures .................................................................................................... 54 
7.1.1 Administrative Procedures .................................................................................. 54 
7.1.2 Clinical Procedures/Assessments ........................................................................ 57 
7.1.3 Laboratory Procedures/Assessments ................................................................... 61 
7.1.4 Other Procedures ................................................................................................. 63 
7.1.5 Visit Requirements .............................................................................................. 63 
7.2 
Assessing and Recording Adverse Events ........................................................... 64 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck .......................................................................................... 65 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck .................. 66 


PROTOCOL 3475-250 
5 | P a g e  
 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck .............. 66 
7.2.4 Evaluating Adverse Events .................................................................................. 68 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators 
in accordance with all applicable global laws and regulations at each institution.
 ............................................................................................................................. 72 
7.2.5 Trial Monitoring/ Quality Assurance .................................................................. 72 
8.0 
STATISTICAL CONSIDERATIONS ..................................................................... 72 
8.1 
Planned Efficacy Evaluations ............................................................................... 72 
8.1.1 Primary Efficacy Variables ................................................................................. 72 
8.1.2 Secondary Efficacy Variables ............................................................................. 73 
8.1.3 Biomarker variables ............................................................................................. 73 
8.2 
Planned populations for study ............................................................................. 73 
8.2.1 Safety population ................................................................................................. 73 
8.2.2 Analysis Population ............................................................................................. 73 
8.3 
Statistical Analysis ................................................................................................. 74 
8.3.1 Patient Demographics and Characteristics Data .................................................. 74 
8.3.2 Efficacy Variables ............................................................................................... 74 
8.3.3 Missing Data Handling ........................................................................................ 75 
8.3.4 Safety Data .......................................................................................................... 76 
8.4 
Determination of Sample Size ................................................................................ 77 
8.5 
Study Data Collection, Monitoring, and Record Retention .............................. 77 
8.5.1 Data Management ................................................................................................ 77 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 77 
9.1 
Investigational Product ......................................................................................... 77 
9.2 
Packaging and Labeling Information .................................................................. 78 


PROTOCOL 3475-250 
6 | P a g e  
 
9.3 
Clinical Supplies Disclosure ................................................................................. 78 
9.4 
Storage and Handling Requirements .................................................................. 78 
9.5 
Returns and Reconciliation .................................................................................. 78 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 79 
10.1 
Confidentiality ....................................................................................................... 79 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 79 
10.3 
Compliance with Law, Audit and Debarment .................................................... 79 
10.4 
Compliance with Trial Registration and Results Posting Requirements ......... 79 
10.5 
Quality Management System ............................................................................... 79 
10.6 
Data Management ................................................................................................. 79 
11.1 ECOG Performance Status ...................................................................................... 80 
11.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ................... 80 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................. 80 
* As published in the European Journal of Cancer: ...................................................... 80 
References: ......................................................................................................................... 83 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL 3475-250 
7 | P a g e  
 
LIST OF ABBREVIATIONS, ACRONYMS, AND DEFINITION OF TERMS 
 
Abbreviation/Acronym Definition 
Μm 
micron 
5HT3 
receptors in the vomiting center, chemoreceptor trigger zone and 
small intestine 
ADA 
anti–drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration - time curve 
BCG 
Bacillus Calmette-Guerin vaccine against tuberculosis 
BID 
twice daily 
BRAF 
protein kinase that is encoded by the BRAF gene 
BRAF V600 
Specific mutation occurring within activation segment of kinase 
domain in BRAF gene 
°C 
degrees Celsius 
CA 125 
cancer antigen 125 
CBC 
complete blood count 
CD3 
cluster of differentiation 3 
CD4 
cluster of differentiation 4 
CD8 
cluster of differentiation 8 
CD14 
cluster of differentiation 14 
CD19 
cluster of differentiation 19 
CD21 
cluster of differentiation 21 
CD24 
cluster of differentiation 24 
CD25 
cluster of differentiation 25 
CD27 
cluster of differentiation 27 
CD28 
cluster of differentiation 28 
CD38 
cluster of differentiation 38 
CD56 
cluster of differentiation 56 
CD279 
cluster of differentiation 279 


PROTOCOL 3475-250 
8 | P a g e  
 
CD45RA 
protein tyrosine phosphatase regulating src-family kinases,
expressed on all hematopoietic cells 
cfDNA 
cell free DNA 
CIRL 
Clinical Immunology Research Laboratory 
CLIA 
Clinical Laboratory Improvement Amendment 
CNS 
central nervous system 
Crcl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography scan 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DAKO ACIS III 
DAKO automated cell imaging system III 
DHEP 
Diethylhexylphthalate 
DNA 
deoxyribonucleic acid  
DP 
drug product 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOC 
epithelial ovarian cancer 
°F 
degrees Fahrenheit 
FACT-O 
Functional Assessment of Cancer Therapy - Ovary 
FFPE 
fresh frozen paraffin embedded 
FoxP3 
forkhead box P3 
GCSF 
granulocyte stimulating growth factors 
GFR 
glomerular filtration rate 
HBsAg 
hepatitis B surface antigen 
HCl 
hydrochloric acid 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA-DR 
MHC class II cell surface receptor encoded by the human 
leukocyte antigen complex on chromosome 6 region 6p21.31 
Ig 
immunoglobulin 


PROTOCOL 3475-250 
9 | P a g e  
 
IgD 
immunoglobulin D 
IgG4 
immunoglobulin G subclass 4 
IgM 
immunoglobulin M 
IgV 
immunoglobulin V 
IHC 
immunohistochemistry 
IRB 
institutional review board 
ITIM 
immunoreceptor tyrosine-based inhibition motif 
ITSM 
immunoreceptor tyrosine-based switch motif 
IV 
Intravenous 
IVEX-II 
IV extension filter infusion set 
IVEX-HP 
IV extension hydrophilic filter infusion set 
LVP 
large volume parenteral 
mAb 
monoclonal antibody 
MRI 
magnetic resonance imaging  
NaOH 
sodium hydroxide 
NCCN 
National Comprehensive Cancer Network 
NK cells 
natural killer cells 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
OTC 
over the counter 
PDAC 
pancreatic adenocarcinoma 
PDCD1 
PDCD1 gene encodes PD-1 protein 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression free survival 
PK 
pharmacokinetic 
PVC 
polyvinyl chloride 
Q / q 
every 
Q3W 
Every 3 weeks 
QOL 
quality of life 
RECIST 
response evaluation criteria in solid tumors 


PROTOCOL 3475-250 
10 | P a g e  
 
T cells 
thymus gland lymphocyte 
TILs 
tumor-infiltrating lymphocytes 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
WBC 
white blood cell 
ZAP70 
zeta-chain-associated protein kinase 70 
 
 


PROTOCOL 3475-250 
11 | P a g e  
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab/Carboplatin/Taxol in epithelial ovarian 
cancer followed by maintenance pembrolizumab 
Trial Phase 
II 
Clinical Indication 
Epithelial Ovarian Cancer 
Trial Type 
Single Arm, Open label non-randomized 
Type of control 
Historical Control  
Route of administration 
IV 
Trial Blinding 
none 
Treatment Groups  
Single arm 
Number of trial subjects 
30 
Estimated 
enrollment 
period 
18 months 
Estimated duration of trial 48 months 
Duration of Participation 
72 months or closure of trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL 3475-250 
12 | P a g e  
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Diagram 
 
 
 
 
 
 
 
Phase II single arm, open label, nonrandomized study.  The aim of our study is to assess the 
Progression Free Survival (PFS) in suboptimally cytoreduced (defined as any gross residual 
disease) epithelial ovarian/ primary peritoneal/ fallopian tube cancer patients treated with the novel 
combination of carboplatin Q3w/Qw paclitaxel IV with pembrolizumab IV Q3w followed by 
maintenance pembrolizumab IV Q3w OR carboplatin and paclitaxel IV Q3w with pembrolizumab 
IV weekly followed by maintenance pembrolizumab IV Q3w.  (Choice of IV chemotherapy 
regimen may be determined by anticipated tolerance per treating physician discretion.) The choice 
between the chemotherapy treatment regimens will be agreed upon by the study patient and their 
enrolling physician prior to entry. 
NOTE: Patients who have not attained a normalized CA-125, have stable disease or partial 
response to therapy on CT imaging at the completion of cycle 6 may continue to receive 
paclitaxel and carboplatin (with pembrolizumab) for up to 9 cycles (if deemed necessary by 
the treating physician). Patients who continue with cycles 7-9 will continue with all study 
assessments as described in the study flow chart. A CT scan should be obtained at the 
completion of combination therapy and prior to the start of maintenance therapy. 
In the case of a hypersensitivity reaction to paclitaxel or baseline neuropathy > grade 2, paclitaxel 
may be substituted with Q3w docetaxel per treating physician discretion after discussion with the 
sponsor (See table 5.4). 
 
 
 
 
 
 
 
Epithelial 
ovarian 
cancer and 
suboptimal 
cytoreduction  
6 cycles of IV 
carboplatin +    IV 
pembrolizumab    
Q3w/ Qw IV 
paclitaxel  
Maintenance 
pembrolizumab 
IV Q3w x 12 
cycles 


PROTOCOL 3475-250 
13 | P a g e  
 
 
 
 
 
 
 
Stage III/IV epithelial ovarian cancer with suboptimal 
cytoreduction and/or 
CT with measurable residual disease 
 
DAY 1 
Carboplatin AUC 6 IV 
and 
Paclitaxel 80 mg/m2 
+ 
Pembrolizumab 200 mg IV  
 
DAY 8 
Paclitaxel 80 mg/m2 IV 
 
DAY 15  
Paclitaxel 80 mg/m2 IV 
 
Repeat every 3 weeks for 6 cycles  
 
Followed by maintenance Pembrolizumab IV  
DAY 1 every (Q) 21 days x 12 cycles  
 
 
*The choice between the chemotherapy treatment regimens will be agreed upon by the study 
patient and their enrolling physician prior to entry. 
 
 
 
 
 
 
 


PROTOCOL 3475-250 
14 | P a g e  
 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective:  Assess Progression Free Survival (PFS) of combination platinum-based therapy 
with anti-Programmed Death (PD)-1 therapy followed by maintenance anti-PD-1 therapy 
in patient with suboptimally/ residual disease following cytoreduction of epithelial ovarian/ 
primary peritoneal/ fallopian tube cancer, which for the purposes of the protocol will be 
referred to as epithelial ovarian cancer (EOC). 
Hypothesis:  Our hypothesis is that anti-PD therapy combined with standard chemotherapy will 
improve the PFS in this population and have a tolerable safety profile. 
3.2 
Secondary Objectives & Hypotheses 
(1)  Objective:  Assess Overall Survival (OS) of combination platinum-based therapy with 
anti-PD-1 therapy followed by maintenance anti-PD-1 therapy in patient with suboptimally/ 
residual disease following cytoreduction of EOC. 
Hypothesis:  Our hypothesis is that anti-PD therapy combined with standard chemotherapy 
will improve the OS in this population and have a tolerable safety profile. 
(2) Objective:  Monitor quality of life during combination therapy and single agent 
maintenance therapy with anti-PD-1 therapy with the Functional Assessment of Cancer 
Therapy (FACT) surveys at intervals during therapy. 
Hypothesis:  We hypothesize that combination chemotherapy and anti-PD-1 therapy will not 
adversely affect quality of life during combined and maintenance therapy duration.   
 
3.3 
Exploratory Objectives:   
The overall objectives pertain to the development of biomarkers for prediction and monitoring of 
disease status.  
(1) Objective:  Assess the PD-1 and PD-L1 expression in preserved tissue obtained at the time 
of initial diagnosis for patients with suboptimally/ residual disease following cytoreduction 
of ovarian cancer using immunohistochemistry (IHC) and correlate with clinical outcomes.   
(2) Objective: Assess serial immune profiles from blood samples obtained post-surgery, prior 
to initiation of chemotherapy, after completion of combination therapy, during anti-PD-1 
maintenance therapy and at time of recurrence with the intention of identifying potential 
correlations with clinical outcomes.    


PROTOCOL 3475-250 
15 | P a g e  
 
Hypothesis:   We hypothesize that analysis of the tumor microenvironment using IHC staining 
for PD-1 and PD-L1 may correlate with response to therapy.  Furthermore, we hypothesize that 
peripheral blood monitoring of immune cell profiles may provide biomarkers that correlate with 
response to therapy.  We hypothesize that tumor immune monitoring during this study will be 
able to be utilized for improvement of the rational design of future trials with better 
understanding of timing, dosing and scheduling of combination therapy.   
3.4   Biomarker Studies: 
(3) Objective:  Collection of serial blood samples for analysis of cell free DNA (cfDNA) in 
ovarian cancer patients over a series of time points and explore the potential role of cfDNA 
as a tool for identifying serum biomarkers. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
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.  
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. 
4.1.1.1 PD-1/PD-L1 pathway plays a critical role in tumor immune evasion  
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/ CD279) is an Ig superfamily member 
related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 
has been resolved.  PD-1 and family members are type I transmembrane glycoproteins containing 
an Ig 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 regulatory cells 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 


PROTOCOL 3475-250 
16 | P a g e  
 
tissues as well as in various tumors.  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in subjects with melanoma.  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. 
 
