Anti-PD-1 Therapy in Combination With Platinum Chemotherapy for Platinum Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Phase: PHASE1
Conditions: Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: University of Washington

 
Product: Pembrolizumab 
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SPONSOR:  University of Washington 
 
TITLE: Anti-PD-1 Therapy in Combination with Platinum Chemotherapy for 
Platinum Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer 
 
IND NUMBER:  CDER 131988 
 
EudraCT NUMBER (Studies in Europe only): 
 
CONTACT INFORMATION:  
 
Principal Investigator: 
John B. Liao, MD, PhD 
 
 
 
 
University of Washington 
 
 
 
 
Gynecologic Oncology 
 
 
 
 
850 Republican Street 
 
 
 
 
Box 358050 
 
 
 
 
Seattle, WA 98109 
 
 
 
 
Phone: 206-221-1513 
 
 
 
 
FAX: 206-221-5529 
 
 
 
 
Email: johnliao@uw.edu 
 
Study/Regulatory 
Coordinator/Contact: 
Jennifer S. Childs, MPH, CCRP 
 
 
 
 
University of Washington 
 
 
 
 
Oncology 
 
 
 
 
850 Republican Street 
 
 
 
 
Box 358050 
 
 
 
 
Seattle, WA 98109 
 
 
 
 
Phone: 206-616-2305 
 
 
 
 
FAX: 206-221-5529 
 
 
 
 
Email: childj@medicine.washington.edu  
 
Research Nurse: 
 
Doreen Higgins, BSN, RN, OCN 
 
 
 
 
University of Washington 
 
 
 
 
Oncology 
 
 
 
 
850 Republican Street 
 
 
 
 
Box 358050 
 
 
 
 
Seattle, WA 98109 
 
 
 
 
Phone: 206-616-9538 
 
 
 
 
FAX: 206-221-5529 
 
 
 
 
Email: dhigg@medicine.washington.edu   
 
 
IRO received 11/23/21
FHCRC IRB Approval  
DEC 09 2021 
Document Released Date

 
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University of Washington  
Pharmacy: 
 
 
 
 
 
 
 
University of Washington Medical Center 
 
 
 
 
Investigational Drug Services 
 
 
 
 
1959 NE Pacific Street 
 
 
 
 
Box 356015, Room EA-146 
 
 
 
 
Seattle, WA 98195 
 
 
 
 
Phone: 206-598-6054 
 
 
 
 
FAX: 206-598-4901 
 
 
 
 
Email: idssam@u.washington.edu 
 
 
 
 
Main Email: uwmcids@u.washington.edu  
 
 
 
 
 
Statistician:  
 
James Y. Dai, PhD 
 
 
 
 
Fred Hutchinson Cancer Research Center 
Public Health Sciences Division 
Biomathematics & Biostatistics 
1100 Fairview Avenue North 
PO Box 19024 
Seattle, Washington 98109-1024  
 
 
 
 
Phone: 206-667-6364 
 
 
 
 
Email: jdai@scharp.org   
 
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Combination MK-3475 plus platinum chemotherapy in platinum resistant 
ovarian cancer 
Trial Phase 
I/II 
Clinical Indication 
Platinum resistant ovarian, fallopian tube and primary peritoneal cancer 
Trial Type 
Single arm non-randomized 
Type of control 
Historical 
Route of administration 
MK-3475 = IV; Carboplatin = IV 
Trial Blinding 
Open label 
Treatment Groups  
Single arm 
Number of trial subjects 
27 
Estimated enrollment period 
January 1, 2017 – June 30, 2018 
Estimated duration of trial 
January 1, 2017-- June 30, 2019 
Duration of Participation 
Up to 2 years (or until progression of disease or toxicity) 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This will be a phase I/II single arm, non-randomized clinical trial designed to examine the 
clinical response rate of platinum and MK-3475 in platinum pretreated ovarian, fallopian tube, 
and primary peritoneal cancer subjects. Subjects who had an initial response to platinum-based 
(cisplatin or carboplatin) chemotherapy and who have progressed within 6 months of 
completing platinum-based chemotherapy and have subsequently received at least one non-
platinum therapy regimen will be eligible to enroll. We will explore the sensitizing effect of 
this treatment on with platinum chemotherapy retreatment. In addition, safety, the role of PD-
L1 expression, and survival benefit of this therapy will be examined.  
A total of 27 eligible subjects will be enrolled to this study. All study subjects will receive 
treatment consisting of 21 day cycles, which will continue for up to 2 years or until progression 
or toxicity (whichever comes first). CT scans will be performed at screening (if not done within 
30 days of first treatment), and then before cycles 4 and 8, then every three months per standard 
of care. 
Treatment Cycle (21 days): 
• Day 1: 200mg of MK-3475 IV 
• Day 8: Carboplatin AUC 2 IV  
• Day 15: Carboplatin AUC 2 IV  
 
Primary endpoints: Response rate and PFS at 6 months (Cycle 8) assessed by RECIST v1.1. 
 
Secondary endpoints: Adverse events evaluated by CTCAE v4.0, PD-L1 expression of primary 
tumor blocks, overall survival, assess best overall response (BOR) and progression free 

 
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survival (PFS) time according to RECIST 1.1, assess the immune-related BOR and immune-
related PFS using irRECIST (Immune-related Response Evaluation Criteria In Solid Tumors) 
derived from RECIST 1.1 
 
2.2 
Trial Diagram 
2.2.1.  Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2.2.2.  Study Schema: Re-treatment 
 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To determine the clinical response rate of platinum chemotherapy and MK-
3475 in platinum chemotherapy pretreated ovarian, fallopian tube, and primary peritoneal 
Hypothesis:  MK-3475 and platinum chemotherapy will improve upon second line 
chemotherapy for ovarian, fallopian tube, and primary peritoneal cancers. 
(2) Objective: To examine whether retreatment with platinum chemotherapy in platinum 
resistant ovarian, fallopian tube, and primary peritoneal cancers improves progression free 
survival by concurrent administration of MK-3475. 
Hypothesis:  MK-3475 can re-sensitize platinum resistant ovarian, fallopian tube, and 
primary peritoneal cancers to respond to platinum chemotherapy 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To assess the safety and tolerability of concurrent administration of MK-3475 
with platinum chemotherapy in patients with platinum resistant recurrent ovarian, fallopian 
tube, and primary peritoneal cancers.  

