Phase Ib Trial of Pembrolizumab (MK-3475) With Platinum-Based Chemotherapy in Small Cell/Neuroendocrine Cancers of Urothelium and Prostate
Phase: PHASE1
Conditions: Bladder Small Cell Neuroendocrine Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Prostate Carcinoma Metastatic in the Bone, Prostate Neuroendocrine Neoplasm, Prostate Small Cell Carcinoma, Stage III Bladder Cancer American Joint Committee on Cancer ( AJCC) v8, Stage III Prostate Cancer AJCC v8, Stage III Urethral Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IV Urethral Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Stage IVB Bladder Cancer AJCC v8, Ureter Small Cell Carcinoma, Urothelial Carcinoma
Sponsor: Jonsson Comprehensive Cancer Center

 
University of California, Los Angeles 
Phase Ib Trial of Pembrolizumab (MK-3475) with Platinum-based Chemotherapy in Small Cell/Neuroendocrine 
Cancers of Urothelium and Prostate 
Principle Investigator: Arnold Chin, M.D. 
Protocol:  22 May 2022 
 
NCT Number: NCT03582475 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab 
(MK-3475) 
with 
Platinum-based 
Chemotherapy in Small Cell/Neuroendocrine Cancers of 
Urothelium and Prostate 
Trial Phase 
Phase Ib 
Clinical Indication 
The treatment of subjects with locally advanced or metastatic 
1) naïve small cell cancer of the bladder (SCB), urethra, or 
upper urinary tract, and 2) primary small cell or 
neuroendocrine prostate cancer (NEPC) 
Trial Type 
Interventional 
Type of control 
No treatment control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Pembrolizumab 200 mg IV q3 weeks for up to 2 years 
Chemotherapy cycle q3 weeks for 4 to 6 cycles: 
Etoposide 100 mg/m2 on day 1-3 + Cisplatin 70-80 
mg/m2 on day 1 OR Carboplatin 4-5 AUC on day 1 
OR 
Docetaxel 60 mg/m2 on day 1 + Carboplatin 4-5 AUC 
on day 1 
Number of trial participants 
Approximately 15 patients will be enrolled. 
Estimated enrollment period 
We estimate that the trial will require approximately 24 
months from the time the first subject signs the informed 
consent until the last subject’s consent. 
Estimated duration of trial 
We estimate that the trial will require approximately 36 
months from the time the first subject signs the informed 
consent until the last subject’s last study-related phone call 
or visit. 
Duration of Participation 
Each subject will participate in the trial from the time the 
subject signs the Informed Consent Form (ICF) through the 
final protocol-specified contact. After a screening phase of up 
to 28 days, eligible subjects will receive pembrolizumab on 
Day 1 of the 3-week (Q3W) dosing cycle and continue for a 
maximum 
of 
35 
cycles 
unless 
specific 
withdrawal/discontinuation criteria are met. Treatment with 
etoposide and cisplatin/carboplatin or docetaxel and 
carboplatin will occur on Day 1 for a maximum of 6 cycles 
unless specific withdrawal/discontinuation criteria are met. 
Treatment on trial will continue until verification of disease 
progression, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, 

 
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investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, non-compliance 
with trial treatment or procedure requirements, or 
administrative reasons. Upon progression on treatment, 
patients will be asked to undergo an additional biopsy and 
blood draw. After the end of treatment, each subject will be 
followed for 30 days for adverse event (AE) monitoring. 
Serious AEs will be collected for 90 days after the trial 
treatment or 30 days after the end of treatment if the subject 
initiates new anti-cancer therapy, whichever is earlier. All 
drug-related SAEs will be reported regardless of time frame. 
All subjects will be followed for overall survival every 12 
weeks until death, withdrawal of consent, or the end of the 
trial. 
Estimated average length of 
treatment per patient 
Average length of treatment per patient can range from 4 to 
24 months. 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a non-randomized, multi-center, multi-cohort, open-label, Phase Ib trial of pembrolizumab 
(MK-3475) in combination with standard-of-care cisplatin-based chemotherapy in subjects with 
locally advanced or metastatic, 1) naïve small cell cancer of the bladder (SCB), urethra, or upper 
urinary tract, and 2) primary small cell or neuroendocrine prostate cancer (NEPC). Chemotherapy 
will include etoposide and cisplatin/carboplatin for Cohorts 1 and 2, with the option of docetaxel 
and carboplatin for Cohort 2. 
 
Approximately 15 subjects will be enrolled in the trial with 7-8 subjects per cohort. Subjects will 
be enrolled regardless of programmed death-ligand 1 (PD-L1) status. Subjects must have 
measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as 
determined by investigator/site radiologist.  
 
For both cohorts, subjects must provide tumor tissue. For Cohort 1, an archival formalin-fixed 
paraffin-embedded (FFPE) tumor tissue within 6 months of screening is required. For Cohort 2, 
an archival formalin-fixed paraffin-embedded (FFPE) tumor from a soft tissue lesion or bone 
biopsy within 6 months of screening is required. Tumor blocks are preferred. Fresh frozen tissue 
will be an adjunct to FFPE. No new systemic anti-neoplastic therapy may be administered between 
the biopsy and initiating study medication. The qualifying biopsy does not need to be obtained 
after consent for this trial is signed.  
 
In both cohorts, subjects will receive pembrolizumab 200 mg on day 1 for each 3-week cycle 
(Q3W). Chemotherapy will consist of etoposide 100 mg/m2 on day 1-3 and cisplatin 70-80 mg/m2 
or carboplatin 4-5 AUC on day 1 for both Cohorts 1 and 2. Carboplatin will be substituted for 
cisplatin-ineligible subjects. Cohort 2 has an option for docetaxel 60 mg/m2 on day 1 and 

 
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carboplatin 4-5 AUC on day 1. Subjects will receive 4-6 cycles of chemotherapy with a maximum 
35 doses of pembrolizumab. 
 
Subjects with small cell of the urothelium may undergo surgery of primary disease site and 
regional lymph nodes (e.g. radical cystectomy or nephroureterectomy) as standard-of-care therapy 
after chemotherapy. Pembrolizumab may be held to allow recovery and then to continue on study. 
Tissue and blood may be obtained at the time of surgery. Subjects with primary small cell of the 
prostate may undergo surgery or radiation of primary disease and regional lymph nodes as 
standard-of-care after chemotherapy. Pembrolizumab may be held to allow recovery and then to 
continue on study. Tissue and blood may be obtained at the time of surgery or prior to radiation. 
 
The primary objective of this trial is to evaluate the preliminary efficacy of pembrolizumab (MK-
3475) in combination with standard-of-care cisplatin-based chemotherapy by assessing the durable 
response rate (DRR), overall response rate (ORR), duration of response (DOR), and progression 
free survival (PFS) by RECIST 1.1 and overall survival (OS) in Cohorts 1 and 2, in addition to 
radiographic PFS (rPFS) by PCWG3 and PSA response in Cohort 2 1. The secondary objectives 
are to determine the safety and tolerability of pembrolizumab in combination with etoposide and 
cisplatin/carboplatin or docetaxel and carboplatin assessed by parameters of adverse events (AEs) 
The exploratory objectives are to correlate response to treatment with tissue and serum biomarkers 
including PD-L1 expression.  
 
Central safety and efficacy will be monitored by the UCLA data safety and monitoring board 
(DSMB). Adverse events will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. Subjects showing clinical benefit in the trial will be allowed to continue treatment 
regardless of a decision to stop enrollment or suspend the study. 
 
Subjects will be evaluated initially at 9 weeks (63 +/- 14 days) with radiographic cross sectional 
imaging to assess response to treatment while on chemotherapy and then every 12 weeks (84 +/- 
14 days, based on the date of the previous scan) thereafter until progression or up to approximately 
2 years from time of treatment initiation. Additionally, in Cohort 2, bone scans will be evaluated 
in conjunction with cross sectional imaging. Prostate-specific antigen (PSA) levels will be 
measured every 6 weeks (± 3 days). All imaging obtained on study will be assessed using RECIST 
1.1 for determination of DRR, ORR, DOR, and PFS, and for rPFS by PCWG3 in Cohort 2. 
Treatment on trial will continue until verification of disease progression, unacceptable AE(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdraws consent, pregnancy of the subject, non-compliance with 
trial treatment or procedure requirements, administrative reasons, or the subject has received 35 
trial treatments of pembrolizumab. If subjects with radiographic progression are clinically stable 
or improved, an exception may be considered to continue treatment upon consultation with 
Sponsor.  
 