4.1.1.2 Pembrolizumab designed to directly block the interaction between PD-1 and its 
ligands PD-L1 and PD-L2.  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype.  KeytrudaTM (pembrolizumab) has recently been approved in the United States 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
In the 1-month and 6- month toxicology study in Cynomolgus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 200 mg/ kg 
resulted in no adverse treatment related effects. The clinical summary of results thus far as of 2014 
for pembrolizumab monotherapy and combination therapy include a total of 6,294 subjects with 
both hematologic and solid tumors in a total of 18 phase I, II, III clinical trials sponsored by Merck.   
Specifically, KEYNOTE-021 (NCT02039674) is a multicohort phase I/II trial of pembrolizumab 
(2mg/kg vs 10 mg/kg) plus platinum- doublet chemotherapy (carboplatin / paclitaxel or carboplatin/ 
pemetrexed) in advanced treatment naïve patients with non-small cell lung cancer.  A total of 65 
patient were enrolled for study.  The overall incidence of adverse events was 95% (62 of 65 
subjects).  The most commonly reported AEs experienced in this population across all dose 
regimens were fatigue (49.2%), constipation and nausea (26.2% each), decreased appetite (23.1%), 
diarrhea (18.5%) and anemia and alopecia (15.4% each).  The incidence of drug related AEs was 
86.2% (56 of 65 subjects).  The most commonly reported drug related AEs in this population were 
fatigue (35.4%), nausea, decreased appetite and alopecia (13.8% each), diarrhea (12.3%), and 
constipation and aspartate aminotransferase elevation (10.8% each).  Grade 3-5 drug related AEs 
were reported 23.1% of subjects (15 of 65 subjects). The most common grade 3-5 drug related AEs 
in this population across all groups were aspartate aminotransferase elevation (6.2%) and anemia 
and alanine aminotransferase elevation (4.6% each).  Adverse events resulting in discontinuation 
of study were reported in 3.1% (2 of 65 subjects).  Interstitial lung disease, dermatitis allergic and 
drug eruption were the only AEs resulting in discontinuation and were reported 1 subject each 
(1.5%).  A total of 8 subjects’ experienced serious drug related AEs as follows:  anemia, febrile 


PROTOCOL 3475-250 
17 | P a g e  
 
neutropenia, atrial fibrillation, colitis, pyrexia, hypersensitivity, alanine aminotransferase elevation, 
aspartate aminotransferase elevation, drug eruption, rash and urticarial.  Preliminary efficacy results 
indicate no difference across all groups suggesting a flat dose-exposure relationship.  The overall 
response rate observed for pembrolizumab in combination with chemotherapy was promising and 
warranted further examination; continuing phase II trials are underway in non-small cell lung 
cancer. 
4.2 
Rationale 
4.2.1 Rationale for this Trial and Selected Subject Population 
4.2.1.1 Epithelial Ovarian Cancer (EOC)  
Epithelial ovarian cancer (EOC), inclusive of peritoneal and fallopian tube cancers, is one of the 
most common gynecologic malignancies and the fifth most common cause of cancer death in 
women.  Approximately 22,000 cases of epithelial ovarian cancer are diagnosed annually in the 
United States. This results in nearly 15,000 deaths annually in the United States 
(http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013). 
Initial treatment for ovarian cancer is usually surgical cytoreduction followed by adjuvant platinum 
and taxane chemotherapy [1-4]. At the time of diagnosis over 75% of patients present with stage III 
or IV disease meaning that disease has spread into the peritoneal cavity or distally[5]. Despite several 
new developments and new chemotherapeutic regimens survival has improved only modestly over 
the last two decades. While overall 5-year survival has improved from 30% to 50%, 5-year survival 
remains only 25% for women with advanced stage disease. 
4.2.1.2 Surgical Cytoreduction and Adjuvant Therapy  
One of the most important prognostic factor for advanced epithelial ovarian cancer is the amount 
of residual tumor at the completion of initial surgical cytoreduction. Virtually all retrospective 
reports have shown an inverse correlation between the largest diameter of the residual tumor and 
survival [6-8]. Patients who undergo optimal cytoreduction (defined as no gross residual tumor after 
surgical cytoreduction) have been found to have the most favorable prognosis as compared to 
patients with any gross residual disease. The reported rates of optimal cytoreduction, however, vary 
widely in the literature and have been reported to range from 20-80%.  A recent meta-analysis 
reported an average rate of optimal cytoreduction of only 42% [6].  The ability to achieve an optimal 
disease status is dependent on the skill of the operating surgeon, patient co- morbidities and 
individual tumor biology.  Those patients who undergo aggressive cytoreductive procedures but do 
not achieve an optimal cytoreduction have demonstrated decreased overall survival placing them 
in a particularly poor prognostic group.  In one review the median overall survival in patients with 
optimal versus suboptimal cytoreduction was 39 versus 17 months [8]. Defining optimal in this 
population is increasingly more difficult and most agree that any residual disease is a negative 
prognostic indicator. 
All patients with advanced EOC will receive chemotherapy as well as surgery.  Modern 
chemotherapy for EOC has incorporated many different methods of the administration of platinum 
based regimens.  Intraperitoneal therapy with combination platinum and taxane agents has 
demonstrated improved progression free survival and overall survival but has not been widely 


PROTOCOL 3475-250 
18 | P a g e  
 
accepted due to its significant toxicity.  This regimen is reserved for patient who have undergone 
optimal cytoreduction; patients who are not optimally cytoreduced are not candidates for this 
therapy.  Conventional regimens are typically recommended in the setting of suboptimal 
cytoreduction and utilize intravenous carboplatin and paclitaxel combination therapy administered 
every 21 days (triweekly).  Alternatively, carboplatin has been administered every 21 days or 
triweekly, while the paclitaxel is given weekly over the 21 day cycle (dose dense regimen).  This 
dose dense regimen has been actively studied in EOC recently due the demonstrated benefit in 
breast cancer patients receiving weekly paclitaxel [9].  Weekly paclitaxel in combination with 
carboplatin every 3 weeks has yielded improved PFS in phase III studies comparing this regimen 
to conventional triweekly carboplatin and paclitaxel (median overall survival of 100 months versus 
62 months) and has had a more manageable toxicity profile making it an attractive option for 
primary therapy [10].   Recent prospective data, however, indicates that the progression free survival 
between Q3w carboplatin and Qw paclitaxel versus Q3w paclitaxel is not significantly different [52].  
Specifically, recent studies utilizing carboplatin with weekly paclitaxel in suboptimally 
cytoreduced (>1 cm residual disease) compared with conventional triweekly carboplatin and 
paclitaxel patients resulted in a favorable median PFS of 17.6 months versus 12.1 months [11].  Dose 
dense therapy has since been adopted as one of the standard of care options for advanced ovarian 
cancer National Comprehensive Cancer Network (NCCN) guidelines.   
Given these limitations for suboptimally cytoreduced patients, it is clear that improved strategies 
for the delivery of cytotoxic therapy, novel strategies or novel combinations should be actively 
pursued for this population.  
4.2.1.3  Rationale for Ovarian Cancer as a Target for Immune Therapy  
Evidence is accumulating to support the significant role the immune system plays in all types of 
malignancies.  Recent evidence has concluded that ovarian cancer is an immunogenic tumor similar 
to melanoma and a valid immunotherapy target [12, 13].  Over the past decade multiple studies have 
greatly increased our understanding of the immune responses in ovarian cancer patients.  Studies 
have demonstrated that those patients with ovarian cancer whose tumors were noted to have greater 
CD3+ tumor infiltrating lymphocytes (TILs) experienced longer progression free and overall 
survival [14-16].  Several investigators have correlated immune escape mechanisms, such as increased 
CD4+CD25+FoxP3+T regulatory cells and programmed death 1 ligand, in ovarian cancer 
populations with a poor survival [14, 17-19].  In addition, several studies have found that higher ratios 
of CD8+ cells / CD4+CD25+FoxP3+ T regulatory cells to be favorable prognostically [20, 21].  
Together these findings indicate that ovarian cancer is a valid target for immunotherapy. 
4.2.1.4 Combining Chemotherapy and Immunotherapy 
Increasing evidence indicates that several agents in the standard EOC chemotherapy, such as 
carboplatin and paclitaxel, initially thought to have immunosuppressive effects actually have 
important immunostimulatory effects.  Hato et al[22] demonstrated that platinum based therapy 
augments the capacity of dendritic cells to induce antigen-specific T cell proliferation, induces 
down regulation of PD L-1 and PD L-2 and effectively decreases the immunosuppressive capacity 
of tumor cells via the STAT6 pathway.  Paclitaxel has been found to be immunostimulatory with 
upregulation of the cytotoxic T-cell function [23] and decrease of T regulatory cell populations [24].  
Specifically, dose dense chemotherapy’s clinical advantage may in fact be linked to its potential 


PROTOCOL 3475-250 
19 | P a g e  
 
immune advantages over conventional therapy.  In a study by Chang et al [25] dose dense 
combination therapy with weekly platinum and paclitaxel was utilized in an ovarian tumor model 
and was found to be less toxic to the immune system, reduced immunosuppression by the tumor 
microenvironment and triggered recruitment of macrophages and tumor-specific CD8+ T cell  
responses to tumors.  These results were then validated in 14 patients with recurrent ovarian cancer.  
As a result of these findings, combining chemotherapy and immunotherapy, once thought to be 
incompatible, is now thought to be a rational therapeutic option. 
The ideal window (dose and scheduling) for combining immunotherapy and chemotherapy is 
currently under investigation, however, preclinical studies by Diaz et al [24] have found that the 
combination of vaccine therapy when combined concomitantly with cytotoxic doses of carboplatin 
and paclitaxel in mice produced an enhanced anti-tumor effect compared with therapy with the 
vaccine alone.  This lends support to the concept that the concomitant combination of 
immunomodulation with standard chemotherapy has potential to be an effective strategy.   In 
addition, in a phase 2 study by Braly et al [26] evaluating the immune adjuvant properties of front-
line carboplatin-paclitaxel with alternative schedules of intravenous oregovomab chemo-
immunotherapy in advanced ovarian cancer, found that treatment emergent CA125-specific cellular 
immunity was measured more commonly with simultaneous (cycle day 1) administration of 
oregovomab therapy with chemotherapy versus one week delayed infusion of oregovomab after 
chemotherapy (p=0.04) and that additional clinical parameters favored this schedule. Timing of 
immunotherapy with chemotherapy is an active area of research.   
Combination chemotherapy and immunotherapy strategies are emerging, and safety data is 
becoming available.  The Merck-sponsored protocol P011 is a combination therapy trial in which 
pembrolizumab monotherapy was compared with pembrolizumab in combination with 
cisplatin/pemetrexed and carboplatin/paclitaxel.   Adverse events were generally manageable and 
infrequently required discontinuation of pembrolizumab treatment.   Thus, the feasibility of the 
combined strategy as well as the safety of the combination has been demonstrated. 
4.2.1.5 Maintenance Therapy in Ovarian Cancer 
The mechanism by which ovarian cancer evades chemotherapy is not fully understood.   The 
concept of ‘ovarian cancer repopulation’ as reviewed by Telleria et al[27] elaborates on the 
phenomenon that a population of cancer cells may have an intrinsic ability to escape cytotoxic 
therapy and have the ability to repopulate into solid tumors.  He emphasizes that the period of time 
in remission is an ideal opportunity to introduce consolidative maintenance therapy as a means of 
blocking tumor repopulation.  Several clinical studies have looked closely at the addition of 
maintenance therapy for prolongation of tumor remission in ovarian cancer patients.  The strongest 
studies to date have incorporated maintenance therapy with additional cycles of cytotoxic 
chemotherapy (paclitaxel) or antiangiogenic agents (bevacizumab).  Both have demonstrated an 
effect on progression free survival but have yet to demonstrate an impact on overall survival.  They 
are hampered as well by their prolongation of toxicity and expense, respectively [3, 28].  Despite this, 
the concept of maintenance therapy remains a rational strategy that requires further evaluation in 
ovarian cancer. 
Our study therefore proposes a strategy to integrate immune therapy with the current standard 
chemotherapy for ovarian cancer via a phase II open label nonrandomized single arm study of 


PROTOCOL 3475-250 
20 | P a g e  
 
intravenous (IV) combination carboplatin /paclitaxel chemotherapy in suboptimally cytoreduced 
patients with stage III/IV epithelial ovarian cancer with concomitant IV administration of anti-PD-
1 antibody Pembrolizumab (200 mg IV) day 1 of each 3 week cycle concomitantly with carboplatin 
every 21 days and paclitaxel administered weekly every 21 days followed by 12 cycles of IV 
Pembrolizumab maintenance monotherapy therapy (200 mg IV q 3 weeks).  Our primary objectives 
will be to determine if this subset of ovarian cancer patients observes an improved progression free 
survival.  In addition, we will assess the safety and overall survival from this regimen compared to 
historical controls.  Our secondary objectives will include documentation of patient quality of life 
(QOL) at intervals throughout the study and evaluation of potential biomarkers with assessment of 
the tumor microenvironment at the time of diagnosis.  We will also accumulate data on the immune 
cell subsets during the study to inform future designs of clinical trials employing immune therapy 
in combination with chemotherapy and/or maintenance therapy. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated, and no dose-limiting toxicities 
were observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W).  No maximum tolerated dose has been identified to date.  10.0 mg/kg Q2W, 
the highest dose tested in Merck protocol 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 pembrolizumab program has shown that a lower dose of 
pembrolizumab and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of pembrolizumab 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 using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab 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.  Pembrolizumab 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 pembrolizumab 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 


PROTOCOL 3475-250 
21 | P a g e  
 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
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.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
4.2.3 Rationale for Endpoints 
We have selected Progression Free Survival as defined by Response Evaluation Criteria in solid 
Tumors (RECIST) 1.1 criteria as the primary endpoint [29].  Response based endpoints are standard 
in phase II trials [30]. 
4.2.3.1 Efficacy Endpoints 
4.2.3.1.1 Primary Efficacy Variables 
The primary efficacy variable is progression free survival for suboptimally cytoreduced (patients 
having any measurable residual disease post-surgical debulking) Stage III/IV ovarian cancer with 
combination platinum based chemotherapy and anti-PD-1 therapy followed by maintenance anti-
PD-1 therapy compared to historical controls [10]. 
Progression of disease or recurrence is defined as increasing clinical, radiological or histological 
evidence of disease as defined in 7.1.2.6.  Patients with progression of disease based on clinical or 
histological basis must also have a CT scan performed for further confirmation.  CT scan will be 
scheduled at specific intervals (Trial Flow Chart 6.0) but may also be performed at discretion of 
investigator if recurrent or progression of disease or symptoms warrant evaluation.   
Progression free survival (PFS) will be defined as date of completion of primary therapy to the date 
of first clinical, biochemical, or radiological evidence of progression or death due to any cause.  
PFS will be censored at the last assessment of disease progression for living patients. 


PROTOCOL 3475-250 
22 | P a g e  
 
PFS is considered the best outcome for a phase II trial and the most informative [31].  
4.2.3.1.2 Secondary Efficacy Variables 
4.2.3.1.2.1 Overall survival for suboptimally cytoreduced Stage III/IV ovarian cancer with 
combination platinum based chemotherapy and anti-PD-1 therapy followed by 
maintenance anti-PD-1 therapy compared to historical controls. 
4.2.3.1.2.2 Fact-O: Quality of life on maintenance anti-PD-1 therapy as measured with QOL 
(FACT-O) surveys at intervals during therapy. 
 
The Functional Assessment of Cancer Therapy questionnaire for ovarian cancer (FACT-O) is a 
short questionnaire grouped by logical categories that can be completed by most patients without 
assistance within 5 minutes. The FACT-O allows patients to weight each category of questions 
based on the categories' perceived importance to the quality of the patients' lives. Internal 
consistency as measured by Cronbach’s alpha is 0.92 and test retest reliability is .81[32].  
 
 
4.2.3.2 Biomarker Research 
4.2.3.2.1.1.1  Tumor micro environment: The relationship of survival to the tumor 
microenvironment at the time of diagnosis for patients with suboptimally cytoreduced 
ovarian cancer using immunohistochemistry (IHC) staining for antibodies of PD-1 
and PD-L1 in paraffin embedded tissue of tumor obtained at the time of their initial 
surgery.  
 