 
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Hypothesis:  MK-3475 can be used safely in combination with weekly platinum 
chemotherapy in patients with platinum resistant ovarian, fallopian tube, and primary 
peritoneal cancer. 
(2) Objective:  To determine the relationship between PD-L1 expression and response to the 
combination of MK-3475 and platinum 
Hypothesis:  PD-L1 expression measured by immunohistochemical staining in tumor 
correlates with treatment response. 
(3) Objective:  To assess the overall survival of patients treated with the combination of MK- 
3475 and platinum 
Hypothesis:  Combination treatment with MK-3475 and platinum improves PFS and OS 
compared to historical controls. 
 
3.3 
Exploratory Objective 
(1) 
Objective: To explore whether treatment with MK-3475 and platinum alters soluble 
factors in sera, peripheral immune responses and immune cell profile. 
Hypothesis:  MK-3475 and platinum therapy in combination will enhance tumor 
immunogenicity and peripheral responses that reverse an immunosuppressive phenotype 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  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 solid tumors, such as ovarian cancer. 
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, 

 
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including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 

 
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4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The mainstay of ovarian cancer chemotherapy has long been platinum-based agents.  The 
majority of patients will achieve a response with initial treatment.[1] Unfortunately, recurrent 
ovarian cancer inevitably becomes resistant to platinum-based chemotherapy.  Response rates 
to any cytotoxic agent in a platinum resistant recurrence are modest.  Single cytotoxic agents 
employed include paclitaxel (21% response rate), pegylated liposomal doxorubicin (20% 
response rate), topotecan (19% response rate), and gemcitabine (9% overall response rate). A 
randomized phase 3 trial comparing pegylated liposomal doxorubicin to patupilone showed a 
mean PFS of 12 weeks and a OS of 13 months in both arms, which is unfortunately emblematic 
of the recent trials studying agents in platinum resistant disease.[2] Combination chemotherapy 
has not shown consistent benefits and NCCN guidelines do not support any combination in 
this setting except with bevacizumab.  The extra value of a second agent has never been tested 
against platinum alone in a randomized trial.[3] While it is the inclination of many oncologists 
to approach a platinum resistant recurrence with a non-platinum regimen, there is evidence that 
even in a platinum resistance recurrence, retreatment with single platinum agent can yield a 
23% response rate that is not inferior to platinum combinations also used in this setting. It is 
hypothesized that successful retreatment with platinum chemotherapy may be related to the 
duration of a platinum free interval, which may be prolonged with the use of non platinum 
agents,[4] however there are no trials that directly test this hypothesis and the biologic rationale 
supporting this is unclear.  At our own institution, we will retreat with platinum after a platinum 
resistant recurrence has been diagnosed and have found similar response rates. 
Ovarian cancer is immunogenic.   The ability of the immune system to recognize ovarian 
cancer is associated with improved prognosis.  The form of immunity associated with this 
improved prognosis is known; T cell infiltrates in ovarian cancers are shown to be associated 
with improved prognosis in a number of studies. The full prognostic significance of T-cell 
infiltration in ovarian cancers rivals optimal surgical cytoreduction.[5] The presence of 
intratumoral T cells was an independent prognostic factor for PFS and OS by multivariate 
analysis.  These findings have been validated in several subsequent studies, and point to the 
specific importance of cytotoxic CD8+ T-cells.[6-12]  
Subsequently, a number of factors that may influence the intraepithelial lymphocyte count in 
ovarian cancers have been studied.  The evidence continues to mount pointing to the 
importance of the PD-1/PD-lL in ovarian cancer.  The expression level of PD-L1 in paraffin 
embedded tumors has been shown to be significantly associated with prognosis by multivariate 
analysis.  In addition there is a significant inverse correlation seen between PD-L1 expression 
and intraepithelial CD8+ T cell count, suggesting that PD-L1 on ovarian cancer cells may 
suppress antitumor CD8+ T cells.[13]  The expression of PD-L1 in human ovarian cancer has 
also been shown to promote peritoneal dissemination suggesting that PD-L1 blockage may be 

 
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a viable strategy for treating metastatic ovarian cancer.[14]  Furthermore, 93% of ovarian 
cancers have been reported to have PD-1 positive tumor infiltrating lymphocytes. [15]  
While cytotoxic chemotherapy has traditionally been viewed as being immunosuppressive, 
recent studies have shown that specific agents may possess significant immune stimulatory 
effects.[16] Platinum agents in particular have been shown to stimulate effector antitumor 
responses through the modulation of the PD-1 receptor.[17, 18]  Blockade of the PD-1/PDL-1 
interaction in 15 ovarian cancer patients with platinum resistant disease has been recently 
reported to yield a response rate of 23% and disease control rate (CR+PR+SD) of 54%.[19] 
Ovarian cancer patients with platinum resistant relapses treated with a weekly platinum based 
regimen have shown to yield serum levels of IL-2 and interferon gamma associated with CD8+ 
cytotoxic T cell activity.[20] Studies combining PD-1 blockade with platinum chemotherapy 
in ovarian cancer mouse models have been shown to significantly increase the tumor control 
compared to the use of each agent alone, both in our own preliminary data and those reported 
by other investigators.[21] 
We hypothesize that therapies targeting the PD-1/PD-L1 pathway may synergize with platinum 
chemotherapy agents and allow ovarian cancers that have become clinically resistant to 
platinum to be successfully retreated with this agent.   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
MK-3475 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses 