After the end of trial treatment, each subject will be followed for 30 days for AE monitoring. 
Serious AEs will be collected for 90 days after trial treatment or 30 days after the end of treatment 
if the subject initiates new anti-cancer therapy, whichever is earlier.  

 
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Subjects who stop the trial treatment after receiving 35 administrations of pembrolizumab for 
reasons other than disease progression or intolerability or who attain a complete response (CR), 
may be eligible for up to 17 administrations of re-treatment upon experiencing disease progression 
at the discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject still meets the safety parameters listed in the inclusion/exclusion 
criteria, and the trial remains open. 
 
Subjects who experience disease progression will be asked to undergo an additional biopsy and 
blood draw. Subjects will have post-treatment follow-up for disease status until death, withdrawing 
consent, or end of the trial. All subjects will be followed for overall survival every 12 weeks until 
death, withdrawal of consent, or the end of the trial, whichever comes first. 
 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in the Trial Procedures - Section 7.0.  
 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1. 
 
Figure 1 Trial Design 
3.0 OBJECTIVE(S) 
Safety and tolerability, will be assessed using all subjects. Additional objectives will be assessed 
by each cohort. There will be no hypothesis testing performed in this study. 

 
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3.1 
Primary Objective 
Objective: To evaluate the preliminary efficacy of pembrolizumab (MK-3475) in combination 
with standard-of-care cisplatin-based chemotherapy by assessing the durable response rate 
(DRR), overall response rate (ORR), duration of response (DOR), and progression free 
survival (PFS) by RECIST 1.1 and overall survival (OS) in Cohorts 1 and 2, and radiographic 
PFS (rPFS) by PCWG3 and PSA response in Cohort 2. 
3.2 
Secondary Objective 
Objective: To determine the safety and tolerability of pembrolizumab in combination with 
etoposide and cisplatin/carboplatin or docetaxel and carboplatin assessed by parameters of 
adverse events (AEs). 
3.3 
Exploratory Objective 
Objective: Determine correlation of biomarkers including PD-L1 expression (PD-L1 positive 
≥1% by immunohistochemistry (IHC) using 22C3 antibody), and serum and tissue molecular 
(including genomic, proteomic) biomarkers that may be indicative of clinic response or safety.  
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator Brochure (IB). 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades 2.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma 3,4. 

 
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4.1.4.1 Etoposide  
Etoposide is a topoisomerase II inhibitor that complexes with DNA and prevents re-ligation of 
DNA strands leading to DNA strand breaks, errors in DNA synthesis, and promotes cellular 
apoptosis.  It is approved for patients with SCLC and testicular cancer.  Major adverse effects 
(>10%) include alopecia, nausea and vomiting, bone marrow suppression, and (1-10%) 
hypotension, peripheral neuropathy, stomatitis, hepatotoxicity, and hypersensitivity. The 
secondary occurrences of acute leukemia (<1%) have been reported after long term use. 
Etoposide can be given for patients on dialysis. For patients on hemodialysis, dose will be 
reduced by 50% with administration on a non-dialysis day and then hemodialysis the following 
day. For patients on peritoneal dialysis, dose will be reduced by 50%, with dialysis performed 
daily 16. 
 
Refer to package insert for complete drug information.   
4.1.4.2 Docetaxel 
Docetaxel promotes the assembly of microtubules in the cell and inhibits depolymerization of 
tubulin, which results in inhibition of DNA, RNA, and protein synthesis predominantly in the M 
phase of the cell cycle.  It is indicated for patients with locally advanced or metastatic breast cancer, 
NSCLC, mCRPC, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck 
cancer.  Major adverse effects (>10%) include neuropathy, alopecia, fluid retention, stomatitis, 
bone marrow suppression, elevated transaminases, hypersensitivity, infection, weakness and 
myalgia, pulmonary toxicity, fever and (1-10%) decreased ejection fraction, motor neuropathy, 
dysgeusia, increased bilirubin, and arthralgia. 
To reduce the severity of hypersensitivity reactions and fluid retention following administration, 
patients are typically premedicated with steroids and continue on steroids during the treatment 
cycle. In TAX 327, dexamethasone 8 mg was given 12, 3, and 1 hour prior to docetaxel infusion 
with prednisone 5 mg PO bid 17. 
Refer to package insert for complete drug information.   
4.1.4.3 Cisplatin 
Cisplatin is a platinum-containing agent that inhibits DNA synthesis by formation of DNA 
crosslinks and is approved for patients with bladder, ovarian, and testicular cancer in 
combinational therapies.  Off-label it is commonly used in combination for small cell carcinomas 
(NCCN guidelines) 18,19. Major adverse effects (>10%) include neurotoxicity, nephrotoxicity, 
nausea and vomiting, bone marrow suppression, increase in liver enzymes, ototoxicity, and (1-
10%) local irritation.  
Cisplatin ineligibility is common 20. Established guidelines (ie, NCCN and European Society of 
Medical Oncology [ESMO]) include the following considerations in determining if a subject is 
clinically ineligible for cisplatin: CTCAE v.4, Grade ≥2 peripheral neuropathy; CTCAE v.4, Grade 

 
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≥2 audiometric hearing loss (25 decibels in 2 consecutive wave ranges); CrCl <60 mL/min but ≥30 
mL/min; New York Heart Association Class III heart failure; and ECOG PS of 2. 
Dose of cisplatin is 70-80 mg/m2 based on treating physician preference.  Alternatively, for 
subjects with CrCl ≥30 and <60, cisplatin dose can be split 50% over two days with the first dose 
given Day 1 and second dose given Day 8 (± 3 Days).  
Refer to package insert for complete drug information.   
4.1.4.4 Carboplatin 
Carboplatin is a second-generation platinum agent that is indicated for patients with ovarian 
cancer, and often used as a substitute in cisplatin-ineligible patients 
Dose of carboplatin is AUC 4-5 based on treating physician preference. Glomerular filtration rate 
(GFR) can be determined using a variety of validated calculators, including but not limited to 
Cockroft-Gault, Jelliffe, or Modification of Diet in Renal Disease (MDRD) etc. Carboplatin can 
be used for patients on dialysis. For patients on hemodialysis, dose (in mg) will be target AUC x 
25 to be administered on a non-dialysis day and then hemodialysis the following day. For patients 
on peritoneal dialysis, dose will be reduced by 75%, with dialysis performed daily 16. 
Major adverse effects (>10%) include central nervous system pain, electrolyte abnormalities 
including hyponatremia and hypokalemia, nausea and vomiting, bone marrow suppression, 
increase in liver function tests, hypersensitivity, neuromuscular weakness, nephrotoxicity, and (1-
10%) peripheral neuropathy, alopecia, constipation or diarrhea, bleeding complications, infection, 
increased bilirubin, visual disturbances, and ototoxicity. 
Refer to package insert for complete drug information.   
4.1.4.5 Response to Etoposide and Platinum (Cisplatin/Carboplatin) or Docetaxel and 
Carboplatin in Small Cell Cancers 
The combination of etoposide and cisplatin is the mainstay chemotherapy regimen for SCLC based 
on clinical activity and toxicity profiles 21,22.  In SCLC, although response rates of 50-80% are 
seen in first-line treatment with etoposide and cisplatin, progression invariable occurs with poor 
outcomes to second-line therapies and median OS of 8 to 12 months and 2 year OS of 5% 13.  Thus, 
despite an initial high response rate, the etoposide and cisplatin doublet shows poor durability of 
responses. 
Systemic therapy plays a major role in the treatment of small cell bladder and prostate carcinomas. 
In SCB there are no randomized clinical trials to base therapy, and regimens have been selected 
on retrospective data and small phase II trials. For localized SCB (including small cell urethral and 
upper urinary tract), systemic therapy using neoadjuvant etoposide and cisplatin followed by 
definitive local therapy improves clinical outcomes 23–25. For metastatic SCB, etoposide and 
cisplatin is the preferred primary therapy with alternative agents including topotecan, 
anthracyclines, and vinca alkaloids 26,27.  