Pembrolizumab is an anti-PD-1 antibody that was FDA approved via the accelerated process for 
patients with ipilimumab-refractory melanoma.  PD-L1 expression is a possible biomarker to 
identify patients for PD-1 directed therapy [33-36]. Several PD-L1 expression assays have been 
described [37-39]; studies addressing assay comparison, standardization, or validation are not yet 
published.  PD-L1 expression is also unlikely to be the only candidate biomarker for predicting 
response to PD-1 directed therapy. 
PD-L1 and PD-1 IHC will be performed on FFPE tissue samples using standard IHC procedures.  
Commercially available, IHC-validated PD-L1 clones have been identified.  The PD-L1 
monoclonal antibodies utilized in this study will be SP142, E1L3N.  Several other validated PD-L1 
monoclonal antibodies, e.g., E1J2J, 5H1 and 28.8 are not commercially available; if these clones 
become available then they will be used as well. The commercially available, IHC- validated PD-1 
clone NAT will be used for analysis of PD-1 expression.    
 
IHC will be optimized by adjusting heat induced epitope retrieval conditions (ie, low pH and high 
pH), PD-L1 and PD-1 titers, and the inclusion or exclusion of a signal-boosting linker.  Specificity 
can be determined if necessary by pre-incubating the antibody with blocking peptides, which should 
compete with the tissue for the PD-L1 epitope binding site.   Tumor-associated lymphocytes will 
be characterized using IHC for CD1, CD3, CD4, CD8, FoxP3, and CD19.  Tonsil and placenta will 
serve as positive controls.  Additional control tissues are non-small cell lung cancer (NSCLC), 


PROTOCOL 3475-250 
23 | P a g e  
 
cervical cancer, Hodgkin lymphoma, pancreatic adenocarcinoma (PDAC), prostate cancer, and skin 
squamous cell cancer (SCC). 
 
IHC stained slides will be analyzed as follows:  PD-L1 and PD-1 expression on tumor membranes 
will be measured by a pathologist.  The percent of tumor cells that stain positive will be determined 
either manually or with an automated cell imaging system (DAKO ACIS III).  Samples will be 
scored as either PD-L1 or PD-1 positive if PD-L1 or PD-1 is detected on > 5% of tumor cells [33, 36-
39].  Tumor-associated lymphocytes will be assessed for PD-L1 and PD-1 expression as well. 
 
4.2.3.2.1.1 The relationship of pembrolizumab treatment and patient survival with immune 
signatures from blood and serum samples. 
 
The clinical reality of immune checkpoint blockade as a cancer immunotherapy has prompted an 
unprecedented need to monitor patient immunity. This need has resulted in an international effort 
to develop peripheral biomarkers that cluster into immune profiles. As part of this initiative, we 
will determine the longitudinal progression of patient peripheral immune signatures when treated 
post-surgically with combination chemotherapy and pembrolizumab (C/P). We will thus have 
longitudinal intra-patient immune monitoring over the course of the study.  An immune profile will 
be determined by combining peripheral immune cell subset and serum cytokine signatures pre and 
post C/P treatment. Blood and serum samples will be obtained following surgery, upon completion 
of the initial phase of C/P treatment (~18 weeks), at the midway time point of the maintenance 
phase of therapy and at completion of maintenance therapy. An additional blood and serum sample 
will be obtained at the time of disease relapse. It is our goal to identify a peripheral immune profile 
that reflects an immunogenic response to pembrolizumab immunotherapy and correlates with an 
increase in survival.  
Immune Cell Subsets 
As a measure of systemic immunity, the relative percentage of circulating immune cells will be 
assessed by multiparametric flow cytometry. Multiparametric flow cytometry will allow for 
identification of immune cell subsets by recording the simultaneous expression of biomarkers 
unique to that cell subset. Flow cytometry will be performed on a LSR II cytometer (BD 
Biosciences) located in the Clinical Immunology Research Laboratory, a CLIA certified lab that 
performs clinical flow cytometry at the Medical College of Wisconsin. We will use flow cytometry 
of antibody stained peripheral blood mononuclear cells (PBMCs) to evaluate the relative percentage 
of cell types including T, B, NK and myeloid cells. As an indirect indicator of T cell function, the 
expression of T cell inhibitory receptors, activation markers, as well as the presence of regulatory 
T cells will be determined. Correlating changes in immune cell subsets with pembrolizumab 
treatment and survival will facilitate the identification of a peripheral immune signature that 
correlates with increased anti-tumor immunity. The antibody panels designed to identify the 
percentage of immune cell subsets present in PBMCs are shown in Table 4.2. 
Serum Cytokines 
Serum cytokine concentration is readily accessible and an efficient means to assess peripheral 
immunity. Changes in serum cytokines have been reported in cancer patients. However, currently, 


PROTOCOL 3475-250 
24 | P a g e  
 
there are no defined cytokine signatures that are cancer specific or predictive of disease outcome. 
For this study, serum cytokines will be analyzed longitudinally before and after pembrolizumab 
therapy. Serum cytokines will be quantified using the human cytokine/chemokine 65-plex array 
(Eve Technologies). This array performs analysis of the following cyto/chemokines: CXCL1, 
CCL1, IFNalpha2, IFNgamma, IL-1alpha, IL-1beta, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-
8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-16, IL-17A, IL-18, IL-20, IL-21, IL-23, 
IL-28a, IL-33, IP-10, LIF, MCP-1, MCP-2, MCP-3, MCP-4, MDC, MIP-1alpha, MIP-1beta, MIP-
1d, PDGF-AA, PDGF-AB/BB, RANTES, SDF-1 a+b, sCD40L, SCF, TARC, TGFalpha, 
TNFalpha, TNFbeta, TPO, TRAIL, TSLP, and VEGF. We envision that subsequent to 
pembrolizumab treatment changes in the cytokine signature combined with changes in the immune 
cell subset signature will define an immune profile that correlates with enhanced anti-tumor 
immunity and prolonged survival.  
Table 4.2 Antibody Panels. 
T, B, NK and 
myeloid cells 
Immune 
suppressive 
myeloid cells 
Checkpoint 
receptors  
T cells (1) 
Checkpoint 
receptors  
T cells (2) 
T 
regulatory 
cells 
Activation 
markers  
T cells 
CD11b 
CD11b 
CD223 
CTLA-4 
CD127 
CD45RA 
CD3 
CD3 
CD3 
CD3 
CD3 
CD3 
CD68 
CD274  
CD279 
CD279 
FoxP3 
CD8 
CD33 
CD33 
CD8 
CD8 
CD25 
CD25 
CD19 
CD273 
LAG 3 
CD39 
CD39 
CD69 
CD56 
CD14 
CD4 
CD4 
CD4 
CD4 
 
 
Clinical Immunology Research Laboratory. 
The Clinical Immunology Research Laboratory (CIRL) is a Clinical Laboratory Improvement 
Amendments (CLIA) certified clinical laboratory specializing in immunodiagnostics.  The 
CIRL currently offers over 30 flow cytometric based assays to evaluate the human immune 
system, and over 2000 samples are processed in the CIRL yearly.  As a clinical reference lab, 
consistent, reproducible, and well-controlled results are not only essential but required by the 
Centers for Medicare and Medicaid Services, the agency that regulates all laboratories testing 
in the United States.  


PROTOCOL 3475-250 
25 | P a g e  
 
 
4.2.3.2.1.2 We will collect serum samples for future exploration of cell free DNA in this population 
as a potential serum biomarker.  
 
Ovarian cancer is typically diagnosed in advanced stages due to its lack of effective screening 
and limited ability to diagnose the disease in its early stages.  Genomic variations are frequently 
found in tumor tissue but determination via tissue is a very costly measure and does not allow 
for the potential benefits of early diagnosis in the setting of ovarian cancer.  It is well known 
that tumor-released DNAs are detectable as cell free DNAs (cfDNAs) in bodily fluids [40-42]. 
Whole genome sequencing has revealed significant DNA copy number variations in tumor 
tissues as well as in cell free DNA plasma of cancer patients.  The collection and analysis of 
cfDNA from circulating blood in patients with cancer diagnoses may provide a means of 
determining the genomic variations present in a patient without direct tumor biopsy.  As a result, 
there has been a growing interest in trying to use tumor-derived cfDNA as a non-invasive 
biomarker to detect the presence of malignancy, follow treatment response, gauge prognosis, or 
monitor for recurrence [43, 44]. The genetic analysis of cfDNA in circulating bodily fluids is often 
referred to as “liquid biopsy” [45-47]. Unlike tissue biopsy, the liquid biopsy is able to capture 
whole landscape of genomic abnormalities derived from both primary and metastatic tumors, 
therefore effectively eliminates heterogeneity issue facing traditional biopsy. In the planned 
future study, we will take advantage of collected plasma from these patients in the trials. Dr. 
Liang Wang, Professor of Pathology, Microbiology and Molecular Genetics at Medical College 
of Wisconsin will analyze the cfDNAs collected from patient plasma samples for copy number 
variations and gene mutations using next generation sequencing technology on plasma samples 
at serial time points during the study. We will correlate the genomic and genetic variations 
discovered in cfDNA with patients’ response to the treatment and clinical outcomes for 
advanced stage ovarian cancer. This study will facilitate the new biomarker discovery for 
monitoring treatment effect and disease progression.  
   
5.0 STUDY DESIGN 
5.1 
Overview of the study 
This is a multi-institutional Phase II single arm, open label, nonrandomized study of 30 patients 
with   suboptimal epithelial ovary cancer where the combination of carboplatin/ paclitaxel/ 
pembrolizumab is followed by maintenance pembrolizumab.  
5.1.1 Rationale for single arm  
The potential pool of patients is limited and with the potential for improving patient outcome it is 
important to complete the study as early as possible.  There is good recent data with historical 
controls.  
5.2 
Diagnosis/condition for Entry into the Trial 
 


PROTOCOL 3475-250 
26 | P a g e  
 
5.2.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
• 
Have advanced stage III/ IV epithelial ovarian, fallopian tube or primary peritoneal cancer 
 
• 
Be willing and able to provide written informed consent/assent for the trial. 
 
• 
Be  18 years of age on day of signing informed consent. 
 
• 
Suboptimal cytoreductive surgery defined as any residual disease noted per operative 
report and/ or have measurable/ macroscopic disease (defined as target and /or non-target 
lesions) based on RECIST 1.1.  
 
• 
Be willing to provide tissue from a newly obtained excisional biopsy of a tumor lesion.  
Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1.  Subjects for whom newly-obtained samples cannot be 
provided (e.g. inaccessible or subject safety concern) may submit an archived specimen 
only upon agreement from the Sponsor. 
 
• 
Have a performance status of 0, 1 or 2 on the ECOG Performance Scale (see Appendix). 
 
• 
Demonstrate adequate organ function as defined in Table 5.1 
 
• 
All screening labs should be performed within 28 days of treatment initiation. Screening 
labs performed within 10 days of treatment initiation can be used for C1D1. If screening 
labs are used for C1D1, serum creatinine must be done within 5 days of C1D1. Female 
subject of childbearing potential should have a negative urine or serum pregnancy within 
72 hours prior to receiving the first dose of study medication.  If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.   
 
• 
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.  Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from 
menses for > 1 year. 
 
• 
Table 5.1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Endocrine 
 
Thyroid function testing (TSH) 
0.350 – 5.500 ulU/mL 
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 
≤1.5 X upper limit of normal (ULN) OR 


PROTOCOL 3475-250 
27 | P a g e  
 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
 
≥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. 
 
5.2.1.1 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
• 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. 
• Has a 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.
 
 
• Has a known history of active TB (Bacillus Tuberculosis) 
 
• 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. 
o Note: Subjects with < Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
o Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
• Has a known additional malignancy within the last 3 years, or that is progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the skin or squamous cell 


PROTOCOL 3475-250 
28 | P a g e  
 
carcinoma of the skin that has undergone potentially curative therapy or in situ cervical 
cancer. 
• Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
• 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.  
• Has an active infection requiring systemic therapy. (Patients with active urinary tract 
infections (UTI) at screening should be treated and a repeat urinalysis should be obtained 
prior to study treatment.) 
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
• Patients with medical history or conditions not otherwise previously specified which in the 
opinion of the investigator should exclude participation in this study. The investigator 
should consult the Study Chair. 
• Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
• Is pregnant or breastfeeding or expecting to conceive children within the projected duration 
of the trial, starting with the pre-screening or screening visit through 120 days after the last 
dose of trial treatment. 
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
• Patients with borderline ovarian tumors, recurrent epithelial ovarian/ primary peritoneal 
cancer/fallopian tube cancer or non-epithelial ovarian cancer are not eligible. 
• 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. 


PROTOCOL 3475-250 
29 | P a g e  
 
5.3 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 5.2. 
 
5.3.1 Dose Selection/Modification 
5.3.1.1 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 are provided in the Pharmacy Manual.   
5.3.1.2 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 
Grade 3-4 hematologic toxicities or Grade 3 non-hematologic toxicities and severe or life-
threatening AEs until resolved to grade 0-1 or as per pembrolizumab guidelines and guidelines for 
carboplatin and paclitaxel.  If drug related toxicity for pembrolizumab or carboplatin or paclitaxel 
is identified, treatment must be held until toxicity resolves to grade 0-1. See pembrolizumab specific 
guidelines and Section 5.3.1.2.1 for guidelines for carboplatin and paclitaxel.  See Section 5.3.9.1.2 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including use 
of corticosteroids. 
Table 5.2.   Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administratio
n 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  
Q21 days 
IV infusion 
Day 1 of each 3-week 
cycle followed by 
maintenance therapy* 
Experimental 
Carboplatin 
AUC 6 
Q21 days 
IV infusion 
Day 1 of each 3-week 
cycle 
Standard 
Paclitaxel 
80 mg/m2 
Q7 days 
IV infusion 
Day 1, 8, 15 of each 
3-week cycle 
Standard 
Paclitaxel 
175mg/m2 
Q21 days 
IV infusion 
Day 1 of each 3-week 
cycle 
Standard 
Docetaxel 
75mg/m2 
Q21days 
IV Infusion 
Day 1 of each 3-week 
cycle 
Standard 
*Maintenance single agent pembrolizumab will be continued day 1 of each 3-week cycle x 12 cycles 
after completion of combination pembrolizumab + standard chemotherapy. 
*If Paclitaxel is discontinued due to toxicity as defined in Section 5.3.1.2.1, upon initiation of 
docetaxel, the carboplatin dose should be reduced by one dose level per institutional standard. 


PROTOCOL 3475-250 
30 | P a g e  
 
Toxicity will be scored using CTCAE Version 5.0 for toxicity and adverse event reporting.  A copy 
of the CTCAE Version 5.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov). 
All adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the patient’s outcome. The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
Any patient whose treatment is delayed must be evaluated on a weekly basis until adequate 
hematologic and non-hematologic parameters have been met. Treatment delays are to be kept to a 
minimum and every effort should be made to maintain the intended schedule. No treatment delays 
are permitted for other than documented toxicity. If delays of greater than three weeks occur, 
patients must be taken off study. 
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, and/or holidays). Subjects 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in the 
patient's study record. 
Table 5.3 Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
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 
Hyperglycemia 
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 
Hyperthyroidism  
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 
Hypothyroidism 
2-4 
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 


PROTOCOL 3475-250 
31 | P a g e  
 
Table 5.3 Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
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 
Hematologic  
3 
Toxicity resolves to grade 0-1 
Permanently discontinue if inability to reduce corticosteroid to 10 
mg or less of prednisone or equivalent per day within 12 weeks. 
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.   
 