 
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to the highest doses studied.  Subsequently, flat dose-exposure-response relationships were 
also observed in other tumor types including head and neck cancer, bladder cancer, gastric 
cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type.  These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W.  Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression.  This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols. 
Carboplatin 
Carboplatin when used in combination chemotherapy regimens for ovarian cancer has been 
shown to be well tolerated with an AUC 2 dose per week.[22]  In addition, the dose intensity 
of platinum in the treatment of ovarian cancer has not shown to offer significant survival 
advantage in randomized trials.[23]  Carboplatin will be infused at an AUC of 2, with the dose 
calculated using the Calvert equation.  
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
Thus, in this regimen, the carboplatin dose will be: 
Carboplatin dose (mg) = (2.0) x (GFR + 25) 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the creatinine 
clearance.  
 
NOTE: THE DOSE OF CARBOPLATIN WILL BE RECALCULATED FOR EACH 
CYCLE.   
 
Dose of carboplatin will be monitored over time to determine if concurrent administration of 
MK-3475 alters carboplatin dose. 
 

 
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Rationale for Endpoints 
4.2.2.1 Efficacy Endpoints 
For each subject, tumor response will be performed by CT scan or MRI imaging of 
chest abdomen and pelvis.  CT scan of chest will be performed if MRI is used.  
RECIST 1.1 criteria and irRECIST (Immune-related Response Evaluation Criteria In 
Solid Tumors) criteria will be used to determine response.   
Both PFS and OS will be measured.  While OS remains the most objective clinical 
measure, because ovarian cancer is a heterogeneous disease, PFS as a surrogate 
endpoint has been proposed and reported in a number of trials for this disease.[24] 
4.2.2.2 Biomarker Research  
There are currently no universally accepted biomarkers to that can identify patients 
mostly likely to respond to either MK-3475 or carboplatin as a single agent in this 
population of patients.  We will examine whether expression of PD-L1 in tumor, 
mutations in cancer associated genes, serum antibody responses against tumor 
associated antigens, and changes in immunomodulatory cells can be associated with 
response in this combination.  We will also assess whether these markers are 
associated with PFS, OS, and toxicities. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Ovarian, fallopian tube, or peritoneal cancer patients who had a complete response to primary 
treatment with platinum based chemotherapy, have progressed within 6 months of completing 
platinum-based chemotherapy, and have subsequently received at least one non-platinum-
based therapy. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have a diagnosis of ovarian, fallopian tube, or primary peritoneal cancer patients who 
had a complete response to primary treatment with platinum based chemotherapy, have 
progressed within 6 months of completing platinum based chemotherapy and have 
subsequently received at least one, non-platinum-based, therapy. 
 
2. Have relapsed, refractory, or progressive disease following last line of treatment. 
3. Have estimated life expectancy of at least 3 months. 
4. Be willing and able to provide written informed consent/assent for the trial. 

 
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5. Be ≥ 18 years of age on day of signing informed consent. 
6. Have measurable disease with at least 1 unidimensional lesion based on RECIST 1.1.   
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total 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. 
 
9. 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.   
10. 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.  

 
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5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy within 4 weeks of the first dose of 
treatment. 
2. 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. 
- 
Short-term administration of systemic steroids (i.e., for allergic reactions or the 
management of irAEs) is allowed 
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. 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. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   

 
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9. 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.  
 
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. 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.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. 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. 
15. Clinically significant cardiovascular disease. 
16. Known severe hypersensitivity reactions to monoclonal antibodies or carboplatin ≥ 
Grade 3, any history of anaphylaxis, or uncontrolled asthma.  
17. Has received prior therapy with pembrolizumab. 
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
20. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 

 
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Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Carboplatin* 
AUC 2** 
 
IV infusion 
Day 8, 15 of each 
3 week cycle 
Standard 
*Given per standard of care 
**Calculated by use of the Calvert formula 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of dose to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.  
Carboplatin is commercially available both from Bristol-Myers Squibb as well as generic 
manufacturers. Please refer to link to carboplatin prescribing information (Appendice 13.4).  
 
5.2.1.2 Dose Modification  
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  
Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion.  Subjects will permanently discontinue study drug for persistent Grade 2 
adverse reactions for which treatment with study drug have been previously held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.   
Subjects will permanently discontinue drug for any severe or Grade 3 drug-related AE that 
recurs or any life-threatening event. 
Pembrolizumab 

 
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Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including 
use of corticosteroids. 
Table 3 Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
1. Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
• 
Monitor participants for signs 
and symptoms of 
pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics 
for opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
Grade 4 
Permanently 
discontinue 

 
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General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
• 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemi
a 
 
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  
Hyperthyroidis
m  
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 
Hypothyroidis
m 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care 
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 2 
Withhold  

 
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General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Nephritis and 
Renal 
dysfunction 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• 
Monitor changes of renal 
function 
 
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 
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).   
 
Carboplatin 
Standard dose adjustments for carboplatin during treatment may be made based on changes in 
hepatic and renal function. 
Some of the adverse events expected with carboplatin treatment are listed below.  
 
1. Hematologic: Myelosuppression is the major dose-limiting toxicity  
 

 
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2. Hepatic toxicity: Elevated alkaline phosphatase, total bilirubin, and AST have been  
observed.  
 
3. Allergic reactions: Hypersensitivity to carboplatin has been reported in 2% of patients 
receiving the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely 
anaphylaxis with bronchospasm and hypotension. The reactions can be successfully managed 
with standard epinephrine, corticosteroid, and antihistamine therapy.  
 