 
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As the majority of SCB have mixed histology, rationale strategies need to account for the urothelial 
carcinoma component. Cisplatin-based chemotherapy is the standard first-line treatment for 
patients with advanced urothelial carcinoma 28–30. Carboplatin is often substituted for cisplatin, but 
is associated with inferior outcomes 31. Thus, the combination of etoposide and cisplatin is the 
preferred regimen for SCB, with carboplatin reserved for cisplatin-ineligible patients. 
A phase II trial in SCB showed a high, but transient response rate to either etoposide/cisplatin or 
ifosfamide/doxorubicin doublets, with a median overall survival of 13 months in the metastatic 
setting 32. This further supports the poor DOR of small cell carcinomas to chemotherapy. 
Primary small cell carcinoma of the prostate is a rare disease and is typically treated with etoposide 
and cisplatin chemotherapy, similar to the treatment of SCLC (NCCN guidelines) 33. NEPC, in 
contrast, is a treatment-emergent disease of patients with metastatic castrate resistant prostate 
cancer (mCRPC) treated with androgen deprivation therapy (ADT), with phenotypes ranging from 
focal neuroendocrine with predominant adenocarcinoma, an intermediate histology between 
adenocarcinoma and small cell carcinoma, to pure small cell differentiated carcinoma 33. Although 
few prospective trials have been conducted, current treatment includes cytotoxic chemotherapy 
with platinum-based regimens including etoposide and cisplatin with continued ADT 34. 
Similar to SCLC and SCB, NEPC has a high response rate to etoposide and platinum-based 
chemotherapy, but at disease progression often exhibits adenocarcinoma. This suggests the need 
to address both histologic phenotypes of this disease and led to use of docetaxel, which is the 
standard first-line chemotherapeutic in mCRPC, in combination with platinum-based 
chemotherapy. A phase II study incorporated first-line docetaxel and carboplatin and second-line 
etoposide and cisplatin in 120 patients with “anaplastic” prostate cancer 35. Because of toxicity 
concerns with cisplatin, carboplatin was used. While 65% were progression free after 4 cycles of 
docetaxel and carboplatin versus 33% with etoposide and cisplatin, median overall survival was 
16 months.  
These studies provide the evidence for use of etoposide and platinum-based chemotherapy for 
small cell cancers of the bladder and prostate, with the option of docetaxel and carboplatin for 
NEPC. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Population 
Small cell carcinomas (SCC) are aggressive malignancies found in multiple tissue types including 
the lung, bladder, prostate, ovaries, and breast 36.  They belong to a larger family of histologically 
defined neuroendocrine cancers that include well-differentiated carcinoid, adenocarcinoma with 
neuroendocrine differentiation, and large-cell carcinomas.  SCCs share common histologic and 
clinicopathologic features such as small, round-to-oval cells with high nuclear-to-cytoplasm ratios, 
frequent expression of markers such as neuron-specific enolase, synaptophysin, and 
chromogranin, rapid progression to metastatic dissemination, and relapse after response to 
chemotherapy 37.  These similarities infer a common molecular underpinning to the disease.  
Depending on the tissue of origin, and despite treatment with etoposide and platinum-based 

 
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chemotherapy, 5-year survival rates are typically less than 20%, making the treatment of small cell 
carcinomas an unmet need 38.  This trial is aimed to generate data that can change the standard-of-
care treatment of small cell carcinomas.  
 
Bladder cancer incidence is over 430,000 cases worldwide and accounting for over 165,000 deaths, 
making it the ninth most common cancer 39.  Approximately 90% of bladder cancers are urothelial 
carcinomas, which arise from the urothelial epithelium and occur not only in the bladder, but also 
renal pelvis, ureter (upper urinary tract) and urethra.  Small cell cancers of the bladder represent 
about 1% of bladder malignancies, and most commonly characterized as a mixed phenotype with 
urothelial carcinomas 40.  Small cell carcinomas are typically diagnosed by histology with poor 
utility of serum markers, and incomplete penetrance of histologic markers including neuron-
specific enolase (25-100%), chromogranin A (22-89%), and synaptophysin (60-76%), as well as 
CK7, CD57, and CD56 41.  Prognosis is worse than urothelial carcinoma with a 5-year overall 
survival rate of 19 to 25%.  With high risk for metastatic disease, the clinical management for even 
localized tumors is primary chemotherapy with etoposide plus platinum chemotherapy followed 
by consolidative surgery if feasible (see Section 4.1.4.5).  Carboplatin can be substituted in patients 
with cisplatin-ineligibility, including but not limited to impaired renal function, low performance 
status, or neurotoxicity.  
 
Analysis of the updated bladder The Cancer Genome Atlas (TCGA) of 412 samples as well as a 
retrospective tissue cohort of 307 transurethral resected untreated muscle-invasive urothelial 
carcinoma have described a neuronal/neuroendocrine subtype associated with a poor prognosis 
that lacks expression of the typical histologic markers 42,43.  This implies that bladder cancers with 
a neuronal/small cell phenotype may be more pervasive than previously described. 
 
Prostate cancer incidence is over 1,600,000 cases worldwide and one of the more common 
malignancies in men 44.  Small cell carcinomas of the prostate can arise de novo, which accounts 
for only approximately 1% of prostate cancer cases.  However, a neuroendocrine prostate cancer 
(NEPC) that emerges in patients with mCRPC following treatment with ADT may occur in up to 
20-40% of patients with mCRPC.  NEPC includes up to 15% of pure small cell differentiated 
cancers and 25% with an intermediate phenotype 45.  Clinically, patients with NEPC may exhibit 
visceral metastases, lytic bone metastases, and disease burden out of proportion to the serum 
marker PSA 35.  As with small cell carcinomas of urothelial origin, detection can be challenging 
as serum or tissue neuroendocrine markers such as chromogranin A, synaptophysin, and neuron-
specific enolase have limited sensitivity.  CEA may be an emerging prognostic marker for NEPC 
33,35.  Histology remains the standard for diagnosis of NEPC.  Prognosis is poor, with a median 
overall survival ranging from 10 to 19 months 45.  With over 26,000 deaths from CRPC in the US 
and 360,000 worldwide, the potential 20-40% of patients with NEPC will be an increasingly 
significant unmet clinical need 44,46. 
 

 
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• 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 differences in exposure.  The 
2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses 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. 
Patient with end-stage renal disease on hemodialysis or peritoneal dialysis have more limited 
treatment options. However, pembrolizumab has been tolerated in hemodialysis and peritoneal 
dialysis patients without dose modifications 51–54. In these patients, pembrolizumab will be given 
in combination with reduced dose etoposide and carboplatin. For patients on hemodialysis, 
pembrolizumab will be administered on non-dialysis days to coordinate with chemotherapy 
administration. There will be no administration changes for patients on peritoneal dialysis. 

 
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4.2.2.2 Chemotherapy 
A number of trials have examined the combination of pembrolizumab with chemotherapy, 
including 
ongoing 
studies 
using 
pembrolizumab 
with 
etoposide, 
docetaxel, 
and 
cisplatin/carboplatin. Toxicities have not been available to review for combination studies in small 
cell cancers, but other studies have suggested side effects are similar to what is expected when the 
drugs are given separately and discussed in 4.1.4. The doses and schedules of chemotherapy have 
been based on these trials and will be the following: etoposide 100 mg/m2 on day 1-3 and cisplatin 
70-80 mg/m2 on day 1 or carboplatin 4-5 AUC on day 1 with Q3W dosing; or docetaxel 60 mg/m2 
and carboplatin 4-5 AUC on day 1 with Q3W dosing. Dose modifications of etoposide and 
carboplatin for patients on dialysis are elaborated in 4.1.4.1 and 4.1.4.4. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
For this phase Ib trial, the primary efficacy endpoints will be to estimate DRR, ORR, DOR, and 
PFS by RECIST 1.1 and OS for Cohorts 1 and 2, and for rPFS by PCWG3 in Cohort 2. In addition, 
in the prostate cancer cohort, PSA will be measured, but may not be reliable in this setting as 
NEPC often exhibits disease disproportionate to PSA 35.  Durable responses have been 
demonstrated with pembrolizumab in subjects with SCLC and DOR will also provide meaningful 
initial evidence for clinical efficacy. 
 