5.3.1.2.1 Dose Modification Guidelines for Carboplatin, Paclitaxel and Docetaxel. 
Hematologic Toxicity:  
• Initial treatment modification will consist of cycle delay and/or up to 1 dose level reduction 
of either carboplatin or paclitaxel or both per anticipated tolerance as determined by treating 
physician discretion. 
• Erythropoietin 
use 
is 
permitted 
based 
on 
standard 
clinical 
guidelines 
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandP
roviders/ucm126481.htm). Erythropoietin should not be used in patients with underlying 
venous thromboembolic disease. 
• Patients will not receive prophylactic growth factors (filgrastim, pegfilgrastim) unless they 
experience recurrent neutropenic complications after specified treatment modifications per 
treating physician discretion. 
• Patients may NOT receive amifostine or other protective reagents. 
• Treatment decisions will be based on the absolute neutrophil count (ANC) rather than total 
white cell count (WBC). 
• Subsequent cycles of therapy will not begin until the ANC is > 1500 cells/mm3 and the 
platelet count is >100,000 cells/mm3 for patients on the Q3W therapy. For patients on 
dose-dense (weekly) paclitaxel, subsequent cycles of therapy will not begin until ANC is 
>1000 cells/mm3 and the platelet count is >75,000 cells/mm3. Therapy will be delayed for 
a maximum of 3 weeks until these values are achieved. Patients who fail to recover 
adequate counts within a 4-week delay may be removed from study per discussion with 
the study sponsor. 


PROTOCOL 3475-250 
32 | P a g e  
 
• The day 8 and day 15 paclitaxel dose will not be given unless the ANC is at least 500 
cells/mcl and the platelet count is at least 50,000/ mcl.  If not given those doses are 
omitted and not made up.  If after omission of a dose the subsequent labs again do not 
meet criteria and a second dose requires omission, then chemotherapy should be reduced 
by one dose level. 
• For first occurrence of febrile neutropenia, and/or documented grade 4 neutropenia (ANC 
< 500) persisting > 7 days, reduce chemotherapy by one dose level (Table 5.4) on 
subsequent cycles. 
• For subsequent occurrences of febrile neutropenia, and/or grade 4 neutropenia (ANC < 
500) persisting > 7 days, chemotherapy may be reduced by second dose level and/ or 
growth factors may be initiated at the discretion of the treating provider.   
• Patients with grade 3 thrombocytopenia (< 50,000 cells/mm3) at any time will have a one 
dose level reduction of carboplatin. 
• If dose modified patients experience recurrent delays of > 2 weeks or develop febrile 
neutropenia during subsequent cycles, then G-CSF (Neupogen or Neulasta) should be 
added if the patient is not already receiving G-CSF. 
• If patients on the Q3w pembrolizumab, carboplatin and Qw taxol regimen experience 
continued treatment delays due to treatment related toxicity then consideration to changing 
regimen to Q3w carboplatin/ paclitaxel (or docetaxel) with pembrolizumab should be 
discussed with the sponsor. Dosing of Q3w carboplatin/docetaxel with pembrolizumab 
will be per institutional standard. 
Neuropathy:  
Paclitaxel weekly (Qw) regimen. 
Grade 2 or greater peripheral neuropathy requires reduction of one dose level of paclitaxel and 
delay in therapy for a maximum of 2 weeks until recovered to grade 1.  If > grade 2 neuropathy 
does not resolve to < grade 1 within 2 weeks, discontinue weekly paclitaxel and initiate paclitaxel 
135 mg/m2 q 3 weekly with carboplatin and pembrolizumab according to their next planned 
administration.  Sponsor should be notified if patients require change of regimen. If > grade 2 
neuropathy does not resolve to a grade 1 or less within 2 weeks for a subject on the q 3 week 
paclitaxel at 135 mg/ m2 regimen, discontinue paclitaxel and start subject on q 3 week docetaxel 
75mg/m2 (or per anticipated tolerance per treating physician) starting on day 1 of the next cycle.  
See dose modifications as noted in table 5.4. 
 
Paclitaxel q 3 weekly (Q3w) regimen. 
Grade 2 or greater peripheral neuropathy requires reduction of one dose level of paclitaxel and 
delay in therapy for a maximum of 2 weeks until recovered to grade 1.  If > grade 2 neuropathy 
does not resolve to < grade 1 within 2 weeks, discontinue paclitaxel and start subject on q 3 
weekly docetaxel 75mg/m2 (or per anticipated tolerance per treating physician) starting on day 1 
of the next cycle.  See dose modifications as noted in table 5.4. 
 
Docetaxel q 3 weekly (Q3w) regimen. 


PROTOCOL 3475-250 
33 | P a g e  
 
If while on docetaxel > grade 3 peripheral neuropathy occurs, then delay docetaxel for a 
maximum of 3 weeks until recovery to < grade 1. If peripheral neuropathy fails to recover to < 
grade 1 within 3 weeks, contact study sponsor before discontinuation of docetaxel. 
Hepatic Toxicity: Grade 3 (or greater) elevations in AST, ALT, alkaline phosphatase or bilirubin 
require reduction of one dose level for paclitaxel and delay in subsequent therapy for a maximum 
of 3 weeks until recovered to grade 1.  
Renal toxicity:   
Grade > 2 renal toxicity requires dose reduction of one dose level of carboplatin and delay in therapy 
until recovered to grade 1 for a maximum of 3 weeks.  If delay greater than 3 weeks occurs, the 
Sponsor must be notified and patient will be removed from study. Serum creatinine should be drawn 
with each cycle per flow chart table 6.0 for calculation of creatinine clearance. 
Alopecia: No dose modification will be made for alopecia. 
Fatigue: No dose modification will be made for fatigue grade < 2. 
Gastrointestinal Toxicity: Bowel obstruction: Patients may continue with study treatment for grade 
1 partial obstructions that do NOT require medical intervention.  
> grade 2 GI toxicity requires dose reduction of one dose level of docetaxel. 
Hypersensitivity Reactions: Hypersensitivity reactions should be managed per institutional 
standards. In the event of a hypersensitivity reaction to paclitaxel, docetaxel should be substituted 
for paclitaxel according to institutional guidelines (See table 5.4). 
Management Guidelines for unrelated adverse events: 
For unrelated adverse events, you can hold treatment week by week to evaluate for up to 3 weeks. 
If after 3 weeks, the adverse event is still unresolved, contact the study sponsor for either 
discontinuation from the study or continuation of treatment. If the treatment delays fall on days 8 
or 15 of a treatment cycle, these days will be eliminated for that treatment cycle only.  
 
Table 5.4. Chemotherapy Dosing Modifications 
Study Drug 
Initial Dose Level 
Dose Level -1 
Dose Level -2 
Paclitaxel 
80 mg/m2 
60 mg/m2 
40 mg/m2 
Paclitaxel 
175mg/m2 
150mg/m2 
135mg/m2 
Carboplatin 
AUC 6 
AUC 5 
AUC 4 
Docetaxel* 
75mg/m2 
60 mg/m2 
50 mg/m2 
*Upon initiation of docetaxel, carboplatin dose should be reduced by one dose level. 


PROTOCOL 3475-250 
34 | P a g e  
 
5.3.2 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).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
Patients may be treated up to 8 weeks from cytoreductive surgery but no sooner than 3 weeks from 
surgery. 
All trial treatments will be administered on an outpatient basis. 
5.3.2.1 Pembrolizumab 
Administration 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Day 1 every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Supplier 
Pembrolizumab will be supplied by Merck. 
Formulation 
Two Drug Product (DP) dosage forms are available for pembrolizumab: a white to off-white 
lyophilized powder, 50 mg/vial, and a liquid, DP 100 mg/vial, both in Type I glass vials intended 
for single use only. 
 
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water for 
injection prior to use.  Pembrolizumab is formulated with L-histidine as a buffering agent, 
polysorbate 80 as surfactant, sucrose as a stabilizer/tonicity modifier, and hydrocholoric acid (HCl) 
and /or sodium hydroxide (NaOH) for pH adjustment if necessary. 
 
Pembrolizumab Solution for Infusion 100mg/vial is a liquid DP, and has the identical formulation 
as that of the reconstituted lyophilized vial. 
 
Preparation 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
Storage 
Both drug product dosage forms are stored under refrigerated conditions (2°C - 8°C). 
The product after reconstitution with sterile water for injection and the liquid drug product are a 
clear to opalescent solution which may contain proteinaceous and extraneous particulates. The 
reconstituted lyophilized product and the liquid product are intended for IV administration. The 


PROTOCOL 3475-250 
35 | P a g e  
 
reconstituted DP solution or the liquid DP can be further diluted with normal saline in IV 
containers made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion solution should 
be immediately administered. If not used immediately, vials and/or IV bags may be stored at 2-8 
°C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be 
allowed to equilibrate to room temperature prior to subsequent use. Pembrolizumab solutions may 
be stored at room temperature for a cumulative time of up to 4 hours. This includes room 
temperature storage of reconstituted or liquid DP solution in vials, room temperature storage of 
infusion solution in the IV bag and the duration of infusion. 
 
5.3.2.2 Carboplatin  
Administration 
Carboplatin will be administered at an AUC of 6 over 30-60 minutes Day 1 every 3 weeks. 
Every effort should be made to keep the schedule of chemotherapy administration to every 3 weeks, 
however, occasionally chemotherapy administration may need to be given off schedule due to 
logistical reasons. 
Supplier 
Carboplatin is commercially available  
Formulation 
Carboplatin is supplied as a sterile lypophilized powder available in single-dose vials containing 
50 mg, 150 mg and 450 mg of carboplatin for administration by intravenous infusion. Each vial 
contains equal parts by weight of carboplatin and mannitol. 
 
Preparation 
Immediately before use, the content of each vial must be reconstituted with either sterile water 
for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP, according to 
the following schedule: 
 
Vial strength 
Diluent volume 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
These dilutions all produce a carboplatin concentration of 10 mg/ml. When prepared as directed, 
carboplatin solutions are stable for eight hours at room temperature, since no antibacterial 
preservative is contained in the formulation it is recommended that carboplatin solutions be 
discarded eight hours after dilution. 
 
NOTE: aluminum reacts with carboplatin causing precipitate formation and loss of potency, 
therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must not be used for the preparation or administration of carboplatin. 
 


PROTOCOL 3475-250 
36 | P a g e  
 
Storage 
Unopened vials of carboplatin are stable for the life indicated on the package when stored at 
controlled room temperature and protected from light. 
 
5.3.2.3 Paclitaxel 
Paclitaxel is a poorly soluble plant product from the western yew, Taxus brevifolia. 
Administration 
Paclitaxel at a dose of 80 mg/ m2 will be administered Day 1, Day 8, and Day 15.  Paclitaxel, at 
the appropriate dose and dilution, will be given as a 1-hour continuous IV infusion. Paclitaxel 
will be administered via an infusion control device (pump) using non-PVC tubing and 
connectors, such as the IV administration sets (polyethylene or polyolefin) which are used to 
infuse parenteral Nitroglycerin. Nothing else other than 0.9% sodium chloride is to be infused 
through the line where paclitaxel is being administered. 
*If the provider’s choice is paclitaxel q 3 weekly, paclitaxel will be administered IV over 3 hours 
on day 1 of every 21 day cycle. 
 
Supplier 
Paclitaxel is commercially available.  
Formulation 
Paclitaxel is supplied as a sterile solution concentrate, 6 mg/ml, in 5 ml vials (30 mg/vial) or 17 ml 
vials (100 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% in dehydrated alcohol, 
USP, 50%. Improved solubility requires a mixed solvent system with further dilutions of either 
0.9% sodium chloride or 5% dextrose in water. The contents of the vial must be diluted just prior 
to clinical use. 
Preparation 
Paclitaxel, at the appropriate dose, will be diluted in 500-1000 cc of 0.9% sodium chloride injection, 
USP or 5% dextrose injection, USP (D5W) (500 cc’s is adequate if paclitaxel is a single agent). 
Paclitaxel must be prepared in glass or polyolefin containers due to leaching of 
diethylhexylphthalate (DHEP) plasticizer from polyvinyl chloride (PVC) bags and intravenous 
tubing by the Cremophor vehicle in which paclitaxel is solubilized. 
NOTE: Formation of a small number of fibers in solution (within acceptable limits established by 
the USP Particulate Matter Test for LVPs) have been observed after preparation of paclitaxel. 
Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtration 
should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater 
than 0.22 microns (e.g.: IVEX-II, IVEX-HP or equivalent) into the IV fluid pathway distal to the 
infusion pump. Although particulate formation does not indicate loss of drug potency, solutions 
exhibiting excessive particulate matter formation should not be used. 
Storage 
The intact vials should be stored between 2-25ºC (36-77ºF). 
 
 


PROTOCOL 3475-250 
37 | P a g e  
 
Stability 
Commercially available paclitaxel will be labeled with an expiration date. All solutions of 
paclitaxel exhibit a slight haziness directly proportional to the concentration of drug and the time 
elapsed after preparation, although when prepared as described above, solutions of paclitaxel 
(0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
 
5.3.2.4 Docetaxel 
Docetaxel is a microtubule inhibitor. 
  
Administration 
The final docetaxel dilution for infusion should be administered as a 1 hour intravenous infusion.   
 
All patients should be pre-medicated with oral corticosteroids (such as dexamethasone 8 mg BID) 
for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and 
severity of fluid retention as well as the severity of hypersensitivity reactions 
 
Supplier 
Docetaxel is commercially available. 
 
Formulation 
Docetaxel is supplied in a single dose vial as a sterile, non-pyrogenic, non-aqueous viscous 
solution with an accompanying sterile, non-pyrogenic, diluent (13% ethanol in water) vial.  It is 
supplied in two vial formulations; 20mg/0.5ml or 80mg/2ml of docetaxel.  Docetaxel is also 
supplied as a pre-diluted 10mg/ml concentration in 80mg and 20mg vials. 
 
Preparation 
Using the pre-diluted 10mg/ml formulation:  Aseptically withdraw the required amount of 
docetaxel (10mg/ml) with a calibrated syringe and inject into a 250ml infusion bag of 0.9% 
Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 
mg/mL.  Thoroughly mix the infusion by manual rotation.  Inspect the final product for 
particulate matter or discoloration prior to administration, if it is not clear or appears to have 
precipitation, the product should be discarded. 
 
NOTE: Contact of docetaxel with plasticized PVC equipment or devices used to prepare solutions 
for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP, 
which may be leached from PVC infusion bags or sets, the final docetaxel dilution for infusion 
should be stored in bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags and 
administered through polyethylene-lined administration sets.  
 
Storage 
Store between 2°C and 25°C (36°F and 77°F).  Retain in the original package to protect from 
bright light.  Freezing does not adversely affect the product.   
 
Stability 
Docetaxel final dilution for infusion is stable for 4 hours (including the 1hour intravenous 
administration time) if stored at room temperature, between 2°C and 25°C (36°F and 77°F).  