4. Neurologic: Peripheral neuropathy, ototoxicity, visual disturbances, change in taste, central 
nervous system symptoms 
 
5. Gastrointestinal: Nausea and vomiting are the most common GI events; both usually  
resolve within 24 hours and respond to antiemetics. Other GI events include diarrhea, weight 
loss, constipation, and gastrointestinal pain.  
 
6. Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has  
been reported in 3% of the patients taking carboplatin. 
*See link to FDA-approved package insert (Appendice 13.4) for a comprehensive list of 
adverse events associated with carboplatin. 
 
5.2.2 Timing of Dose Administration 
Trial drug 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.  Carboplatin may be administered up to 3 days before or after scheduled 
day due to administrative reasons.   
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Carboplatin AUC 2 will be administered as a 30 minute IV infusion (-5 min/+10 min) on days 
8 and 15 of a 21 day cycle. Carboplatin is considered to have moderate emetic risk and 
administrations of antiemetics will follow NCCN guidelines Version 1.2015. 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pd 
For the management of Day 1, option A will be preferred: 

 
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Serotonin (5-HT3) antagonist + Steroid (category 1) ± NK-1 antagonist · Serotonin (5-HT3) 
antagonist (Select one): 
Day 1 antiemetic management: 
Serotonin  (5-HT3) antagonist  
    Select one:   
    Option A.            
+  Steroid (category 1) ± NK-1 antagonist 
Dolasetron 100 mg PO once 
Dexamethasone 12 mg 
PO/IV once 
Aprepitant 125 mg PO 
once 
Granisetron 2 mg PO or 1 mg PO BID, 
or 0.01 mg/kg ( max 1 mg) IV once,  
or 3.1 mg/24h transdermal patch 
applied 24-48 h prior to first dose of 
chemotherapy 
 
Fosaprepitant 150 mg 
IV once 
 
Ondansetron 16-24 mg PO once or 
 8-16 mg IV once 
 
Palonosetron 
0.25 
mg 
IV 
once 
(preferred) 
 
 
For Days 2 and 3, option A will be preferred with 5-HT3 antagonist monotherapy used first 
line and NK1 antagonist without steroid used second line. Option C Olanzapine will be used 
third line: 
Day 2 and 3 antiemetic management: 
First line treatment 
Serotonin  (5-HT3) antagonist 
Option A 
 
Second line treatment (without 
steroid use) 
NK-1 antagonist 
Third 
line 
treatment 
Dolasetron 100 mg PO on  
days 2, 3 
Aprepitant 125 mg PO daily on days 
2, 3 
Olanzapine 10 
mg PO daily on 
days 2, 3 
Granisetron 2 mg PO or 1 mg PO 
BID, or 0.01 mg/kg ( max 1 mg) 
IV daily on days 2, 3 
Fosaprepitant used day 1 
Ondansetron 8mg PO BID or 16 
mg PO daily or 8-16 mg IV daily 
on days 2, 3 
 

 
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5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.2.4 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 3.   
5.3 
Randomization or Treatment Allocation 
Not applicable. 
5.4 
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.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  Medications administered during a hospitalization, not related to study treatment, 
will be reviewed and recorded only if clinically significant to the study.  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment or initiation of new treatment should be 

 
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recorded.  Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs Events of Clinical Interest (ECIs) as defined in Sections 
5.2.4 and7.2. 
5.4.2 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  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  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. 
5.5 
Rescue Medications & Supportive Care 
5.5.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail.  
• Pneumonitis:  

 
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o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 

 
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• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 

 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
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). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
5.6 
Diet/Activity/Other Considerations 
5.6.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 

 
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5.6.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the 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. 
5.6.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 

 
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5.6.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.7 
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 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 

 
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Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.5 
• 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 or prior to initiation of new treatment for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment as described in 
Section 7.2.3.1).  Subjects who discontinue for reasons other than progressive disease will have 
post-treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed for overall survival until death, withdrawal 
of consent, or the end of the study, whichever occurs first. 
5.7.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.8 
Subject Replacement Strategy.  
Up to 4 patients may be replaced if patients withdraw or are withdrawn from the trial 
prior to completing their first cycle.  
5.9 
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 

 
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In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

 
 
 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cyclesa, g 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screeningh (Visit 
2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discone 
Safety 
Follow-
upe 
 
Survival 
Follow-Upb 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
 
Every 12 weeks 
after discona  
Administrative Procedures 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trial Treatment Administration (Day 1) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Carboplatin Administration (Day 8, 15) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Eventsk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
 
 
Full Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
PT/INR and aPTT 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CA125 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Comprehensive Serum Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

 
 
 
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Trial Period: 
Screening Phase 
Treatment Cyclesa, g 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screeningh (Visit 
2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discone 
Safety 
Follow-
upe 
 
Survival 
Follow-Upb 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
 
Every 12 weeks 
after discona  
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, T3, FT4 and TSH 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Efficacy Measurements 
Tumor Imagingc 
 
X 
 
 
 
X 
 
 
 
Xc 
 
 
X 
X 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue Availabilityl, m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collectionf, i 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Trial Period: 
Screening Phase 
Treatment Cyclesa, g 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screeningh (Visit 
2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discone 
Safety 
Follow-
upe 
 