4.2.3.2 Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with etoposide and cisplatin/carboplatin or docetaxel and 
carboplatin in subjects with small cell cancers of the bladder and prostate. The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE Version 4.0 
criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects 
who have received pembrolizumab. The attribution to drug, time-of-onset, duration of the event, 
its resolution, and any concomitant medications administered will be recorded. Adverse events 
will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and clinically significant 
laboratory changes. The mandatory Safety Follow-up Visit will be conducted approximately 30 
days after the last dose of trial treatment or before the initiation of a new anti-neoplastic treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-up Visit should be recorded. 
Subjects with an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or 
until the beginning of a new anti- neoplastic therapy, whichever occurs first. Serious AEs will be 
collected for 90 days after the trial treatment or 30 days after the end of treatment if the subject 
initiates new anti-cancer therapy, whichever is earlier.  
4.2.3.3 Biomarker Research 
 
Introduction 
 
Cancer immunotherapies represent an important and novel class of antitumor agents. However, 

 
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the mechanism of action of these exciting new therapies is not completely understood and much 
remains to be learned regarding how best to leverage these new drugs in treating patients. Thus, to 
aid future patients, it is important to investigate the determinants of response or resistance to cancer 
immunotherapy as well as determinants of AEs in the course of our clinical trials. These efforts 
will identify novel predictive biomarkers and generate information that will better guide single-
agent and combination therapy with immuno-oncology drugs. To identify novel biomarkers, we 
will collect biospecimens (e.g., blood components, tumor material) to support analyses of cellular 
components (e.g., protein, DNA, ribonucleic acid [RNA], metabolites) and other circulating 
molecules. Investigations may include but are not limited to:  
 
Germline (blood) Genetic Analyses (eg., single-nucleotide polymorphism analyses, whole exome 
sequencing, whole genome sequencing): This research will evaluate whether genetic variation 
within a clinical trial population correlates with response to the treatment(s) under evaluation. If 
genetic variation is found to predict efficacy or AEs, the data might inform optimal use of therapies 
in the patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations. Finally, microsatellite instability 
may be evaluated as this is an important biomarker for some cancers (ie, colorectal cancer).  
 
Genetic (DNA) analyses from tumor: The application of new technologies, such as next-generation 
sequencing, has provided scientists the opportunity to identify tumor-specific DNA changes (e.g., 
mutations, methylation status, microsatellite instability). Key molecular changes of interest to 
immune-oncology drug development include the mutational burden of tumors and the clonality of 
T-cells in the tumor microenvironment. Increased mutational burden (sometimes referred to as a 
‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. 
Mutational load can be estimated by exome sequencing or targeted sequencing. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all genes in 
the tumor genome. Thus, genome-wide approaches may be used for this effort. Note that in order 
to understand tumor-specific mutations, it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability may also be evaluated as this is an important biomarker 
for some cancers (ie, colorectal cancer). Microsatellite instability can be determined by PCR using 
a standard National Cancer Institute consensus of five microsatellite loci, including three 
dinucleotide repeat markers (D2S123, D5S346, D17S250) and two mononucleotide repeat 
markers (BAT 25 and BAT 26). Defects in mismatch repair genes can be determined by 
immunohistochemistry. 
 
Tumor and blood RNA analyses: Both genome-wide and targeted mRNA expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that correlate 
to clinical response to treatment with pembrolizumab or other immunotherapies. Pembrolizumab 
induces a response in tumors that likely reflects an inflamed/immune phenotype. Specific immune-
related gene sets (such as those capturing interferon-gamma transcriptional pathways) may be 
evaluated and new signatures may be identified. Individual genes related to the immune system 
may also be evaluated (e.g., IL- 10). MicroRNA profiling may also be pursued.  
 
Proteomics and Immunohistochemistry (IHC) using Blood or Tumor: Tumor and blood samples 
from this study may undergo proteomic analyses (e.g., PD-L1 IHC). PD-L1 protein level in tumor 
sections, assessed by IHC, has been shown to correlate with response to pembrolizumab in subjects 

 
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with NSCLC, and an in vitro diagnostic (IVD) device has been developed for use with 
pembrolizumab in NSCLC. Preliminary data indicates that this association may also be true in 
additional cancer types (ie, triple-negative breast cancer, head and neck, and gastric). Additional 
tumor- or blood-derived proteins may also correlate with response to pembrolizumab. Therefore, 
tumor tissue may be subjected to proteomic analyses using a variety of platforms that could 
include, but are not limited to, flow cytometry, immunoassays, liquid chromatography/mass 
spectrometry. This approach could identify novel protein biomarkers that could aid in subject 
selection for pembrolizumab therapy.  
Other blood and urine derived Biomarkers: In addition to expression on the tumor tissue, PD-L1 
and other tumor-derived proteins can be shed from tumor and released into the blood or urine. 
Assays such as enzyme-linked immunoassay measure such proteins in serum or urine. Correlation 
of expression with response to pembrolizumab therapy may identify new approaches for predictive 
biomarkers in blood or urine, representing a major advance from today’s reliance on assessing 
tumor biomarkers. This research would serve to develop such assays for future clinical use.  
 
4.3 
Benefit/Risk 
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness.  
Pembrolizumab has been administered in a large number of cancer subjects with a well-
characterized safety profile and has received regulatory approval for advanced melanoma, 
NSCLC, and urothelial carcinoma. Ongoing studies are investigating pembrolizumab as 
monotherapy or in combination in subjects with mCRPC and SCLC. 
Etoposide and cisplatin/carboplatin is the current standard-of-care treatment for small cell cancers 
of the urothelium and prostate and alternatively docetaxel and carboplatin for neuroendocrine 
prostate cancer. This regimen is determined from prior clinical responses described in 4.1.4.5. 
As the efficacy and safety profile of the pembrolizumab combination therapies has not been well 
characterized, there is risk that participating subjects may experience new side effects or will not 
respond to the combinations.  
Additional details regarding specific benefits and risks for subjects participating in this clinical 
trial may be found in the accompanying IB and Informed Consent documents. 
5.0 METHODOLOGY 
5.1 
Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of locally advanced or metastatic 1) naïve 

 
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small cell cancer of the bladder, urethra, or upper urinary tract, or 2) primary small cell or 
neuroendocrine prostate cancer will be enrolled in this study. 
 
2. Histological diagnosis of pure or mixed small cell or neuroendocrine cancer by a 
genitourinary pathologist is sufficient and confirmatory immunohistochemistry is not 
required. 
 
3. Cohort 1 will include subjects with no prior systemic chemotherapy for locally advanced 
or metastatic urothelial carcinoma, with the following exception(s): 
 
a. Platinum-based chemotherapy with recurrence > 12 months from completion of 
therapy is permitted. 
 
4. Cohort 2 will include subjects with no prior systemic chemotherapy for primary small cell 
prostate cancer, with the following exception(s): 
 
a. Platinum-based chemotherapy with recurrence > 12 months from completion of 
therapy is permitted. 
 
5. Cohort 2 will include subjects with ongoing/prior treatments for mCRPC including: 
 
a. Prior chemotherapy with 2 other agents is allowed if > 6 months elapsed from last 
dose (if docetaxel chemotherapy is used more than once for hormone-sensitive and 
for mCRPC it will be considered 1 therapy). 
b. Ongoing androgen deprivation therapy with up to 2 second-generation hormonal 
manipulations (e.g. including but not limited to abiraterone acetate and/or 
enzalutamide). Subjects will remain on androgen deprivation therapy while on 
study treatment. 
c. Ongoing treatment with for bone metastasis (e.g. denosumab or zoledronic acid) is 
permitted. 
d. Prior immunotherapy with sipuleucel-T is allowed if completed > 4 weeks prior to 
trial enrollment.  
 