PROTOCOL 3475-250 
38 | P a g e  
 
Adverse Effects: Consult the package insert for the most current and complete information. 
 
5.3.2.5 Biometric Considerations 
Actual body weight will be used for paclitaxel/docetaxel dose calculations and adjusted body 
weight will be used for carboplatin dose calculations. However, if the Actual Body weight is < Ideal 
Body weight, then use Actual Body weight to calculate the creatinine clearance. 
• The patient’s initial weight will be used to determine the dosing of all agents for the duration 
of the study. If a patient’s weight changes by > 10% during the course of the study, the dose 
for all agents will be recalculated with the new weight per institutional standard. 
 
Dose Calculation 
The patient’s height and weight will be determined at the screening visit. Weight should be obtained 
prior to treatment on day 1 of every treatment cycle. If the patient’s weight changes by greater than 
10% prior to the start of the cycle, then the drug doses will be recalculated. 
• The dose of carboplatin will be calculated using the Calvert Formula using a glomerular 
filtration rate (GFR) from the modified Cockcroft-Gault formula. 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
• For the purposes of this protocol, the GFR is considered to be equivalent to the creatinine 
clearance. The creatinine clearance is calculated by the modified Cockcroft-Gault formula.   
CrCl = [ ((140 - age in years)) x (adjusted body weight in kg)) / (72 x serum creatinine in 
mg/dl))] x 0.85 
• In patients with an abnormally low serum creatinine (less than or equal to 0.6 mg/dl), due to 
reduced protein intake and/or low muscle mass, the creatinine clearance should be estimated 
using a minimum value of 0.6 mg/dl. 
• The maximum absolute dose of carboplatin (AUC 6) given to each patient will be limited to 
900mg.   
 
5.3.3 Sequence 
• On cycle day 1, pembrolizumab should be administered first over 30 minutes followed by 
paclitaxel administration over 1-hour infusion followed by carboplatin as a 30-60 min 
minute infusion last. The regimen can be administered in an outpatient setting.  
• On cycle Day 8 and 15 paclitaxel will be administered over 1 hour in an outpatient setting.   
• During maintenance therapy cycles, single agent pembrolizumab will be administered 
over 30 minutes. 
 
*Patients who experience a hypersensitivity reaction to paclitaxel or toxicity (see section 5.3.1.2.1) 
may be switched to docetaxel per investigator’s discretion. 
*Paclitaxel and Carboplatin reactions will be managed according to each individual institution’s 
approved Standard of Care guidelines. 
 


PROTOCOL 3475-250 
39 | P a g e  
 
*Please discuss prevention of hypersensitivity reactions to Carboplatin in patients receiving more 
than 6 cycles of carboplatin, with the study sponsor.  
 
Table 5.5 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of pembrolizumab. 
 
5.3.4 Paclitaxel Ancillary Medications 
Dexamethasone (20 mg po or 12 mg IV or equivalent) administered 30 minutes prior to 
paclitaxel.  Steroids administered for paclitaxel premedication are allowed per protocol with 
pembrolizumab administration.   
• Diphenhydramine (25 mg IV) (or equivalent) 30 minutes prior to paclitaxel. 
• Famotidine (or equivalent) (20 mg IV) 30 minutes prior to paclitaxel. 
• An antiemetic regimen containing a 5HT-3 antagonist (ondansetron, granisetron, or 
palonosetron) is recommended. 
 
*Docetaxel Pre-medications: It is recommended that patients be pre-medicated with 
dexamethasone 8mg orally taken the night before, morning of and evening after each treatment. 
5.3.5 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered. 
5.3.6 Randomization or Treatment Allocation 
This is a single arm open label trial.   
5.3.7 Stratification 
There is no stratification. 
5.3.8 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.  
5.3.8.1 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 


PROTOCOL 3475-250 
40 | P a g e  
 
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 
(Medication received by the subject for surgery related to study indication may be excluded) 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. 
5.3.8.2 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 or to the brain may be allowed 
at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than chemotherapy premedications or to 
modulate symptoms from an event of clinical interest of suspected immunologic etiology.  The 
use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.3.9 Rescue Medications & Supportive Care 
5.3.9.1 Adverse Events and Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below 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 


PROTOCOL 3475-250 
41 | P a g e  
 
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 5.3 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document in section 5.3.9.1.2. 
 
Table 5.5 Potential expected adverse reactions with pembrolizumab therapy. 
System Organ Class 
Adverse Event Term 
-    Endocrine disorders 
-    Adrenal insufficiency 
-    Endocrine disorders 
-    Hyperthyroidism 
-    Endocrine disorders 
-    Hypophysitis 
-    Endocrine disorders 
-    Hypopituitarism 
-    Endocrine disorders 
-    Hypothyroidism 
-    Endocrine disorders 
-    Secondary adrenal insufficiency 
-    Endocrine disorders 
-    Thyroid disorder 
-    Eye disorders 
-    Uveitis 
-    Gastrointestinal disorders 
-    Abdominal pain 
-    Gastrointestinal disorders 
-    Colitis 
-    Gastrointestinal disorders 
-    Diarrhea 
-    Gastrointestinal disorders 
-    Pancreatitis 
-    General disorders and administration site conditions 
-    Asthenia 
-    General disorders and administration site conditions 
-    Pyrexia 
-    Hepatobiliary disorders 
-    Autoimmune hepatitis 
-    Hepatobiliary disorders 
-    Hepatitis 
-    Injury, poisoning and procedural complications 
-    Infusion related reaction 
-    Metabolism and nutrition disorders 
-    Diabetic ketoacidosis 
-    Metabolism and nutrition disorders 
-    Hyponatremia 
-    Metabolism and nutrition disorders 
-    Type 1 diabetes mellitus 
-    Musculoskeletal and connective tissue disorders 
-    Arthralgia 
-    Musculoskeletal and connective tissue disorders 
-    Back pain 
-    Musculoskeletal and connective tissue disorders 
-    Myositis 
-    Nervous system disorders 
-    Guillain-Barré syndrome 
-    Renal and urinary disorders 
-    Nephritis 
-    Respiratory, thoracic and mediastinal disorders 
-    Cough 
-    Respiratory, thoracic and mediastinal disorders 
-    Pneumonitis 
-    Skin and subcutaneous tissue disorders 
-    Pruritus 
-    Skin and subcutaneous tissue disorders 
-    Rash 
-    Skin and subcutaneous tissue disorders 
-    Severe skin reaction 
-    Skin and subcutaneous tissue disorders 
-    Vitiligo 


PROTOCOL 3475-250 
42 | P a g e  
 
 
 
5.3.9.1.2 Events of Clinical Interest (ECI) Reporting and ECI Treatment Guidelines 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, thyroid disorders (hypothyroidism/hyperthyroidism), hepatitis, hypophysitis, Type I 
diabetes mellitus, uveitis, and nephritis. After a recent review of data, events newly characterized 
as identified risks also include pancreatitis, myositis, and severe skin reaction; these are included 
in the reference safety information below. The majority of immune-mediated adverse events 
were mild to moderate in severity, were manageable with appropriate care, and rarely required 
discontinuation of therapy.  Further details around frequency, reporting, and management of 
immune-related adverse events (irAEs) are specifically described below. In addition to the 
previously noted identified risks, infusion-related reactions are a risk but are not considered 
immune mediated; these are further described below. 
 
Immune-related adverse reactions. 
  An irAE is defined as a clinically significant AE of any organ that is associated with study drug 
exposure, is of unknown etiology, and is consistent with an immune-related mechanism. The most 
commonly reported immune-related adverse events across the dose schedules are hypothyroidism 
(7.2%), pneumonitis (2.9%), hyperthyroidism (2.2%), colitis (1.3%) and skin 
AEOSI (1.3% including all terms).  
 
 
Table 5.6 Frequency of immune-related adverse reactions 
 
Pembrolizumab 
2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks 
n=2117 
Adverse Reaction 
All Grades 
(%) 
Grade 2 
(%) 
Grade 3 
(%) 
Grade 4 
(%) 
Grade 5 
(%) 
Hypothyroidism 
7.8 
5.9 
0.1 
0 
0 
Hyperthyroidism 
2.9 
0.6 
0.1 
0 
0 
Pneumonitis 
2.4 
0.9 
0.6 
0.1 
<0.1 
Colitis 
1.7 
0.4 
1.7 
0.1 
0 
Hepatitis 
0.8 
0.1 
0.5 
0.1 
0 
Hypophysitis 
0.7 
0.2 
0.3 
<0.1 
0 
Nephritis 
0.3 
0.1 
0.1 
<0.1 
0 
Diabetes Mellitus 
0.1 
<0.1 
<0 
<0.1 
0 
 
 
 
 


PROTOCOL 3475-250 
43 | P a g e  
 
 
 
Table 5.7: 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 corticosteroids cannot be reduced to <10mg 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 
(CTCAEv5.0) 
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 1-2mg/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. 
Diarrhea/Colitis 
Grade 2 or 3 
Withold 
• Administer 
corticosteroids (initial 
dose 1-2mg/kg 
prednisone or 
equivalent) followed 
by taper 
• Monitor participants for 
signs and symptoms of 
enterocolitis (i.e diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation (i.e 
peritoneal signs andileus). 
• 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 
AST/ALT elevation 
or Increased 
bilirubin 
Grade 2 
Withold 
• Administer 
corticosteroids (initial 
dose of 0.5-1mg/kg 
prednisone or 
• Monitor with liver function 
tests (consider weekly or 
more frequently until liver 


PROTOCOL 3475-250 
44 | P a g e  
 
equivalent) followed 
by taper 
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 β-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 
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 


PROTOCOL 3475-250 
45 | P a g e  
 
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).   
 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 
hours of the event: 
 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 
– Hemolytic Uremic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. 
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, 
bone marrow biopsy or Coomb’s test, etc., should be considered to confirm the diagnosis. 
However, the AE should be reported regardless of etiology. 
 
 
Infusion Reactions:  
Table 5.7 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. 
Report as ECI 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
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). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 


PROTOCOL 3475-250 
46 | P a g e  
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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. 
Report as ECI. 
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. 
 
 
Follow-up to Resolution 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with 
information regarding duration and clinical course of the event. Information obtained from the 
consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-
text fields should be used to record narrative information: 
– Clinical course of the event 
– Course of treatment 
– Evidence supporting recovery 
– Follow-up to the clinical course 
Any treatments administered for the event should also be entered in the Concomitant Medication 
eCRF. 
 


PROTOCOL 3475-250 
47 | P a g e  
 
5.3.10 Diet/Activity/Other Considerations 
5.3.10.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.3.10.2 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  
Reporting of Pregnancy and Lactation to the Sponsor and to Merck.  If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.3.11 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours 
to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in Section 
7.2.2. 


PROTOCOL 3475-250 
48 | P a g e  
 
5.3.11.1 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. 
5.3.12 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in 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 7.1.2.7. 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
7.1.2. 
• Unacceptable adverse experiences as described in Section 5.3 
• 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 planned study protocol. 
• 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 7.2.3.1).  Subjects who discontinue for reasons other 
than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.   
 
5.4 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
and completed 12 cycles (36 weeks) of IV pembrolizumab maintenance therapy.   


PROTOCOL 3475-250 
49 | P a g e  
 
5.5 
Subject Replacement Strategy.  None 
5.6 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made.


PROTOCOL 3475-250 
 
 
 
 
50 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
Additional 
Cycles (per 
treating 
physician’s 
discretion) 
Maintenance 
Therapy 
 Begins 3 weeks after 
completion of 
combination 
chemotherapy  
 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
  
 
2 
 
 
 
 
 
 
 
12 Cycles  
(every 3 weeks = 1 
cycle)  
 
Safety 
Follow-up 
Follow Up 
Visits n 
Survival 
Follow-Up o 
3 
4 
5 
6 
 
7 
 
8 
 
9 
 
Scheduling Window 
(Days): 
-28  
 
Day 
8 i 
Day 
15i 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
+ 3 
 
 
+ 3 
 
 
+ 3 
+ 7 days 
 
30 days (± 7 
days) post 
discontinue 
Every 12 weeks 
(+14 days) post 
discontinue 
Every 4-6 
months  
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Trial Treatment 
Administration 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer 
therapy status k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures/Assessments 


PROTOCOL 3475-250 
 
 
 
 
51 
 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
Additional 
Cycles (per 
treating 
physician’s 
discretion) 
Maintenance 
Therapy 
 Begins 3 weeks after 
completion of 
combination 
chemotherapy  
 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
  
 
2 
 
 
 
 
 
 
 
12 Cycles  
(every 3 weeks = 1 
cycle)  
 
Safety 
Follow-up 
Follow Up 
Visits n 
Survival 
Follow-Up o 
3 
4 
5 
6 
 
7 
 
8 
 
9 
 
Scheduling Window 
(Days): 
-28  
 
Day 
8 i 
Day 
15i 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
+ 3 
 
 
+ 3 
 
 
+ 3 
+ 7 days 
 
30 days (± 7 
days) post 
discontinue 
Every 12 weeks 
(+14 days) post 
discontinue 
Every 4-6 
months  
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Full Physical Examination 
X 
X p 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs and Weight l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECOG Performance Status 
 
X p 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or 
Serum -HCG 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
CBC with Differential 
X 
X m 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
CA125 
X 
X m 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Comprehensive Serum 
Chemistry Panel 
X 
X m 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Xb 
 
X 
 
 
Efficacy Measurements 


PROTOCOL 3475-250 
 
 
 
 
52 
 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
Additional 
Cycles (per 
treating 
physician’s 
discretion) 
Maintenance 
Therapy 
 Begins 3 weeks after 
completion of 
combination 
chemotherapy  
 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
  
 
2 
 
 
 
 
 
 
 
12 Cycles  
(every 3 weeks = 1 
cycle)  
 
Safety 
Follow-up 
Follow Up 
Visits n 
Survival 
Follow-Up o 
3 
4 
5 
6 
 
7 
 
8 
 
9 
 
Scheduling Window 
(Days): 
-28  
 
Day 
8 i 
Day 
15i 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
+ 3 
 
 
+ 3 
 
 
+ 3 
+ 7 days 
 
30 days (± 7 
days) post 
discontinue 
Every 12 weeks 
(+14 days) post 
discontinue 
Every 4-6 
months  
Tumor Imagingc 
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection 
Archival or Newly 
Obtained Tissue Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
 
Correlative Studies Blood Collection  
 Immune studies blood 
collection 
X 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
X q 
Xj 
Xj 
Biomarker blood collection 
X 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
X q 
Xj 
Xj 
Quality of Life Survey 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Xg 
 
X 
Xh 
 
 
 
Key: 
a: Obtain for women of childbearing potential. 
b. Thyroid function tests to be obtained every 2nd cycle while on pembrolizumab 


PROTOCOL 3475-250 
 
 
 
 
53 
 
c: CT scan of abdomen/ pelvis with contrast (if contrast clinically feasible) to be performed.  CT of the chest if clinically applicable. 
d: CT chest/abdomen/ pelvis with contrast (if contrast clinically feasible) should be done at the completion of combination therapy 
(prior to start of maintenance therapy), at the end of maintenance therapy (prior to safety follow-up) and if clinically indicated.  
 