Survival 
Follow-Upb 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
 
Every 12 weeks 
after discona  
a Treatment Cycles: Up to 24 months for this study 
b Follow-Up Visits (Post Discontinuation): Year 1 patients will be followed with CT scan approximately every three months per standard of care; Year 2 patients 
will be followed with CT scan approximately every 6 months per standard of care 
c Tumor Imaging: : CT scan or MRI (if MRI is used then CT scan of chest required) of the chest, abdomen and pelvis may be done at screening or 30 days prior 
to study treatment and again prior to cycles 4 and 8 then will be repeated approximately every 3 months per standard of care 
d Adverse events will be collected for 30 days or prior to initiation of new treatment.  Serious adverse events will be collected for 90 days after the end of treatment 
as described in Section 7.2.3.1 
e If subject initiates a new anticancer 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 (Section 7.1.1.6.3).  Discontinuation Visit and Safety Follow Up may be the same visit. 
f Correlative blood draw is up to 200mls; this blood will be used for correlative analysis (PBMC, serum, DC phenotyping, etc.) 
g Re-treatment procedures will last for 1 year (Section 7.1.5.5). 
h The screening visit and Cycle 1 could happen on the same day 
i After Cycle 6; correlative blood draws will occur every six cycles (prior to cycles 12, 18, and 24)  
 j Has been deleted, no longer an active instruction.Through subject self reporting and clinician observation. Events may be clarified from previous medical 
records 
l Tissue slides are shipped to QualTek for PDL1 analysis.  The QualTek manual which details shipping can be found in the “Lab Certification” Binder 
m We will obtain archival tumor, for immunohistochemical staining.  Patients who have not been tested for germline mutations in BRCA1 and BRCA2 will be 
tested. 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 

 
 
 
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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 or Study Physician 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/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial prior to study treatment.  

 
 
 
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7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, 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.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECI  should be recorded as 
defined in Sections 5.4.2 and7.2. 
7.1.1.5 Treatment Schedule 
Subjects will receive repeat cycles of combination pembrolizumab and carboplatin for 2 years 
or until progression of disease or toxicity.  
7.1.1.5.1 Research Treatment 
Pembrolizumab will be administered on Day 1 of the treatment cycle. 
7.1.1.5.2 Carboplatin Administration 
Carboplatin is administered on Days 8 and 15 of the treatment cycle per standard of clinical 
care. 
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. 

 
 
 
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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/Discontinuation Visit 
every effort is to be made to occur before the first dose of the new therapy.  Once new anti-
cancer therapy has been initiated the subject will move into survival follow-up.  
7.1.1.7 Assignment of Screening Number 
The University of Washington will screen all potential subjects entering the study.  We have a 
system that allows us to identify and follow a potential subject going through the screening 
process.   
This system allows us to track the number of subjects we have screened for a specific study, 
where in the screening process a subject is at a given time, and those that did not make it to 
study treatment enrollment.  
7.1.1.8 Assignment of Randomization Number 
The University of Washington will assign a Unique Patient Number (UPN) to each subject at 
the time of signing study enrollment and the start of study procedures.  This UPN does not 
hold any patient identifiers and will be used for Case Report Form documentation and research 
specimens for the correlative science. 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject on Day 1 of each cycle to 
evaluate for potential new or worsening AEs as specified in the Trial Flow Chart and more 
frequently if clinically indicated.    Lab values are to be reviewed for Days 1, 8, 15 and 
documented in the database as adverse events, if applicable (clinically significant). Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized in 
terms described in Table 6.  
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).  
For subjects who are hospitalized, due to their disease, the PI will review their records and 
determine what events, procedures, and medications shall be documented in the study record. 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   

 
 
 
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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 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.   
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease  
A CT scan or MRI (if MRI is used then CT scan of chest required) of the chest, abdomen and 
pelvis will be performed days prior to trial (if not done within 30 days of first treatment) in 
order to document the baseline status of tumor using RECIST 1.1 target and non-target lesions.  
Baseline screening scan does not need to be repeated if performed within 4 weeks prior to first 
treatment.   
For each subject, tumor response will be assessed by CT scan or MRI.  Scans performed prior 
to cycle 1need to be repeated at subsequent visits as outlined in Section 6.0 (prior to cycles 4 
and 8, then approximately every three months per standard of care).  Lesions detected at 
baseline need to be followed using same imaging methodology.   
Due to data from cancer immunotherapy trials showing that despite new lesions that may 
appear at the beginning of treatment, total tumor burden may not increase substantially, and 
tumor regressions and stabilization may occur later, we will also use the proposed irRECIST 
(Immune-related Response Evaluation Criteria In Solid Tumors) criteria in addition to RECIST 
1.1 to assess responses.[25]   
7.1.2.6 Tumor Tissue Availability/Collection and Correlative Studies Blood Sampling 
The identification of biomarkers that can predict response and allow the identification of 
patients most likely to benefit from therapy represents a significant gap in the treatment of 
recurrent ovarian cancer given the toxicity profiles and low response rates of the agents 
available.  The expression of PD-L1 in tumor has been shown in melanomas, non-small cell 
lung carcinoma, renal carcinoma, colorectal carcinoma, and prostate cancer to be most closely 
correlated with response to anti-PD-1 blockade.[26]  We will obtain archival tumor, for 
immunohistochemical staining.  The median time to response reported for MK-3475 in 

 
 
 
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melanoma is 12 weeks.[27] Expression of PD-L1 will be correlated with response, OS, and 
PFS and toxicities.   
Although ovarian cancer is immunogenic, the phenotype of the immune response is important 
to improved survival.  Comprehensive multifactorial immune analysis resulting in immune 
profiles have been proposed a way to identify biomarkers for response of immune therapies in 
ovarian cancer.[28] Both regulatory T cells and myeloid derived suppressor cells have been 
reported have a negative impact on ovarian cancer outcomes.[29, 30]  Control of these 
immunomodulatory elements may be possible with immune-base therapies.  Upregulation of 
PD-1 on regulatory T cells has been shown to suppress CD8+ immune response through the 
PD-1/PD-L1 interaction.[31]  We will collect peripheral blood mononuclear cells (up to 200 
mls) before treatment and after 3 and 5 cycles to perform flow cytometry analysis on the 
regulatory T cell population and MDSC populations.  We will also assess the percentage of 
regulatory T cells that have upregulated PD-1.  Monocyte derived dendritic cells exposed to 
platinum chemotherapy during maturation have been shown to induce higher T cell 
proliferation and produce higher levels of interferon gamma and IL-2 compared to untreated 
DC.[18]  Therefore, we will also assess DC phenotype at baseline and after cycles 3 and 5.  
We will correlate these findings with response rates, OS, PFS, and toxicities. 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   