Male participants: 
 
6. A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 120 days after the last dose of 
pembrolizumab or 180 days after chemotherapy and refrain from donating sperm during 
this period. 
 
 
Female participants: 
 
 
7. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
 

 
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a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during 
the treatment period and for at least 120 days after the last dose of pembrolizumab 
or 180 days after chemotherapy. 
 
8. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
9. Have measurable disease based on RECIST 1.1, with the following exception(s): 
 
a. Patients with locally advanced disease defined as muscle-invasive or involving 
prostatic stroma who are eligible for systemic chemotherapy as standard of care. 
Lesions situated in a previously irradiated area are considered measurable if progression 
has been demonstrated in such lesions. 
 
10. Have provided archival tumor tissue sample of a tumor lesion not previously irradiated 
within 6 months of screening.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks 
are preferred to slides. In addition, the availability of fresh frozen tissue is encouraged.  
 
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7 days prior to the date of treatment 
initiation. 
 
12. Have adequate organ function as defined in the following table (Table 1).   
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
≥70 000/µL for participants with biopsy proven 
malignancy infiltrating bone marrow 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl  using a variety of validated GFR 
calculators) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN OR 
End-stage renal disease on hemodialysis or 
peritoneal dialysis 

 
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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
 
1. Has disease suitable for local treatment with curative intent. 
 
2. A WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving the 
first dose of trial medication (see Appendix 3).  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. 
 
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, 
OX-40, CD137). 
 
4. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks prior to first dose of trial treatment. 
 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
 
Note: If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment. 
 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

 
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5. Has received prior radiotherapy within 2 weeks of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation 
(≤2 weeks of radiotherapy) to non-CNS disease. 
 
6. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
7. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment. 
 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
 
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
 
9. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  Note:  Participants with basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in 
situ) that have undergone potentially curative therapy are not excluded. 
 
a. For Cohort 1, a history of prostate cancer that was identified incidentally following 
cystoprostatectomy for bladder cancer is acceptable provided that the PSA is <0.2. 
 
10. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, 
i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the 
repeat imaging should be performed during study screening), clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
 
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
 

 
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13. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
 
14. Has an active infection requiring systemic therapy. 
 
15. Has known active Human Immunodeficiency Virus (HIV) infection. However, subjects 
who are on anti-retroviral therapy, have a viral load < 200 copies/milliliter, and CD4 count 
> 200/microliter, with a low risk of AIDS-related outcomes will be considered for 
enrollment. 
 
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority.  
 
17. Has active TB (Bacillus Tuberculosis).   
 
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
 
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Chemotherapy including etoposide, 
cisplatin, and carboplatin are Pregnancy Category D and may have hazardous effects on a fetus in 
utero.  Refer to Appendix 3 for approved methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   

 
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5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, 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 Merck.  If a male participant impregnates his 
female partner, the study personnel at the site must be informed immediately and the pregnancy 
must be reported to Merck and followed as described in Section 7.2.2. 
5.1.5 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, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2 Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Chemotherapy Regimen: 
Etoposide 
 
 
100 mg/m2 
 
 
Q3W 
 
IV infusion 
 
 
Day 1, 2, 3 of each 
3 week cycle 
Treatment 
of 
small 
cell 
cancer 
OR 
Docetaxel + 
Prednisone 
 
Dexamethasone 
60 mg/m2 
5 mg 
 
8 mg 
Q3W 
 
 
IV infusion 
Oral 
 
IV or Oral 
Day 1 of each 3 
week cycle/Qd to 
Bid 
8 mg bid day prior 
and one dose prior 
to docetaxel 
Treatment 
of 
neuroendocrine 
prostate cancer 
Plus 
Cisplatin 
 
70-80 
mg/m2 
 
Q3W 
 
IV infusion 
 
Day 1 of each 3 
week cycle 
 
Treatment 
of 
small 
cell 
cancer 

 
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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
 
 
 
OR 
Carboplatin  
 
 
AUC 4-5 
 
 
Q3W 
 
 
IV infusion 
 
Day 1 of each 3 
week cycle 
Treatment 
of 
small 
cell 
cancer 
 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Pembrolizumab will be 
administered first, followed by premedication and then the assigned chemotherapy if applicable 
according to local guidelines and practices. Trial treatment may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle due to administrative reasons. 
5.2.1.1 Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.1.2 Etoposide 
For subjects receiving etoposide, etoposide will be administered as an IV infusion on Day 1, 2, 
and 3 of each 3 week cycle according to local guidelines and practices. The first dose of etoposide 
can be administered on Day 2-3 as per local guidelines.  
The use of steroid premedication to reduce hypersensitivity reactions can be used as clinically 
directed by the treating physician. Premedication with dexamethasone (typically 8 mg PO or IV 
prior to administration of etoposide) is allowed.  
5.2.1.3 Docetaxel 
For subjects receiving docetaxel, docetaxel will be administered as an IV infusion on Day 1 of 
each 3 week cycle according to local guidelines and practices. Docetaxel can be administered on 
Day 2-3 as per local guidelines. 
Premedication with dexamethasone (typically 8 mg PO bid day prior to and 8 mg PO or IV prior 
to administration of docetaxel) as well as daily dose of prednisone (typically 5 mg qd up to bid) 

 
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while on chemotherapy cycles is allowed. After cessation of docetaxel treatment, prednisone 
should be discontinued. 
5.2.1.4 Cisplatin 
For subjects receiving cisplatin, cisplatin will be administered as an IV infusion on Day 1 of each 
3 week cycle according to local guidelines and practices. Cisplatin can be administered on Day 2-
3 as per local guidelines. 
The use of steroid premedication to reduce hypersensitivity reactions can be used as clinically 
directed by the treating physician. Premedication with dexamethasone (typically 8 mg PO or IV 
prior to administration of cisplatin) is allowed. 
5.2.1.5 Carboplatin  
Established guidelines will be used as described in 4.1.4.3 for criteria on cisplatin-ineligibility. 
The treating physician will ultimately make the decision for cisplatin-ineligibility. 
For subjects receiving carboplatin, carboplatin will be administered as an IV infusion on Day 1 of 
each 3 week cycle according to local guidelines and practices. Carboplatin can be administered on 
Day 2-3 as per local guidelines. 
The use of steroid premedication to reduce hypersensitivity reactions can be used as clinically 
directed by the treating physician. Premedication with dexamethasone (typically 8 mg PO or IV 
prior to administration of carboplatin) is allowed. 
5.2.2 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 one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, 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.  
 
Dose interruptions will be allowed, but no dose modifications will be allowed with 
pembrolizumab. If pembrolizumab is withheld, the entire chemotherapy regimen can be held up 
to 21 days (+ 3 days) in order to not disrupt the cycle sequence. 

 
 
 
 
 
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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 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 2 
Withhold  
• 
Monitor changes of renal function 

 
 
 
 
 
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Nephritis and 
Renal 
dysfunction 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 
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).   
 
 
 
 

 
 
 
 
 
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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
4.  
 
Table 4  Pembrolizumab Infusion Reaction Dose Modification and 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 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
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 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 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 participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 

 
 
 
 
 
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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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 

 
 
 
MISP 56710 v11 03-22-2022 
33
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants 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 small cell of the urothelium may undergo surgery of primary disease site (e.g. 
radical cystectomy or nephroureterectomy) as standard-of-care therapy. Pembrolizumab may 
be withheld to allow recovery and then to continue on study.  
 
Subjects with primary small cell of the prostate may undergo surgery or radiation of primary 
disease site (e.g. prostate and pelvic lymph nodes) as standard-of-care therapy. Pembrolizumab 
may be withheld to allow recovery and then to continue on study. 
 