*NOTE: If a patient has not attained a normalized CA-125 value and /or a patient has stable disease or partial response on CT imaging 
at the completion of 6 cycles of combination therapy, the patient may continue to receive combination therapy for up to 9 cycles (per 
treating physician’s discretion). A CT scan should be obtained prior to the start of maintenance therapy. 
 
e: If new tissue available from histologic confirmation of recurrent disease through tissue block. 
f: Immune panel and biomarker blood will be collected after completion of combination therapy before onset of maintenance therapy (i.e. 
Prior to treatment maintenance Cycle 1), after 6 cycles of maintenance therapy and at the completion of maintenance therapy 
g: Quality of life survey to be done Cycle 7 Day 1 of maintenance therapy and at the safety follow-up visit. 
h: QOL survey will be obtained at one final point at approximately 6 months after completion of maintenance therapy (i.e. at follow-
up visit 2). 
i:  Day 8 and Day 15 flow chart specifications apply to all cycles with weekly paclitaxel. 
j:  At every follow-up and Survival follow-up visit and at the time of recurrence or suspected recurrence. 
k: Subjects should be followed for survival and post study anticancer therapy until new anticancer drug therapy begins.  
l:  Weight will only be collected on Day 1 of each Treatment Cycle. Both Height and Weight should be collected at screening. 
m: Cycle 1 Day 1 safety labs do not need to be repeated if screening labs were done within 10 days of treatment initiation. Serum 
creatinine should be obtained no more than 5 days prior to the start of treatment.   
n: Follow Up: Every 12 weeks (±14 days) post discontinuation for up to 24 months. 
o: Survival Follow-Up: Every 4-6 months for up to 36 months. Note: Patients who do not progress during the survival follow-up will 
continue to be followed for overall survival via phone calls and/or chart until disease progression, death, withdrawal of consent or 
lost to follow-up. 
p: Screening physical examinations and ECOG performance status do not need to be repeated if done within 10days of treatment 
initiation. 
q: Immune studies blood collection and Biomarker blood collection should be collected at the safety follow-up visit if patient 
discontinues for any reason other than disease progression or recurrence. 


PROTOCOL3475-250 
 
 
 
 
54 
 
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 Sponsor 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 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 


PROTOCOL3475-250 
 
 
 
 
55 
 
7.1.1.2 Site Activation and Subject Enrollment 
7.1.1.2.1 Once the IRB approval is received at the coordinating site (MCW), Sponsor 
Investigator will inform Merck and the participating site. Participating site must 
submit the most current protocol, informed consent forms and other documents as 
prepared and submitted by the MCW site to their respective IRB. Informed 
consent language may vary based on the requirements of the local IRB of each 
site. A site initiation visit (SIV) will be conducted via teleconference to train the 
study staff at both sites and to discuss important milestones.  An initial in person 
visit may also be necessary for initial training. 
7.1.1.2.2 Screening will be performed for potential study patients after they have consented 
to trial participation. If a patient is screened - regardless of whether or not they are 
registered to the study – their details should be entered into the MCW Oncore 
CTMS.  The Participating Institution will receive Oncore CTMS training from the 
MCW Oncore CTMS Administrator. The Coordinating Site will conduct monthly 
conference calls to discuss any ongoing questions or concerns regarding the 
conduct of the study. Patients will receive a screening ID that will be used to 
identify the patient throughout the study. At this time patients will be considered 
registered on the study.  
7.1.1.2.3 Documentation of both the informed consent process and that the process occurred 
prior to a subject’s entry into this study is recorded in the subject’s source 
documents. The original consent form, signed and dated by the subject and by the 
person consenting the subject prior to the subject’s entry into the study, must be 
maintained in the investigator’s study files at each participating institution.  
7.1.1.2.4 Participating Sites will upload all de-identified source documents with patient 
study IDs confirming patient eligibility into Oncore CTMS. The coordinating 
center will review all documents and confirm eligibility.   
7.1.1.2.5 Enrollment.  Patients will be considered enrolled in the study once the 
coordinating site has confirmed that all screening eligibility criteria have been met. 
7.1.1.3 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.  
7.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered 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.   


PROTOCOL3475-250 
 
 
 
 
56 
 
7.1.1.5 Prior and Concomitant Medications Review 
7.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.6 Disease Details and Treatments 
7.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.   


PROTOCOL3475-250 
 
 
 
 
57 
 
7.1.1.7 Assignment of Screening Number   
Unique number will be generated at each site corresponding to site designation assignment 
and then numerically according to the order in which patient was screened. 
7.1.1.8 Assignment of Randomization Number:  None. 
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other)   
Assessment will be made prior to each cycle as noted in Trial Flow Chart Section 6.0.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
Each participating site will be responsible for adverse event assessing and reporting to the 
respective site IRBs. Each serious unexpected event must be reported to the Sponsor-
Investigator within 24 hours as specified in the protocol. The Sponsor-investigator will further 
evaluate the event and report to regulatory agencies. 
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 5.0 (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).  The principle investigator may report any event considered as potentially 
immune related as an event of clinical interest regardless of the listed events of clinical interest 
listed in the ECI guidelines. 
A member of the study staff from each site should complete the SAE eCRF within 24 hours 
of learning of the event and email (uyarIITMerck3475-250@mcw.edu) or fax (414-805-
6622) the completed form signed by the site investigator to the Medical College of 
Wisconsin.  
 
The initial SAE should be followed until resolution and updated in the SAE eCRF. Follow-
up SAE information is sent to the same contacts listed above. Each site is responsible for 
reporting SAEs to their local Institutional Review Board per institutional guidelines. 
 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  Please refer to section 5.3.9.1 for information regarding identification and management 
of irAEs and ECIs. 


PROTOCOL3475-250 
 
 
 
 
58 
 
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 (Section 6.0), the 
investigator or qualified designee will perform a directed physical exam as clinically indicated 
prior to trial treatment administration.   
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, and blood pressure.  Weight will be collected on Day 1 of each Treatment Cycle. 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 at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart (Section 6.0). 
7.1.2.6 Functional assessment of Cancer Therapy –Ovary Trial of Outcome Index 
(FACT-O TOI) 
This 26 item summary score captures the FACT- General (FACT-G) QOL dimensions of 
Physical Well-Being (7 items), Functional Well-Being (7 items), and the Ovarian Cancer 
subscale (12 items).  By combining these three subscales, we are assured of including the full 
range of physical aspects of QOL in advanced EOC [32].  
7.1.2.7 Tumor Imaging and Assessment of Disease 
Completion of combined carboplatin, paclitaxel and pembrolizumab therapy 
Patients must have in the opinion of the investigator, clinical complete response or partial 
response and have no evidence of disease progression on the post-treatment scan or a rising 
CA 125 level following completion of this initial regimen to proceed to maintenance therapy.    
Parameters of Response-RECIST 1.1 Criteria [29] 
Measurable disease is defined as at least one lesion that can be accurately measured in at 
least one dimension (longest dimension to be recorded). Each lesion must be 20 mm when 
measured by conventional techniques, including plain x-ray, CT, and MRI, or 10 mm when 
measured by spiral CT. 
 


PROTOCOL3475-250 
 
 
 
 
59 
 
Baseline assessment 
Baseline documentation of ‘Target’ and ‘Non-Target’ lesions. All measurable lesions up to 
a maximum of 5 lesions per organ and 10 lesions in total representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the longest dimension) and 
their suitability for accurate repetitive measurements by one consistent method of assessment 
(either by imaging techniques or clinically).  A sum of the longest dimension (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD 
will be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease. 
 
All other lesions (or sites of disease) should be identified as Non-Target lesions and should 
also be recorded at baseline.  Measurements are not required, and these lesions should be 
followed as “present” or “absent”. All baseline evaluations of disease status should be 
performed as close as possible to the start of treatment and never more than 4 weeks 
before the beginning of treatment. 
 
Best Response 
 Measurement of the longest dimension of each lesion size is required for follow-up. Change 
in the sum of these dimensions affords some estimate of change in tumor size and hence 
therapeutic efficacy. All disease must be assessed using the same technique as baseline. 
Reporting of these changes in an individual case should be in terms of the best response 
achieved by cases since entering the study. 
 
Complete Response (CR) is disappearance of all target and non-target lesions and no 
evidence of new lesions documented by two disease assessments at least 4 weeks apart.  
Normalization of CA125, if elevated at baseline, is required for ovarian carcinoma studies. 
 
Partial Response (PR) is at least a 30% decrease in the sum of longest dimensions (LD) of 
all target measurable lesions taking as reference the baseline sum of LD.  There can be no 
unequivocal progression of non- target lesions and no new lesions.  Documentation by two 
disease assessments at least 4 weeks apart is required.  In the case where the ONLY target 
lesion is a solitary pelvic mass measured by physical exam, which is not radiographically 
measurable, a 50% decrease in the LD is required. 
 
Increasing disease is at least a 20% increase in the sum of LD of target lesions taking as 
references the smallest sum LD or the appearance of new lesions within 8 weeks of study 
entry.  Unequivocal progression of existing non-target lesions, other than pleural effusions 
without cytological proof of neoplastic origin, in the opinion of the treating physician within 
8 weeks of study entry is also considered increasing disease (in this circumstance an 
explanation must be provided).  In the case where the ONLY target lesion is a solitary pelvic 
mass measured by physical exam, which is not radiographically measurable, a 50% increase 
in the LD is required. 
 


PROTOCOL3475-250 
 
 
 
 
60 
 
Stable Disease is any condition not meeting the above criteria.  Patients with a stable disease 
response or better (CR, PR) will be eligible to continue onto maintenance therapy with 
pembrolizumab. 
 
Inevaluable for response is defined as having no repeat tumor assessments following 
initiation of study therapy for reasons unrelated to symptoms or signs of disease. 
 
Progression (measurable disease studies) is defined as ANY of the following: 
 
• At least a 20% increase in the sum of LD target lesions taking as reference the 
smallest sum LD recorded since study entry. 
• In the case where the ONLY target lesion is a solitary pelvic mass measured by 
physical exam which is not radiographically measurable, a 50% increase in the LD 
is required taking as reference the smallest LD recorded since study entry. 
o The appearance of one or more new lesions. 
• Death due to disease without prior objective documentation of progression. 
• Global deterioration in health status attributable to the disease requiring a change in 
therapy without objective evidence of progression. 
• Unequivocal progression of existing non-target lesions, other than pleural effusions 
without cytological proof of neoplastic origin, in the opinion of the treating 
physician (in this circumstance an explanation must be provided). 
 
Recurrence (non-measurable disease studies) is defined as increasing clinical, 
radiological or histological evidence of disease since study entry. 
 
7.1.2.7.1 Survival Times 
Survival time is the observed length of life from entry into the study (first dose of therapy) to 
death or the date of last contact. 
 
Progression-Free Survival (measurable disease studies) time is the period from study entry 
(first dose of therapy) until disease progression, death or date of last contact. PFS will be 
censored at the last assessment of disease progression for living patients. 
Recurrence-Free Survival (non-measurable disease studies) time is the period from 
study entry (first dose of therapy) until disease recurrence, death or date of last contact. 
 
Overall Survival (OS) time will be defined as observed length of life from entry into the 
protocol (first dose of therapy) to death, or for living patients, date of last contact (regardless 
of whether or not this contact is on a subsequent protocol). Patients who do not progress 
during the survival follow-up will continue to be followed for overall survival via phone calls 
and/or chart until disease progression, death, withdrawal of consent or lost to follow-up. 
Progression-Free Interval (PFI) time will be defined as date from entry onto the protocol 
(first dose of therapy) to the date of clinical or radiologic evidence of progressive disease. 
 


PROTOCOL3475-250 
 
 
 
 
61 
 
7.1.2.7.2 Subjective measurements 
Subjective Parameters including performance status, specific symptoms, and side effects 
are graded according to the CTC. 
 
7.1.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Archival tissue will be utilized, and correlative blood sampling will be performed according to 
Section 4.2.3.2 and will be collected according to Trial Flow Chart Section 6.0. 
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 7.1.   


PROTOCOL3475-250 
 
 
 
 
62 
 
Table 7.1 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
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. 
 
 
 


PROTOCOL3475-250 
 
 
 
 
63 
 
Laboratory tests for screening should be done within 28days of treatment initiation. Screening 
laboratory tests done within 10 days of treatment initiation can be used for C1D1. Laboratory 
tests done within 10 days prior to entry into the Second Course Phase (maintenance phase) can 
be used for D1 of the maintenance phase.  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.  
7.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations.  None 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete planned maintenance treatment 
with pembrolizumab may discontinue treatment.  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). 
7.1.4.2 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:  Estimated period for screening and enrollment is 18 months. 
7.1.5.2 Treatment Period:  Treatment period is estimated to be 48 months. 
7.1.5.3 Post-Treatment Visits:  The initial post treatment visit will occur at 4 weeks (+ 7 
days) post completion of all therapy and may coincide with Safety Follow-Up Visit 
detailed below. 
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 


PROTOCOL3475-250 
 
 
 
 
64 
 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.   
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 clinically assessed every 12 weeks (± 14 days) to 
monitor disease status.  For the first 2 years the clinical assessment time point will occur every 
12 weeks (± 14 days). After 2 years the clinical assessment time point will change to every 4-
6 months. Every effort should be made to collect information regarding disease status until the 
start of a new anti-neoplastic therapy, disease progression, death, or end of the study.  
Information regarding post-study anti-neoplastic treatment will be collected if new treatment 
is initiated. 
7.1.5.4.1 Survival Follow-up 
Progression of disease or recurrence is defined as increasing clinical, radiological or 
histological evidence of disease.  Patients with progression of disease based on clinical or 
histological basis must also have a CT scan performed for further confirmation.  CT scan may 
be performed at discretion of investigator if recurrent or progression of disease or symptoms 
warrant evaluation.  Progression will not be defined as rising CA 125 alone.   
Progression free survival (PFS) will be defined as of study entry (first dose of therapy) to the 
date of first clinical or radiological evidence of progression or death due to any cause.  PFS 
will be censored at the last assessment of disease progression for living patients. 
Overall survival (OS) will be defined as observed length of life from entry into the protocol 
(first dose of therapy) to death due to any cause, or for living patients, date of last contact or 
completion of study. Patients who do not progress during the survival follow-up will 
continue to be followed for overall survival via phone calls and/or chart until disease 
progression, death, withdrawal of consent or lost to follow-up. 
  
Visit requirements are outlined in Section 6.0 – Trial Flow Chart 6.1. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 


PROTOCOL3475-250 
 
 
 
 
65 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
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 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. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose > 20% of 
the recommended 200 mg dose for pembrolizumab.  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed closely 
for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
Definition of overdose of carboplatin:   


PROTOCOL3475-250 
 
 
 
 
66 
 
The GFR used in the Calvert formula to calculate AUC-based dosing should not exceed 125 
mL/min.  Maximum carboplatin dose (mg) should not exceed target AUC (mg x min/mL) x 
150 mL/min.  In trials with AUC of 6 this would result in a maximum dose of 900 mg.   
Definition of overdose for paclitaxel:  
There is no established threshold identified as an overdose for paclitaxel.  
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 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 7.2 for additional details regarding each of the above criteria. 