 
 
 
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
ANA 
 
Chloride 
 
CA-125 
 
Glucose 
 
Blood for correlative studies 
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

 
 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.4 Sample Collection and Storage.   
Samples will be labeled with a unique patient identifier (without PHI).  The samples will be 
processed within 24 hours, logged into our specimen tracking system and stored in a 
temperature monitor freezer.  
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 24 months of treatment 
with pembrolizumab may discontinue treatment with the option of restarting treatment if they 
meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment following 
assessment of CR, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding 
The trial is open label. 
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 
During this time we are collecting source documents to be used to assess the subject’s 
eligibility to the study. 
7.1.5.1.1 Screening Period 
There is not a set screening period for this study.  Subjects must meet the eligibility 
requirements prior to initiation of study treatment. 

 
 
 
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7.1.5.2 Treatment Period 
The treatment period is 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study drug, whichever is later, or until progression of disease.  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. Subjects with disease progression may continue 
study drug per discretion of PI. 
7.1.5.3 Post-Treatment Visits 
Once a subject discontinues the study (either early or after study completion) we will perform 
a follow-up safety evaluation approximately 30 days after last treatment.  We will continue 
collect tumor imaging reports approximately every 12 weeks per standard of care post the 
discontinuation of study until death, withdrawal of consent, or the end of the study, whichever 
occurs first.  
In addition, survival data will be collected every 12 weeks until death, withdrawal of consent, 
or the end of the study, whichever occurs first.  
7.1.5.4 Safety Follow-Up  
The mandatory Safety Follow-Up evaluation 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 should be recorded.  Subjects 
with an AE of Grade > 2 related to study treatment will be followed until the resolution of the 
AE to baseline or grade 1 or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded.  Subjects who are eligible for 
retreatment with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety 
follow-up visits, one after the Treatment Period and one after the Second Course Phase. 
Safety follow up may be done at the Discontinuation/End of Treatment visit. 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and every 12 weeks will be assessed for 
survival status until death, withdrawal of consent, becoming lost to follow-up or the end of the 
study, whichever occurs first.  
7.1.5.5 Second Course Phase (Re-treatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 

 
 
 
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• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 

 
 
 
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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. 
Adverse events may occur during the course of the use of the Merck product (pembrolizumab) 
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. 
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 End of 
Treatment/Discontinuation visit.  Adverse events will be collected on day 1 of each cycle 
through subject self reporting and clinician observation. Events may be clarified from previous 
medical records. Lab values are to be reviewed for treatment days 1, 8, 15 and documented in 
the database as adverse events, if applicable.  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 of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab.  Appropriate supportive treatment should be 
provided if clinically indicated.  In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of the 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.” 

 
 
 
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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 215 661-6229) 
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 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 215 661-6229) 
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 an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause 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 

 
 
 
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reported within one business day 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:  +1-215-661-6229 
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 215 661-6229) 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 215 221-6229)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, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 

 
 
 
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1. Additional adverse events: 
 
 
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 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 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

[Type text] 
[Type text] 
 
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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 

[Type text] 
[Type text] 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 
 

 
 
 
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7.2.4.1 Pembrolizumab Expected Adverse Events 
Likely (≥10% of patients) 
 
Less likely (≥5%) 
 
Rare but serious (≥0.2%) 
• 
Anemia 
• 
Fatigue 
• 
Itching 
• 
Cough 
• 
Nausea 
• 
Decreased appetite 
• 
Diarrhea 
• 
Shortness of breath 
• 
Arthralgia 
• 
Rash 
• 
Constipation 
• 
Headache 
• 
Vomiting 
• 
Weakness 
• 
Fever 
• 
Back pain 
• 
Swelling (limbs) 
 
 
• 
Fatigue 
• 
Decreased appetite 
• 
Hypothyroidism  
• 
Thyroiditis 
• 
Itching 
• 
Diarrhea 
• 
Arthralgia 
• 
Weakness 
• 
Nausea 
• 
Myalgia 
• 
Vitiligo 
 
 
• 
Pneumonitis* 
• 
Diarrhea 
• 
Colitis 
• 
Fever 
• 
Autoimmune hepatitis 
• 
Hyper thyroidism 
• 
Shortness of breath 
• 
Nausea 
• 
Low sodium in blood 
• 
Adrenal insufficiency 
• 
Pneumonia 
• 
Immune-mediated 
myocarditis 
• 
Stevens-Johnson Syndrome 
(SJS)  
• 
Toxic Epidermal Necrolysis 
(TEN) 
• 
Encephalitis 
• 
Scarcoidosis 
• 
Myasthenic syndrome 
• 
Graft vs. host disease 
(GVHD) in patients with a 
history of allogenic 
hematopoietic stem cell 
transplant (HSCT).  
Sometimes this condition can 
lead to death. 
• 
If you have had a solid organ 
transplant, you may 
experience rejection of the 
transplanted organ. 
• 
Arthritis (inflammation of the 
joints which may include 
joint pain, stiffness and/or 
swelling) 
 
7.2.4.2 Carboplatin Expected Adverse Events   

 
 
 
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Likely (>20% of patients) 
 
Less likely (4-20%) 
 