5.2.2.1 Dose modifications for chemotherapy 
Dose modifications for etoposide, docetaxel, cisplatin, and/or carboplatin will be implemented 
according to local guidelines, practices, and approved labeling. 
5.2.2.2 Dose interruptions for chemotherapy 
If any chemotherapy regimen is withheld secondary to chemotherapy-related toxicity or 
intolerance, then the entire cycle including study treatment can be delayed up to 21 days (+ 3 
days) in order to not disrupt the cycle sequence. If chemotherapy is stopped according to local 
guidelines, practices, and approved labeling per treating physician’s discretion, then the study 
treatment can continue as monotherapy; provided the subject is deriving benefit from 
treatment, the subject is in agreement and refusing alternative treatments. 
5.2.3 Second Course * 
All participants who stop study treatment with stable disease (SD) or better may be eligible for 
up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they 
progress after stopping study treatment from the initial treatment phase.  This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains open 
and the participant meets the following conditions: 
Either 
• Stopped 
initial 
treatment 
with 
study 
treatment 
after 
attaining 
an 
investigator-determined confirmed CR based on RECIST 1.1, and 
o Was treated with at least 8 cycles of study treatment before discontinuing treatment, 
and 

 
 
 
MISP 56710 v11 03-22-2022 
34
o Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression 
or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 or PCWG3 after stopping initial treatment, and 
o No new anticancer treatment was administered after the last dose of study 
treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and 
o The participant declines additional chemotherapy and investigator feels the Second 
Course Phase will be beneficial for the patient, and 
o The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study. 
*Note: patients must have measurable disease at the start of protocol treatment to be eligible 
for this provision by RECIST 1.1 or PCWG3 for bone only metastases. 
5.3 
Randomization or Treatment Allocation 
This is a non-randomized open label study. The Sponsor, investigator, and subject will know 
the treatment administered. 
5.4 
Stratification 
No stratification based on age, gender, or other characteristics will be used in this trial. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants' primary physician.  

 
 
 
MISP 56710 v11 03-22-2022 
35
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  This includes growth factors used in conjunction with chemotherapy. All 
concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Participants 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, to the brain, or to the 
prostate gland and pelvic lymph nodes for consolidation following completion 
of initial cycles of chemotherapy may be allowed at the investigator’s 
discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology or as standard-of-care in 
combination with chemotherapy.  The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 

 
 
 
MISP 56710 v11 03-22-2022 
36
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor 
and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related 
to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
5.6 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 

 
 
 
MISP 56710 v11 03-22-2022 
37
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 4 cycles of the combination including 2 doses of 
pembrolizumab beyond the date when the initial CR was declared. These participants 
may be eligible for second course treatment described in Section 5.2.3. 
• The participant is lost to follow-up 
• Completion of 35 treatments (approximately 2 years) with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.  Participants who 
stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 5.2.3. Participants may be re-treated in the Second Course 
Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year). 
• Administrative reasons 
5.7 
Participant Replacement Strategy 
Subject participants will not be replaced if they started study treatment. 
5.8 
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 

 
 
 
MISP 56710 v11 03-22-2022 
38
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 

 
 
 
 
 
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41
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening  
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
 
Survival Follow-Up 
5 
6 
7 
8 
Follow Up 
Visitsb 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon  
(± 3) 
Every 12 
weeks 
post 
discon 
(± 3) 
Every 12 weeks (± 
14 days) 
fAdditional tissue may be obtained in subjects who undergo surgery/radiation or at time of progression. 

 
 
 
 
 
MISP 56710 v11 03-22-2022 
 
 
 
42
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to participant 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 participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’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 participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about the 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. 
 

 
 
 
 
 
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43
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 participant qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the participant 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 participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant 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 participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  

 
 
 
 
 
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44
7.1.1.6 Assignment of Screening Number 
Each subject will be assigned only one screening number. Screening numbers must not be re-
used for different subjects. Any subject who is screened multiple times will retain the original 
screening number assigned at the initial screening visit. 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 18 weeks between 
pembrolizumab doses due to toxicity will require written documentation on subject 
management. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 

 
 
 
 
 
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45
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
 
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the 
abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when 
CT with iodinated contrast is contraindicated, or when local practice mandates it. CT urogram 
is an acceptable substitute for CT abdomen/pelvis.  MRI is the strongly preferred modality for 
imaging the brain.  The same imaging technique regarding modality and the use of contrast 
should be used in a participant throughout the study to optimize the reproducibility of the 
assessment of existing and new tumor burden and improve the accuracy of the assessment of 
response or progression based on imaging. 
For Cohort 1, imaging will include the chest, abdomen, and pelvis. For Cohort 2, imaging will 
include the chest, abdomen, and pelvis and a radionuclide bone scan.  
Local review of imaging (investigator assessment with site radiology reading) will be used for 
subject management and evaluation of response to treatment.  
7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed 28 days prior to the date of treatment 
initiation.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1. Scans performed as part of routine clinical management 
are acceptable for use as screening tumor imaging if they are of diagnostic quality and 
performed within 28 days prior to date of treatment initiation. 
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
this study allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant 
to enable a broader sampling of tumor burden. 
Brain imaging, if performed to document the stability of existing metastases, should be by MRI 
if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable alternative. 
Patients with locally advanced disease will not be required to have measurable disease by 
RECIST 1.1. These patients will be eligible for extirpative surgery as discussed in 5.2.2 for 
dose interruption.  
7.1.2.6.1 Tumor Imaging During the Study 
The first on-study imaging assessment should be performed within 63 days (±14 days) from 
the date of treatment initiation.  Subsequent tumor imaging (regular scheduled imaging) should 

 
 
 
 
 
MISP 56710 v11 03-22-2022 
 
 
 
46
be performed every 12 weeks (84 days ±14 days) thereafter based on the date of the previous 
scan, including confirmatory scans.  Imaging timing should follow calendar days and should 
not be adjusted for delays in cycle starts.  Imaging should continue to be performed until 
disease progression is identified by the Investigator.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm partial response (PR) or complete response (CR) should be performed at least 4 weeks 
after the first indication of a response is observed.  Participants will then return to regular 
scheduled imaging.   
For patients with locally advanced disease without measurable disease by RECIST 1.1, 
response to treatment including PR or CR will be determined by pathologic staging following 
extirpative surgery.  Disease progression will be defined as a new measurable lesion by 
RECIST 1.1. 
Per iRECIST (Section 9.2.1.6), disease progression should be confirmed by the site over 4 
weeks after first radiologic evidence of progressive disease (PD) in clinically stable 
participants.  Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the Investigator until progression is confirmed by the site 
provided they have met the conditions detailed in Section 9.2.1.6.  Participants who receive 
confirmatory imaging may resume tumor imaging at the subsequent scheduled imaging time 
point, if clinically stable.  Participants who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study treatment.  Exceptions are detailed in 
Section 9.2.1.6. 
Radiographic progression for bone lesions will be determined as described in the consensus 
guidelines of the PCWG3.  Radiographic progression of bone lesions will be defined as the 
appearance of ≥2 new bone lesions on radionuclide bone scan. Progression in bone if 
unaccompanied by soft tissue progression, requires a second radionuclide bone scan ≥4 weeks 
later. Progression is confirmed to have occurred if the confirmation bone scan shows ≥2 
additional new lesions.  
 