PROTOCOL3475-250 
 
 
 
 
67 
 
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 other than progression of the cancer under study 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 product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck 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 Sponsor 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. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and 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 Sponsor and to Merck, 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.* 


PROTOCOL3475-250 
 
 
 
 
68 
 
*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: 
 
ECIs (both non-serious and serious adverse events) identified in Section 5.3.9.1 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 24 
hours to the Sponsor and 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. 
 
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. 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. 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. 


PROTOCOL 3745-250 
 
 
 
 
69 
 
Table 7.2 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V5.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: 
This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for 
an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 
An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action 
taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation 


PROTOCOL 3745-250 
 
 
 
 
70 
 
with the components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event 
(AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host 
or environmental factors 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck 
product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT 
POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST 
BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug 
class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best 
clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product 
relationship). 


PROTOCOL 3745-250 
 
 
 
 
71 
 
 
 
 
 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration 
of the Merck product is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck 
product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without 
an associated AE.) 


PROTOCOL 3475-250 
 
 
 
 
72 
 
7.2.4.1 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations at each institution. 
Serious adverse events experienced after signing consent should be reported according to the 
institution’s IRB and regulatory authorities as well as the Medical College of Wisconsin if the 
investigator suspects a causal relationship to study treatment. 
7.2.5 Trial Monitoring/ Quality Assurance 
7.2.5.1 Study Monitoring will be conducted by the CTSI’s Clinical Trial office, which will 
be responsible for ongoing oversight, monitoring, source documentation 
confirmation, protocol compliance, adverse events, etc. The MCW Principal 
Investigator will have access to the study data for all of the patients entered onto this 
study. Data storage is carried out according to MCW Institutional Policy.   The 
MCW Principal Investigator will oversee the conduct of the study. 
7.2.5.2 Quality Assurance 
•The study will be reviewed annually by MCW.  
• 10% of subject files will be selected randomly for review (max 10 subjects at each 
monitoring timepoint).  
• Consent/eligibility and objective based data will be reviewed for those files selected  
• 1 file will be selected randomly for a comprehensive review at each monitoring time point.  
 
After each QA review, a letter/report will be provided to the study staff and the DSMC. 
Necessary corrective action or training will be provided to the staff as needed throughout and 
following each QA review. Directed audits may be requested at any time by the CCCTO QA 
Staff, DSMC, Research Manager, study staff member, or administrative staff. 
 
8.0 STATISTICAL CONSIDERATIONS 
 
8.1 
 Planned Efficacy Evaluations 
8.1.1 Primary Efficacy Variables 
The primary efficacy variable is progression free survival for suboptimally cytoreduced Stage 
III/IV ovarian cancer with combination platinum based chemotherapy and anti-PD-1 therapy 
followed by maintenance anti-PD-1 therapy compared to historical controls. 
Progression of disease or recurrence is defined as increasing clinical, radiological or 
histological evidence of disease as defined in 7.1.2.7. Patients with progression of disease 


PROTOCOL 3475-250 
 
 
 
 
73 
 
based on clinical or histological basis must also have a CT scan performed for further 
confirmation.  CT scan may be performed at discretion of investigator if recurrent or 
progression of disease or symptoms warrant evaluation.   
Time to progression free survival (PFS) will be defined as date of completion of primary 
therapy to the date of first clinical, biochemical, or radiological evidence of progression or 
death due to any cause or to data of last assessment.  PFS will be censored at the last assessment 
of disease progression for living patients. 
8.1.2 Secondary Efficacy Variables 
• Overall survival for suboptimally cytoreduced Stage III/IV ovarian cancer with 
combination platinum based chemotherapy and anti-PD-1 therapy followed by 
maintenance anti-PD-1 therapy compared to historical controls. 
• Quality of life on maintenance anti-PD-1 therapy as measured with QOL (FACT-O) 
surveys at intervals during therapy as noted in Trial Flow Chart (Section 6.0). 
8.1.3 Biomarker variables 
• The relationship of survival to the tumor microenvironment at the time of diagnosis for 
patients with suboptimally cytoreduced ovarian cancer using immunohistochemistry 
(IHC) staining for antibodies of PD-1 and PD-L1 in paraffin embedded tissue of tumor 
obtained at the time of their initial surgery  
• The relationship of survival and serial immune profiles from blood samples obtained 
post-surgery, prior to initiation of chemotherapy and during anti-PD-1 maintenance 
therapy.   
 
8.2 
Planned populations for study 
8.2.1 Safety population 
The safety population will consist of all patients who have received at least one dose of 
study medication, whether withdrawn prematurely or not.  
 
8.2.2 Analysis Population 
8.2.2.1 The observed cases (OC) 
This will include all  patients must have undergone tumor assessment at baseline, received at 
least the first cycle of pembrolizumab in combination with first line platinum based 
chemotherapy, and must have had at least one post-dose tumor assessment.  
This population (OC) will be the primary population for all analyses of primary and 
secondary efficacy variables of the observed cases (i.e. the actual assessments at each 
visit). 
 


PROTOCOL 3475-250 
 
 
 
 
74 
 
8.2.2.2 The completers population (CS) 
This will include the subset of OC who completed all treatments. 
8.2.2.3 Per-protocol population 
The per-protocol population will be defined as the subset of the OC who completed all 
treatments and who did not have any major protocol violations (such as lack of compliance to 
the study medication schedule). The definitions of these protocol violations will be finalized 
before the database closure and will be documented in the analysis plan.  
8.3 
Statistical Analysis 
8.3.1 Patient Demographics and Characteristics Data 
To evaluate comparability between study patients and historical controls regarding patient 
characteristics at baseline, demographic and disease characteristics will be summarized using 
descriptive statistics. In addition, previous and concomitant diseases and medications will be 
summarized by treatment group to assess comparability between the groups. 
All information will be listed by group (study or historical) and patient, and will be 
summarized. Frequencies will be presented for the categorical variables (e.g. race) and 
descriptive statistics will be presented for continuous variables (e.g. weight, age). 
8.3.2  Efficacy Variables 
8.3.2.1 Statistical Method 
All efficacy data will be analyzed including CS patients. Per-protocol analysis will be done 
only if more than 10% of the CS patients do not qualify for the per-protocol analysis. For all 
efficacy variables, the baseline value will be defined as the last value taken prior to the start of 
the first study medication. 
8.3.2.2 Continuous Variables 
8.3.2.2.1 Survival 
 The efficacy parameters of survival will be analyzed using Kaplan Meier curves stratified by 
group where the groups are compared using a log rank sum test.  
8.3.2.2.1.1 Additional Analysis 
In addition to the above described primary analysis, the following analysis will be done. 
 
1.  As a supportive model a Cox proportional hazard model with clinical covariates such 
as interruption or not and age if the model is appropriate. If it is not appropriate, other 
models which do not assume proportionality will be investigated.  
 


PROTOCOL 3475-250 
 
 
 
 
75 
 
8.3.2.2.2 QOL 
QOL will be analyzed using a mixed effects covariance pattern model to utilize all the data 
collected over time with consideration of the variance-covariance matrix of the repeated 
measures. This method allows a general unstructured variance-covariance matrix and allows 
patients to have incomplete data across scheduled time points. The method applied is also 
known as mixed-effects repeated measures analyses (MMRM). 
The primary model will include independent variables of the fixed, categorical effects of 
assessment visit, along with the continuous effects of baseline and baseline-by-assessment 
interaction up to week 4. An unstructured variance-covariance structure will be used to model 
the within-patient errors and different variance-covariance structures will be tried for 
goodness-of-fit exploration. The 95% confidence intervals (CI) of change from baseline will 
be reported.  
8.3.2.2.3 Tumor microenvironment at the time of diagnosis 
We will examine the relationship of PFS the for patients with suboptimally cytoreduced 
ovarian cancer with immunohistochemistry (IHC) staining for antibodies of PD-1 and PD-L1 
in paraffin embedded tissue of tumor obtained at the time of their initial surgery by stratifying 
by those with a “positive stain”  in a Kaplan Meier analysis.  
8.3.2.2.4 Serial immune profiles from blood samples 
The relationship of survival and obtained post-surgery, prior to initiation of chemotherapy and 
during anti-PD-1 maintenance. 
We will examine the trajectory of serum levels over time with plots. We will examine PFS 
using a generalized linear mixed model with survival as a repeated outcome and cytokine levels 
as a time varying covariates.  
We will look for a “signature” of cytokine levels that predicts PFS of 18 months or better using 
principal component analysis, un-supervised (using a factor approach) and supervised 
clustering. Further we will examine changes in the signature over time. 
8.3.3 Missing Data Handling 
The dropout pattern will be plotted and summarized. To assess effects of dropouts, the dropout 
cohort analysis will be performed by summarizing the change of primary and secondary 
efficacy variables by using different dropout cohorts. Dropout cohorts will be formed by 
patients that had their last primary efficacy measurement in the same assessment interval 
Patients who drop out or removed from the study due to an adverse symptom profile will be 
reported as a safety outcome.  
To allow for bias due to varying assessment times, symptomatic/non-radiologic events  and 
missing data due to lack of follow-up, sensitivity analyses as per Bhattacharya[48] will be 


PROTOCOL 3475-250 
 
 
 
 
76 
 
performed. Briefly simulation studies with varying hypothetical progression times simulated 
by a uniform distribution within the assessment times will be used and also times backdated to 
the last progression free assessment.  In another analysis we will restrict the definition of lack 
of PFS to only include those who have radiologic evidence. Finally we will make conservative 
assumptions for the treatment arm and not for the historical controls in a comparison.  
8.3.4 Safety Data 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE) version 5.0.  Any adverse event 
which changes the CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report worksheet.  All adverse events regardless of 
CTCAE grade must also be evaluated for seriousness.   
The regimen would be considered unfeasible for further study if a definite drug related grade 
3 or higher SAE occurs in at least 33% of patients. This study design reflects the desire to 
terminate accrual early if sufficient evidence accumulates to consider the regimen unfeasible. 
The total accrual will be 30 patients. The study will use a 2-group sequential design to assess 
feasibility of delivering the study regimen. Fifteen (15) patients will be entered into each stage 
of the trial, unless excessive toxicity is observed in a previous stage. The decision rules for 
whether or not to advance to the next stage of the study are summarized in the following table 
8.1: 
 
Table 8.1 Safety requirement 
Stage 
Cumulative accrual 
Minimum cumulative number of 
events to stop and consider regimen 
unfeasible 
1 
15 
5 in 15 patients 
2 
30 
10 in 30 patients 
 
In the case of a safety event suspending the study, a prompt cumulative examination of all 
data and circumstances of these events will be conducted by the Medical College of 
Wisconsin DSMC to determine whether the study should be resumed, whether the protocol 
will be revised, or whether the study will be discontinued permanently.  
 
Each participating site’s IRB will be notified of any event that triggers postponement of 
enrollment in this study. If the study is suspended for safety reasons and it is deemed 
appropriate by the sponsor to resume the study, approval from the relevant IRBs will be 
obtained prior to resuming the study at each participating institution.  
Decisions regarding ongoing study participation of patients on study will be made on a case 
by case basis after discussion with the participating site’s Principal Investigator and Study 
Principal Investigator. 


PROTOCOL 3475-250 
 
 
 
 
77 
 
8.4 
Determination of Sample Size      
The primary outcome is progression free survival.  The primary comparison is the PFS of the 
treatment sample compared to controls. The comparison is a log rank sum test at an alpha of 
0.05. It will only be feasible in a five year period to recruit 30 patients. Using the study by 
Katsumata [11] the median survival time was~18 months for a dose dense regime for those with 
>1cm remaining post-surgery. We plan to accrue patients over 18 months   with a follow-up 
of at least 18 months. Realistically an increase of median PFS by 6 months would indicate 
efficacy but with a treatment sample of 30 and the control sample from Karsumata of 168, we 
would have at least 80% power to detect at least an increase from 18 months to 39 months, an 
optimistic outcome. We expect that the PFS is likely to be 24 months rather than 18 months 
and that would certainly be clinically significant and would consider this encouragement to 
pursue a larger study as this is a pilot study. The sample size calculation was done using PASS 
11, with the sample size base on the work of Lakatos [49, 50]. It was assumed that the percentage 
of dropouts in each group was 1% and the rate of accrual was uniform.   
 
8.5 
Study Data Collection, Monitoring, and Record Retention 
8.5.1 Data Management 
This study will report clinical data using The Online Enterprise Research Management 
Environment (OnCore™), a web based Oracle® database utilizing study specific electronic 
case report forms (eCRFs).  Key study personnel are trained on the use of OnCoreTM and will 
comply with protocol specific instructions embedded within the OnCoreTM forms.  Patient 
demographics, patient specific study treatment calendars, adverse events, reporting of deaths, 
and other information required for annual reporting will be placed in OnCoreTM and other 
research databases maintained by MCW IT. 
8.5.1.1 Case Report Forms 
Participant data will be collected using protocol specific electronic case report forms (e-CRFs) 
developed within OnCoreTM based on its library of standardized forms.  The e-CRF will be 
approved by the study’s Principal Investigator and the biostatistical team prior to release for 
use.  The Study Coordinator or designee will be responsible for registering the patient into 
OnCoreTM at time of study entry, completing e-CRFs based on the patient specific calendar, 
and updating the patient record until the end of required study participation. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
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. 


PROTOCOL 3475-250 
 
 
 
 
78 
 
Clinical Supplies will be provided by Merck as summarized in Table 9.1. 
Table 9.1. 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 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
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. 


PROTOCOL 3475-250 
 
 
 
 
79 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS   
10.1 Confidentiality 
10.2 Compliance with Financial Disclosure Requirements 
All financial disclosure requirements will be complied with for this study. 
10.3 Compliance with Law, Audit and Debarment 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.5 Quality Management System 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data Safety 
Monitoring Committee (MCW CC DSMC). A summary of the MCW CC DSMC activities 
are as follows:  
• Review the clinical trial for data integrity and safety  
• Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events 
must be reported to the DSMC within 5 calendar days of study staff’s knowledge.) 
Review all DSM reports.  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for patients  
 
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee 
will review reports from the study PI twice annually (or more frequently if needed) and 
provide recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
10.6 Data Management 
The OnCore data management system will be utilized for this study. 


PROTOCOL 3475-250 
 
 
 
 
80 
 
11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 


PROTOCOL 3475-250 
 
 
 
 
81 
 
11.4 Translational Research Specimen Instructions 
Required 
Specimen Code 
Collection Time 
Point 
Instructions 
Shipping Specification 
                                           All patients 
 
FFPE Primary or 
Metastatic Tumor 
(T01) 
Block 
 
Prior to all treatment. 
Pathology report must 
accompany all 
specimens. 
 