Rare but serious (<3%) 
• 
Hair loss 
• 
Vomiting, nausea 
• 
Infection, especially 
when white blood cell 
count is low 
• 
Anemia which may cause 
tiredness, fatigue, or may 
require blood transfusions 
• 
Bruising, bleeding 
• 
Belly pain 
 
• 
Diarrhea, Constipation 
• 
Numbness and tingling in 
fingers and toes 
• 
Allergic reaction: which may 
cause rash, low blood 
pressure, wheezing, shortness 
of breath, swelling of the face 
or throat 
• 
Changes in taste 
• 
Changes in vision 
 
• 
Damage to organs which 
may cause hearing and 
balance problems 
 
 
7.2.4.3 Potential Overlapping Toxicities 
The combination of pembrolizumab and carboplatin could cause side effects we do not know 
about yet.  When recording adverse events we will be making every attempt to distinguish 
which study treatment contributes to the adverse event: (1) pembrolizumab, (2) carboplatin, 
(3) both pembrolizumab and carboplatin or (4) neither of the treatments. 
From the tables above there are some common side effects for pembrolizumab and carboplatin.  
Likely (≥10% of patients) 
 
Less likely (≥5%) 
 
Rare but serious (≥0.2%) 
• 
Anemia 
• 
Fatigue 
• 
Nausea 
• 
Diarrhea 
• 
Shortness of 
breath 
• 
Constipation 
• 
Vomiting 
 
• 
Fatigue 
• 
Diarrhea 
• 
Nausea 
• 
Constipation 
• 
Allergic reaction: which may cause shortness 
of breath 
 
• 
Diarrhea 
• 
Nausea 
• 
Shortness of breath 
 
7.2.5 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.  
8.0 STATISTICAL CONSIDERATION AND ANALYSIS PLAN 
8.1 
Sample size and power 
Assume the response rate for the platinum re-treatment therapy in platinum pre-treated ovarian, 
fallopian tube, and primary peritoneal cancer patients is 23%. One of the primary objectives of 
this phase I/II trial is to test whether a new combinatory therapy (platinum + anti-PD1 

 
 
 
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antibody) can achieve a higher response rate (RR). We hypothesize that the true clinically 
significant response rate for the new therapy is 40~50%. The following table shows the sample 
size required to have either 80% or 90% power to declare statistical significance at level 0.05 
for a true response rate at 40%, 45%, or 50%. A sample size of 27 patients will be required to 
have 80% power when the true response rate of the new combinatorial therapy is around 50%.  
 
Response Rate of the new Therapy 
Power 80% 
Power 90% 
40% 
66 
88 
45% 
41 
54 
50% 
27 
37 
 
 
Furthermore, it is desirable to determine the response rate of the new combinatory therapy with 
sufficient precision. We can compute the standard error (SE) of the estimated response rates 
as the measure of precision for a range of true response rates. For the true response rate being 
in the range of 40%-50%, the SE does not vary much (0.07~0.09), and so there is adequate 
precision to detect the targeted response rate at 40-50%.  
The median progression-free survival time is another efficacy endpoint of interest. Suppose 
the median progression-free survival time is 17, 20, or 23, and for the target sample size 27, 
the power to detect a statistically significant improvement in median progression-free survival 
time assuming accrual time is 1 year and the follow-up time is 1 year is listed in the following 
table. This table shows that our targeted sample size provides good power to detect 40% or 
more improvement in median progression-free survival time. 
 
The median PFS in historical control 
 
40% improvement in the 
new therapy 
60% improvement in 
the new therapy 
 
17 weeks 
0.68 
0.89 
 
0.66 
0.88 

 
 
 
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20 weeks 
 
23 weeks 
0.65 
0.89 
 
8.2 
 Statistical analysis plan 
Clinical characteristics of the study cohort at the time of initial diagnosis will be tabulated, 
including age, stage, surgical optimality, and disease status after initial platinum therapy. The 
clinical characteristics and outcome of platinum-resistant patients will be also tabulated when 
retreated with the combinatory therapy.  
 
The RR is the primary efficacy variable. The point estimate and the 95% exact confidence 
intervals will be reported for RR. The comparison with the historical control rate will be 
conducted by examining whether the 95% confidence internal covers the historical control rate.  
Additional analyses will be conducted to evaluate in logistic regression models the odds ratio 
of response rate on predictors such as platinum-free interval, time to progression after previous 
platinum treatment, number of prior platinum regimens etc. Other efficacy endpoints, which 
included progression free survival (PFS) and overall survival (OS), were also analyzed. Time-
to-event variables were analyzed using the Kaplan-Meier method. Kaplan-Meier estimates of 
the survival function with 95% CIs at specific time points (using Greenwood’s formula for the 
standard error) were computed.  Comparisons with the historical control PFS and OS will be 
conducted by examining whether the 95% confidence internal covers the historical control 
proportions.   
 
The safety population included all patients who received at least one dose of study medication. 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
The number and the percentage of patients who are removed from the study or altered dose 
regimen due to adverse effects will be reported.  
 
 
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. 

 
 
 
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Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
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.  
10.0 ADMINISTRATIVE AND REGULATORY DETAILS  
10.1. Institutional Review Board 

 
 
 
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In accordance with federal regulations, an Institutional Review Board that complies with the 
regulations in 21 CFR 56 must review and approve this protocol and the informed consent 
form prior to initiation of the study. 
 
10.2. Study Team Roles and Responsibilities 
Dr. Liao, the PI, will be responsible for the oversight of the research.  Dr. Liao is responsible 
for ensuring that all information and documentation related to the conduct and safety of the 
study is disseminated to the proper agencies in the proper timeframe.  In addition, Dr. Liao 
will delegate study responsibilities to qualified and trained research staff. 
 