If a subject with radiographic progression is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the Sponsor. Clinically stable subjects 
should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in non-target lesions and no additional new lesions develop (non-
worsening progressive disease) to continue study treatment.  
7.1.2.6.2 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  In participants who discontinue study treatment due to documented disease 

 
 
 
 
 
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47
progression and the Investigator elects not to implement iRECIST, this is the final required 
tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging using 
the same imaging schedule used while on treatment. Imaging should continue every 12 weeks 
(84 days ±14 days, based on the date of the previous scan) for approximately 2 years to monitor 
disease status until the start of a new anticancer treatment, disease progression, death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
7.1.2.6.3 Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab.  Local reading (Investigator assessment with site radiology reading) will be 
used to determine eligibility. 
The first on-study imaging assessment should be performed every 12 weeks (84 days ±14 days, 
based on the date of the previous scan) after the restart of treatment.  
Per RECIST 1.1 (Section 9.1.2.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression.  Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and 
may wait until the next scheduled imaging time point, if clinically stable. 
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  Disease progression may be confirmed 4 to 8 weeks after the first tumor imaging 
indicating PD, by the Investigator using iRECIST, in clinically stable participants. 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  In participants who discontinue study treatment due to documented disease 
progression, this is the final required tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 12 weeks (84 days ±14 days, based on the date of the previous scan) until either the start 
of a new anticancer treatment, disease progression, death, or the end of the study, whichever 
occurs first. 
7.1.2.6.4 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 

 
 
 
 
 
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48
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 
5 per organ, if clinically relevant to enable a broader sampling of tumor burden. 
Patients with locally advanced disease will not be required to have measurable disease by 
RECIST 1.1.  These patients will be eligible for extirpative surgery as discussed in 5.2.2 for 
dose interruption.  Response to treatment including PR or CR will be determined by pathologic 
staging following extirpative surgery.  Disease progression will be defined as a new 
measurable lesion by RECIST 1.1.   
7.1.2.6.5 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  When clinically stable, participants should not be discontinued 
until progression is confirmed by the Investigator, working with local radiology, according to 
the rules below.  This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first few 
months after the start of immunotherapy, and then experience subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 4, with 
additional detail in the iRECIST publication 55.  iRECIST will be used by the Investigator to 
assess tumor response and progression, and make treatment decisions.  
7.1.2.6.6 PCWG3 Assessment of Progression 
Radiographic progression for metastatic prostate cancer in bone only disease is described in 
the consensus guidelines of the PCWG3 (REF).  Pseudoprogression in the absence of 
symptoms or other signs of progression are excluded.  Radiographic progression of bone 
lesions will be defined as the appearance of ≥2 new bone lesions on first radionuclide bone 
scan with at least 2 additional lesions on the next confirmatory scan ≥4 weeks later. Date of 
progression is the date of the first post-treatment scan.  
 
 
 

 
 
 
 
 
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49
Table 5 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required. 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor). 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments. 
Continue study treatment at the 
Investigator’s discretion. 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor image should 
occur according to the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1. 

 
 
 
 
 
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50
Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 

 
 
 
 
 
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51
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.2.7.1 Tumor Tissue Collection 
An archival formalin-fixed paraffin-embedded (FFPE) tumor tissue within 6 months of 
screening is required.  Tissue may also be obtained if the patient undergoes surgery or radiation 
if indicated as standard-of-care. Subjects will undergo a research biopsy to collect tissue at the 
time of disease progression. 
Although inclusion in this study is not contingent on PD-L1 status, tumor tissue will be tested 
to evaluate PD-L1 status. 
Sample collection, storage and shipment instructions will be in the Procedures Manual.  
Leftover tissue will be stored at the end of the study for future biomedical research (FBR) if 
the subject consents to FBR. This may include but not limited to exome sequencing, RNA 
sequencing, and immunohistochemistry. 
7.1.2.7.2 Blood Collection for RNA Analysis, Plasma and Serum Biomarker Analyses  
Blood should be collected pre-dose every other cycle starting at Cycle 1 and at time of 
treatment discontinuation. Analysis may include neuroendocrine markers such as serum CEA, 
chromogranin, neuron-specific enolase, and synaptophysin levels that may be part of standard 
of care. Leftover samples will be kept for future biomedical research if the subject signs the 
FBR consent. 
Sample collection, storage and shipment instructions will be in the Procedures Manual.  
7.1.2.7.3 Blood Collection for Circulating Tumor DNA  
Blood for circulating tumor DNA (ctDNA) will be collected pre-dose every other cycle starting 
at Cycle 1 and at time of treatment discontinuation. Analysis may include but not limited to 
biomarker analysis and exome or gene panel sequencing. Leftover samples may be kept for 
future biomedical research if the subject signs the FBR consent. 
Samples will be placed in appropriate tubes and collection, storage, and shipment instructions 
will be in the Procedures Manual.  
7.1.2.7.4 Blood Collection for CTCs 
Blood for CTC will be collected pre-dose every other cycle starting at Cycle 1 and at time of 
treatment discontinuation. Analysis may include but not limited to cell enumeration, 
expression of PD-L1, and analyses of cellular heterogeneity by single cell RNA sequencing. 
Leftover samples may be kept for future biomedical research if the subject signs the FBR 
consent.  
Samples will be placed in appropriate tubes and collection, storage, and shipment instructions 
will be in the Procedures Manual.  

 
 
 
 
 
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7.1.3 Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.  

 
 
 
 
 
 
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Table 6 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)  
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Total triiodothyronine (T3) (reflex) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Free thyroxine (T4) (reflex) 
 
Uric Acid 
 
Lactate Dehydrogenase (LDH) 
 
Calcium 
 
Lipase 
 
Chloride 
 
Prostate Specific Antigen (PSA) – Cohort 2 
only 
 
Glucose 
 
  
 
Phosphorus 
 
 Blood for correlative studies 
 
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.   
 
 
 
 

 
 
 
 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 28 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 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant 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.  Participants who a) attain a CR or b) complete 35 doses with pembrolizumab 
may discontinue treatment with the option of restarting treatment if they meet the criteria 
specified in Section 5.2.3.  After discontinuing treatment following assessment of CR, these 
participants 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 
7.1.5.3.2). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements. 
Subjects must sign the main trial consent prior to submitting existing tissue samples and/or 
undergoing a new biopsy. Results of a test performed prior to the subject signing consent as 
part of routine clinical management are acceptable in lieu of a screening test if performed 
within the specified time frame. Screening procedures are to be completed within 28 days prior 
to the first dose of trial treatment, except for the following:  
• Laboratory tests are to be performed within 2 weeks of trial initiation. 
• For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the local 
trial site laboratory). 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 

 
 
 
 
 
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Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.  The subject identification card will be updated with the 
screening number. 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.    
7.1.5.3 Post-Treatment Visits 
The discontinuation visit should be conducted approximately within 28 days ± 7 days after the 
last dose of trial treatment or before the initiation of a new anti-neoplastic treatment, whichever 
comes first. 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer 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.  Participants who are eligible for retreatment with 
pembrolizumab (as described in Section 5.2.3) may have up to two safety follow-up visits, one 
after the Initial Treatment Period and one after the Second Course Treatment. 
7.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 14 days, based 
on the date of the previous scan) by radiologic imaging to monitor disease status for 2 years.  
Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, disease progression, death, end of the study or if the participant begins 
retreatment with pembrolizumab as detailed in Section 5.2.3.  Information regarding post-study 
anti-cancer treatment will be collected if new treatment is initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
7.1.5.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first.  

 
 
 
 
 
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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 participant 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, 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. 
All laboratory findings will be reviewed by an Investigator. All laboratory results outside the 
reference range will be categorized as clinically significant or not clinically significant. Only 
clinically significant abnormal results will be recorded as an AE. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
● All AEs from the time of initial consent through 30 days following cessation of study 
treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of initial consent through 90 days following 
cessation of study treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy, whichever is earlier must be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of initial consent through 
120 days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy must be reported by the 
investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, 

 
 
 
 
 
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at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
UCLA DSMB and to Merck 
For purposes of this study, 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. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215-661-6229) 
7.2.2 Reporting of Pregnancy and Lactation to the UCLA DSMB and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). 
If the pregnancy continues to term, the outcome (health of infant) must also be reported. 

 
 
 
 
 
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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; 
• Results in a congenital anomaly/birth defect; 
• Is an other important medical event. 
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
that occurs to any participant must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety if it causes the participant to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause whether or not related to the Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 

 
 
 
 
 
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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. 
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 reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must 
be reported within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to Merck Global Safety. 
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.  
 
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 

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

 
 
 
 
 
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Table 7 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 participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 

 
 
 
 
 
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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 participant 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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to 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 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

 
 
 
 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to 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) 
Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 

 
 
 
 
 
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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.  
7.3 
Trial Governance and Oversight 
7.3.1 UCLA JCCC Data Safety and Monitoring Board (DSMB) Oversight 
This trial will be overseen by the UCLA Jonsson Comprehensive Cancer Center (JCCC) 
DSMB.  The JCCC DSMB meets monthly to review all SAE reports for trials overseen by the 
JCCC DSMB.  All SAE reports, which have been filed since the previous meeting, are 
presented to the committee for review.  
 