Please see Laboratory 
Manual 
MCW Department of 
OB/GYN 
Department of Obstetrics & 
Gynecology 
FMCLB 
Medical College of 
Wisconsin 
9200 W Wisconsin Ave., 
Milwaukee, WI 53226 
Post Op Serum 
(SB01) 
7-10 ml of blood 
drawn into red top 
tube 
Prior to all treatment. 
See Laboratory Manual MCW Department of 
OB/GYN 
Post Op Plasma 
(PB01) 
7-10 ml blood 
drawn into purple 
top EDTA tube 
 
Prior to all treatment. 
See Laboratory Manual MCW Department of 
OB/GYN 
Post op Whole 
blood (WB01) 
7-10 cc collected in 
sodium heparin 
tube dark green top 
tube 
Prior to all treatment. 
 See Laboratory 
Manual 
Clinical Immunodiagnostic 
& Research Laboratory 
(CIRL) 
 
Serum (SB02) 
After completion of 
combined therapy 
before maintenance. 
 See Laboratory 
Manual 
MCW Department of 
OB/GYN 
Plasma (PB02) 
 MCW Department of 
OB/GYN  
Whole Blood 
(WB02) 
CIRL 
Serum (SB03) 
After 6 cycles of 
maintenance therapy 
completed. 
 See Laboratory 
Manual 
MCW Department of 
OB/GYN 
Plasma (PB03) 
 MCW Department of 
OB/GYN 
Whole Blood 
(WB03) 
CIRL 
Serum (SB04) 
At completion of 
maintenance therapy. 
See Laboratory Manual MCW Department of 
OB/GYN 
Plasma (PB04) 
 MCW Department of 
OB/GYN 


PROTOCOL 3475-250 
 
 
 
 
82 
 
Whole Blood 
(WB04) 
CIRL 
 
 
 
 
 
 
 
Serum (SB05) 
Follow up Visit 1 
See Laboratory Manual 
MCW Department of 
OB/GYN 
Plasma (PB05) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB05) 
CIRL 
Serum (SB06) 
Follow up Visit 2 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB06) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB06) 
CIRL 
Serum (SB07) 
Follow –up Visit 3 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB07) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB07) 
CIRL 
Serum (SB08) 
Follow-up Visit 4 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB08) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB08) 
CIRL 
Serum (SB9) 
Follow-up Visit 5 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB9) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB9) 
CIRL 
Serum (SB10) 
Follow-up Visit 6 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB10) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB10) 
CIRL 
Serum (SB11) 
Follow-up Visit 7 
See Instructions above 
MCW Department of 
OB/GYN 
Plasma (PB11) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB11) 
CIRL 


PROTOCOL 3475-250 
 
 
 
 
83 
 
Serum (SB12) 
Follow-up Visit 8 
See instructions above 
MCW Department of 
OB/GYN 
Plasma (PB12) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB12) 
CIRL 
Serum (SB13) 
At time of Disease 
Progression/Recurrence
See instructions above 
MCW Department of 
OB/GYN 
Plasma (PB13) 
MCW Department of 
OB/GYN 
Whole Blood 
(WB13) 
CIRL 
 
 
References: 
1. 
McGuire, W.P., et al., Cyclophosphamide and cisplatin compared with paclitaxel 
and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med, 
1996. 334(1): p. 1-6. 
2. 
Alberts, D.S., et al., Improved therapeutic index of carboplatin plus 
cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the 
Southwest Oncology Group of a phase III randomized trial in stages III and IV 
ovarian cancer. J Clin Oncol, 1992. 10(5): p. 706-17. 
3. 
Ozols, R.F., et al., Phase III trial of carboplatin and paclitaxel compared with 
cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: 
a Gynecologic Oncology Group study. J Clin Oncol, 2003. 21(17): p. 3194-200. 
4. 
Swenerton, 
K., 
et 
al., 
Cisplatin-cyclophosphamide 
versus 
carboplatin-
cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the 
National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 1992. 
10(5): p. 718-26. 
5. 
Kosary, C.L., FIGO stage, histology, histologic grade, age and race as prognostic 
factors in determining survival for cancers of the female gynecological system: an 
analysis of 1973-87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, 
and vagina. Semin Surg Oncol, 1994. 10(1): p. 31-46. 
6. 
Bristow, R.E., et al., Survival effect of maximal cytoreductive surgery for advanced 
ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol, 2002. 
20(5): p. 1248-59. 
7. 
Griffiths, C.T., L.M. Parker, and A.F. Fuller, Jr., Role of cytoreductive surgical 
treatment in the management of advanced ovarian cancer. Cancer Treat Rep, 1979. 
63(2): p. 235-40. 
8. 
Hoskins, W.J., et al., The effect of diameter of largest residual disease on survival 
after primary cytoreductive surgery in patients with suboptimal residual epithelial 
ovarian carcinoma. Am J Obstet Gynecol, 1994. 170(4): p. 974-9; discussion 979-
80. 


PROTOCOL 3475-250 
 
 
 
 
84 
 
9. 
Seidman, A.D., et al., Randomized phase III trial of weekly compared with every-3-
weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 
overexpressors and random assignment to trastuzumab or not in HER-2 
nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J 
Clin Oncol, 2008. 26(10): p. 1642-9. 
10. 
Katsumata, N., et al., Dose-dense paclitaxel once a week in combination with 
carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, 
randomised controlled trial. Lancet, 2009. 374(9698): p. 1331-8. 
11. 
Katsumata, N., et al., Long-term results of dose-dense paclitaxel and carboplatin 
versus conventional paclitaxel and carboplatin for treatment of advanced epithelial 
ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, 
controlled, open-label trial. Lancet Oncol, 2013. 14(10): p. 1020-6. 
12. 
Kandalaft, L.E., et al., Immunotherapy for ovarian cancer: what's next? J Clin 
Oncol, 2011. 29(7): p. 925-33. 
13. 
Zsiros, E., et al., Immunotherapy for ovarian cancer: recent advances and 
perspectives. Curr Opin Oncol, 2014. 26(5): p. 492-500. 
14. 
Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high 
CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian 
cancer. Proc Natl Acad Sci U S A, 2005. 102(51): p. 18538-43. 
15. 
Zhang, L., et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian 
cancer. N Engl J Med, 2003. 348(3): p. 203-13. 
16. 
Hwang, W.T., et al., Prognostic significance of tumor-infiltrating T cells in ovarian 
cancer: a meta-analysis. Gynecol Oncol, 2012. 124(2): p. 192-8. 
17. 
Park, A., et al., Substantially modified ratios of effector to regulatory T cells during 
chemotherapy in ovarian cancer patients return to pre-treatment levels at 
completion: implications for immunotherapy. Cancers (Basel), 2012. 4(2): p. 581-
600. 
18. 
Hamanishi, J., et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ 
T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci 
U S A, 2007. 104(9): p. 3360-5. 
19. 
Duraiswamy, J., G.J. Freeman, and G. Coukos, Therapeutic PD-1 pathway 
blockade augments with other modalities of immunotherapy T-cell function to 
prevent immune decline in ovarian cancer. Cancer Res, 2013. 73(23): p. 6900-12. 
20. 
Preston, C.C., et al., The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and 
FOXP3- T cells correlate with poor clinical outcome in human serous ovarian 
cancer. PLoS One, 2013. 8(11): p. e80063. 
21. 
Curiel, T.J., et al., Specific recruitment of regulatory T cells in ovarian carcinoma 
fosters immune privilege and predicts reduced survival. Nat Med, 2004. 10(9): p. 
942-9. 
22. 
Hato, S.V., I.J. de Vries, and W.J. Lesterhuis, STATing the importance of immune 
modulation by platinum chemotherapeutics. Oncoimmunology, 2012. 1(2): p. 234-
236. 
23. 
Zhang, L., et al., Differential impairment of regulatory T cells rather than effector 
T cells by paclitaxel-based chemotherapy. Clin Immunol, 2008. 129(2): p. 219-29. 


PROTOCOL 3475-250 
 
 
 
 
85 
 
24. 
Diaz, Y., et al., Concomitant combination of active immunotherapy and carboplatin- 
or paclitaxel-based chemotherapy improves anti-tumor response. Cancer Immunol 
Immunother, 2013. 62(3): p. 455-69. 
25. 
Chang, C.L., et al., Dose-dense chemotherapy improves mechanisms of antitumor 
immune response. Cancer Res, 2013. 73(1): p. 119-27. 
26. 
Braly, P., et al., The Immune adjuvant properties of front-line carboplatin-
paclitaxel: a randomized phase 2 study of alternative schedules of intravenous 
oregovomab chemoimmunotherapy in advanced ovarian cancer. J Immunother, 
2009. 32(1): p. 54-65. 
27. 
Telleria, C.M., Repopulation of ovarian cancer cells after chemotherapy. Cancer 
Growth Metastasis, 2013. 6: p. 15-21. 
28. 
Burger, R.A., et al., Incorporation of bevacizumab in the primary treatment of 
ovarian cancer. N Engl J Med, 2011. 365(26): p. 2473-83. 
29. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
30. 
Seymour, L., et al., The design of phase II clinical trials testing cancer therapeutics: 
consensus recommendations from the clinical trial design task force of the national 
cancer institute investigational drug steering committee. Clin Cancer Res, 2010. 
16(6): p. 1764-9. 
31. 
Fleming, T.R., M.D. Rothmann, and H.L. Lu, Issues in using progression-free 
survival when evaluating oncology products. J Clin Oncol, 2009. 27(17): p. 2874-80. 
32. 
Basen-Engquist, K., et al., Reliability and validity of the functional assessment of 
cancer therapy-ovarian. J Clin Oncol, 2001. 19(6): p. 1809-17. 
33. 
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX-
1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75. 
34. 
Mu, C.Y., et al., High expression of PD-L1 in lung cancer may contribute to poor 
prognosis and tumor cells immune escape through suppressing tumor infiltrating 
dendritic cells maturation. Med Oncol, 2011. 28(3): p. 682-8. 
35. 
Gadiot, J., et al., Overall survival and PD-L1 expression in metastasized malignant 
melanoma. Cancer, 2011. 117(10): p. 2192-201. 
36. 
Thompson, R.H., et al., Tumor B7-H1 is associated with poor prognosis in renal cell 
carcinoma patients with long-term follow-up. Cancer Res, 2006. 66(7): p. 3381-5. 
37. 
Taube, J.M., et al., Association of PD-1, PD-1 ligands, and other features of the 
tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer 
Res, 2014. 20(19): p. 5064-74. 
38. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody 
in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
39. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J 
Med, 2013. 369(2): p. 122-33. 
40. 
Schwarzenbach, H., D.S. Hoon, and K. Pantel, Cell-free nucleic acids as 
biomarkers in cancer patients. Nat Rev Cancer, 2011. 11(6): p. 426-37. 
41. 
Garcia-Olmo, D.C., et al., Cell-free nucleic acids circulating in the plasma of 
colorectal cancer patients induce the oncogenic transformation of susceptible 
cultured cells. Cancer Res, 2010. 70(2): p. 560-7. 


PROTOCOL 3475-250 
 
 
 
 
86 
 
42. 
Zhou, J., Y.H. Shi, and J. Fan, Circulating cell-free nucleic acids: promising 
biomarkers of hepatocellular carcinoma. Semin Oncol, 2012. 39(4): p. 440-8. 
43.   
Xia, Shu et al Genomic variations in plasma cell free DNA differentiate early stage 
lung cancers from normal controls.  Lung Cancer, 2015.  90: p78-84. 
44. 
Kaiser, J., Medicine. Keeping tabs on tumor DNA. Science, 2010. 327(5969): p. 
1074. 
45. 
Heitzer, E., et al., Establishment of tumor-specific copy number alterations from 
plasma DNA of patients with cancer. Int J Cancer, 2013. 133(2): p. 346-56. 
46. 
Dawson, S.J., et al., Analysis of circulating tumor DNA to monitor metastatic breast 
cancer. N Engl J Med, 2013. 368(13): p. 1199-209. 
47. 
Murtaza, M., et al., Non-invasive analysis of acquired resistance to cancer therapy 
by sequencing of plasma DNA. Nature, 2013. 497(7447): p. 108-12. 
48. 
Leary, R.J., et al., Detection of chromosomal alterations in the circulation of cancer 
patients with whole-genome sequencing. Sci Transl Med, 2012. 4(162): p. 162ra154. 
49. 
Bhattacharya, S., et al., Role of sensitivity analyses in assessing progression-free 
survival in late-stage oncology trials. J Clin Oncol, 2009. 27(35): p. 5958-64. 
50. 
Lakatos, E., Designing complex group sequential survival trials. Stat Med, 2002. 
21(14): p. 1969-89. 
51. 
Lakatos, E., Sample sizes based on the log-rank statistic in complex clinical trials. 
Biometrics, 1988. 44(1): p. 229-41. 
52.  
Chan JK et al, Weekly vs every 3-week pclitaxel and carboplatin for ovarian 
cancer.  2016.  N Engl J Med 374: 738-48  
 
 

SAP_001.pdf: 
 
ID UYAR 25680 IIT MERCK:  Phase II Pembrolizumab/Carbo/Taxol in Epithelial Ovary Cancer 
NCT02766582 
Date:  3/15/23 
 
 
Statistical Analysis Plan  
 
Progression-free survival (PFS) is defined as the date of completion of primary therapy to the date of the 
first clinical, biochemical, or radiological evidence of progression or death due to any cause.  PFS will be 
censored at the last assessment of disease progression for living patients. The efficacy parameters of 
survival will be analyzed using Kaplan-Meier curves stratified by the group where the groups are 
compared using a log-rank sum test. Using Pass 12, the primary comparison is the PFS of the treated 
sample compared to historical controls. We planned to accrue patients over 3 years with a follow-up of 
at least 18 months.  The calculation was done with the sample size calculation based on the work of 
Lakatos. 18 The comparison is a two-sided log-rank sum test, at an alpha of 0.05. Using the study by 
Katsumata the median survival time was an estimated 18 months for the conventional carboplatin-
paclitaxel chemotherapy regimen for those with >1cm remaining post-surgery. Realistically an increase 
of median PFS by 6 months would have indicated efficacy but with a treatment sample of 30 and the 
control sample from Katsumata of 168, we would have at least 80% power to detect at least an increase 
for 1.5 years to ~3 years, an optimistic outcome. 
 
A waterfall plot illustrates the maximum percent change in tumor measurement per RECIST from 
baseline. Continuous variables are summarized as median (interquartile range) and categorical variables 
and number (%). This included treatment-related adverse events assessed by the investigator as at least 
possibly related to treatment.  FACTG scores were analyzed using a mixed-effects covariance pattern 
model to utilize all the data collected over time with consideration of the variance-covariance matrix of 
the repeated measures. This method allows a general unstructured variance-covariance matrix and 
allows patients to have incomplete data across scheduled time points.  All analyses were conducted 
using SAS 9.4 and SPSS 26.0.