Research physicians/sub-investigators will be responsible for conducting consent conferences.  
Research physicians/physician extenders may perform assessment as per the delegation log.  
 
Research Nurses/Coordinators will be responsible for initial screening and scheduling patient 
visits.  The Research Coordinators will ensure that the clinical data is entered into the database 
in a timely manner, so as to have real time data to review and report any safety concerns trends.  
They will also be responsible for maintaining regulatory documentation to the various agencies 
involved with this research and ensure that all research team members are following the 
protocol and all regulations.   
 
All clinical research staff are required to complete the following training: 
1. Human Subjects Protections 
2. HIPAA 
3. Good Clinical Practice 
 
New staff will also be required to review any existing standard operating procedures.  This 
review will be documented that they understand the information.  Existing staff will also be 
trained on new standard operating procedures and this training will also be documented on a 
Training Log for monitors to review at a site visit, if inclined.    
 
10.3 
Confidentiality 
All eligible patients will be assigned a UPN that will not contain any personally identifying 
information, such as name, initials, medical record number, social security number, etc.  To 
maintain confidentiality, we protect the link between the patients’ personal identifying 
information and UPN number by limiting who has access to the patients’ chart documentation.  
Only delegated clinical research staff has access to the data, which remain locked at all times 
when not in use. 
 
All hard copy research records collected on potential and enrolled patients are stored in a 
locked filing cabinet that can only be accessed by approved clinical research staff when not in 
use.  This staff includes: PI/study physician(s), and designated clinical research staff.  These 
are also the only people that have access to the link between the patients’ personal identifying 
information and their assigned UPN codes. 
 
In terms of the protections and security of electronic clinical data, it is being performed by the 
University of Washington Information Technology (UW IT) Services.  The UW IT information 

 
 
 
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security policy is to protect University of Washington (UW) information and information 
systems. It also ensures compliance with UW policy and state and federal regulations.  
  
10.4 Compliance with Financial Disclosure Requirements 
We will comply with the Financial Conflict of Interest Policy (GIM 10) mandated by the Office 
of Sponsored Programs of University of Washington. 
http://www.washington.edu/research/osp/gim/gim10.html 
10.5 Compliance with Law, Audit and Debarment 
We will follow the terms of the signed contract and any subsequent amendments. 
10.6 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.     
10.7 Quality Management System 
Our group has extensive experience running investigator initiated Phase I and II clinical trials.  
We have established collection materials and database which we are capable of entering, 
tracking and reporting clinical trial information, laboratory samples, and reporting 
requirements.  We meet regularly to discuss active clinical trials in terms of recruitment, 
adverse events or any other issue that might arise.   In addition, all clinical staff are trained in 
HIPAA, Human Subjects and GCP.   
10.7.1  Data Management  
10.7.2  Collection 
We have developed collection methods (case report form and source documentation) to capture 
study specific data.  This includes, but in not limited to the capture of a patients prior disease 
treatment, clinical laboratory values, adverse events, medications and post enrollment 
treatments.   
10.7.3 Database 
10.7.3.1. Deviation Tracking 

 
 
 
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We have developed a deviation tracking tool within our database, which allows us to track the 
deviation, reporting requirements and study and regulatory outcomes. 
This report can easily be pulled for reporting purposes. 
10.7.3.2 Auditing 
We perform regular internal audits and track the results.  By doing this we are able to determine 
a trend in data collection methods and allow for improvements in data collection instruments 
or training.   
The database incorporates a robust data auditing and tracking feature that documents any data 
change made to an existing record in the study database, who made the data changes, and when 
the update was made.  The module also tracks the creation and deletion of any records in 
individual tables and the user who deleted or added the record 
 
 
10.7.3.3 Long Term Follow Up 
We have the ability to develop report(s) that allow us to determine when a subject is due to for 
a study procedure (i.e. imaging or survival data). 
10.7.4 Security 
The database is password protected.  Passwords are changed every 90 days.  Access privileges 
are obtained when a new employee is hired.  If something is developed or requires new 
privileges then access will be assessed at that time. 
If there is a change in a clinical research staff responsibilities access will reassessed at that 
time.  However, once someone has access privileges they can maintain this until they leave 
their position. 
 
10.7.5  Systems Backup 
The database is stored on a HIPAA compliant secure server with access granted only to the 
Tumor Vaccine Group.  The database is backed-up on tape and stored off-site and the tape is 
handled according to HIPAA regulations.  
11.0 
MONITORING  
12.0 
PLAN 
12.1 Institutional Study Monitoring:  
Institutional support of trial monitoring will be in accordance with the FHCRC/UW Cancer 
Consortium Institutional Data and Safety Monitoring Plan.  Under the provisions of this plan, 
FHCRC Clinical Research Support (CRS) coordinates data and compliance monitoring 

 
 
 
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conducted by consultants, contract research organizations, or Fred Hutch employees 
unaffiliated with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits 
per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/UW Cancer Consortium Institutional Review Board (IRB).  The review committees 
evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and safety 
monitoring plan for studies actively enrolling or treating patients.  The IRB reviews the study 
progress and safety information to assess continued acceptability of the risk-benefit ratio for 
human subjects.  Approval of committees as applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
12.2 Medical Monitor 
The Medical Monitor, Ron Swensen, M.D., will review data with the P.I., designee, and/or other 
members of the clinical team, approximately every 6 months.  All patients are reviewed for 
adverse events.  Conduct of the study is reviewed and changes/clarifications can be 
requested/discussed with the Medical Monitor 
 
13.0   APPENDICES  
13.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 

 
 
 
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13.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
13.3 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. 
13.4 Carboplatin Package Insert 
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4180b_03_05_Carboplatin%20label%201-9-04%20FDA.pdf  
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