For trials overseen by the JCCC DSMB, the DSMB reviews all dose-limiting toxicities (DLTs) 
for dose-escalation studies.  Protocol suspensions and re-opening of accrual to the next cohort 
based on DLT evaluation fall under the purview of the DSMB.  
 
For all JCCC oncology trials and TRIO-US studies where the JCCC DSMB has primary 
oversight, all SAEs shall be reported to the JCCC DSMB in a timely manner [ten days, two 
days for a death] regardless of relationship and expectedness.  The JCCC ORC will review all 
submissions and the ORC staff will enter the information into the JCCC Clinical Trials 
database.  Reports are generated for full JCCC DSMB review.  For trials where the JCCC 
DSMB has primary DSMB review responsibility, the DSMB requires that the PI generate 
cumulative adverse event reports for quarterly, biannual or annual review.  
 
The DSMB reviews each SAE report and determines whether or not protocol modifications 
are warranted to ensure subject safety.  In this review, prior occurrences of similar toxicity 
with the therapy under study are taken into consideration, as well as the severity of the event 
and the likelihood that it was related to a study drug.  The DSMB may recommend no changes 
to the study if the event is expected or related to other causes such as the subject’s underlying 
condition.  The DSMB may request an expert’s advice of another non-Principal Investigator 
with national experience to support their deliberations and decisions.  
 
The JCCC DSMB has the authority to recommend to the UCLA IRB the immediate halt to a 
study (i.e., discontinuation of any further treatment of enrolled subjects and discontinuation of 
enrollment of new subjects) should there be any serious unexpected toxicity that warrants 
further investigation.  
 
Requests for single subject exceptions/waivers from the approved study protocol, including 
out of window procedures and eligibility deviations, must be reviewed and approved by a 
member of the DSMB.  Each trial is assigned a primary and secondary reviewer who is 
responsible for reviewing each exception/waiver request for that trial.  Approvals and 
disapprovals of the request are sent to the Principal Investigator via email and copied to the 
UCLA IRB. Requests for single subject exceptions/waivers are made by the Principal 
Investigator via email utilizing the “Single Subject Exception Request Form.”  

 
 
 
 
 
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JCCC DSMB correspondence are addressed to the Principal Investigator and copied to the 
UCLA IRB.  Minutes of the DSMB meetings are maintained in a computer file. 
 
Confidentiality:  Each member of the JCCC DSMB is responsible for maintaining strict 
confidentiality of the study data.  Members will not share any study data or information about 
the study with any individual external to the JCCC DSMB or the statistical working group for 
the study.  The DSMB members may contact the statistical working group directly with 
questions regarding the operational details associated with the data analysis and summary 
presentations.  Communication of deliberations or recommendations of the JCCC DSMB, 
either written or oral, should not be made outside of the Committee or the statistical working 
group. Outcome results are strictly confidential and must not be divulged to any non-member 
of the JCCC DSMB except in those cases where DSMB is required to inform the UCLA IRB 
of its determinations.  Disclosure of outcome results to the IRB must only occur with written 
approval of the DSMB.  A member who believes he or she may have a potential intellectual or 
financial conflict of interest during the course of review of the data must inform the chairperson 
of the DSMB.  In such case, the meeting minutes will record the disclosure of the potential 
conflict of interest and that the individual recuse himself from the discussions and abstains 
from voting on the DSMB decision.  
 
7.3.2 Assignment of Risk – Level 2 
All interventional clinical trials undergo scientific review by the Internal Scientific Peer 
Review Committee (ISPRC), which requires that a Data and Safety Monitoring Plan is in place 
before a trial can be approved to begin.  For trials overseen by the JCCC DSMB, the JCCC 
DSMB will determine the degree of risk of the study and will ensure that there are procedures 
in place to ensure the safety of the subjects that are enrolled in the trial.  The intensity level of 
study oversight is determined by the risk category.  Some of the factors that are considered 
when assigning the Level of Risk category include:  
 
• A biostatistical design and appropriate procedures for proper data management so that 
the information collected can be properly validated.  
 
• Appropriate Serious Adverse Event reporting procedures must be in place.  
 
• The study duration must be appropriate and must be based on a realistic rate of 
enrollment.  
 
• Data collection and data management must be adequate to verify and ensure subject 
eligibility.  
 
7.3.2.1 Assignment of Risk  

 
 
 
 
 
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This protocol is assigned a Level 2 Risk. Assigning risk ensures that the data and safety 
monitoring is based on the level of risk (low, medium, or high) to ensure that the data and 
safety monitoring activities are appropriate.  Level 2 Risk assignment includes the data and 
safety monitoring activities listed below:  
 
• Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system. Compliance Officer provides real time monitoring 
to determine eligibility prior to enrollment onto the protocol.  
• Real time QA monitoring of the subjects and data collection occurs for all subjects 
entered onto the trial.  
• Comprehensive QA auditing within first year or first 10 subjects enrolled, whichever 
comes first. Subsequent audit frequency will be annually.  
• Frequency of DSMB Summary Report is typically on a biannual basis or approximately 
every six months.  
 
7.3.3 Monitoring and Auditing Activities 
The compliance officer of the JCCC Office of Regulatory Compliance [ORC] will monitor and 
audit the clinical records for all human subjects enrolled onto JCCC trials overseen by the 
JCCC DSMB.  The JCCC compliance officer will perform real time review of informed 
consent processes and the meeting of all inclusion and exclusion criteria and screening results 
at study entry.  Active monitoring will offer the JCCC study teams prospective information 
that can be used to enhance the quality of research being performed contemporaneously.  
Auditing is a review of historic performance of the research effort and is performed on case 
report forms, regulatory files and source documents to measure the quality of the research 
effort in a retrospective manner.  
 
8.0 STATISTICAL ANALYSIS PLAN SUMMARY 
8.1 
Statistical Analysis Plan 
This section outlines the statistical analysis plan for the study. This is a non-randomized, multi-
center, multi-cohort, open-label, Phase Ib trial of pembrolizumab (MK-3475) in combination 
with platinum-based chemotherapy with Cohort 1) naïve small cell cancer of the bladder, 
urethra, or upper urinary tract, and with Cohort 2) primary small cell or neuroendocrine 
prostate cancer.  
 
8.1.1 Efficacy Analysis Plan  
In both cohorts, all assessments will be based on investigator assessments of tumor response, 
recurrence, progression, and cause of death. The efficacy endpoints for this study are as 
follows: 
 
• DRR will be defined as the durable response rate (PFS at 6 month). 

 
 
 
 
 
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• ORR based on RECIST 1.1 criteria (Cohort 1 and 2) and biochemical PSA response 
(Cohort 2).  ORR will be determined as the proportion of subjects who have a CR or 
PR by RECIST 1.1.  PSA response will be defined as a PSA decline of ≥50% from 
baseline measured twice at least 3 weeks apart. 
 
• DOR based on RECIST 1.1 criteria (Cohort 1 and 2) and biochemical PSA response 
(Cohort 2).  DOR will be defined as the time from the first documented CR or PR until 
radiograph disease progression by RECIST 1.1 or PSA progression.  PSA progression 
will be defined as the date that an increase of 25% or more and an absolute increase of 
≥2 ng/ml above nadir occurs. 
 
• PFS based on RECIST 1.1 criteria (Cohort 1 and 2) and biochemical PSA response 
(Cohort 2).  PFS will be defined as the time from the first day of study treatment to first 
documented disease progression or PSA progression as defined above.  
 
• rPFS based on PCWG3 criteria (Cohort 2).  rPFS will be defined as the time from the 
first day of study treatment to first documented disease progression as defined above. 
 
• OS is defined as the time from the first day of study treatment to the time of death from 
any cause.  Patients who have not died will be censored at the last date known to be 
alive. 
 
There is no formal hypothesis testing for the trial.  All statistical analyses will be performed 
after the study is completed and the database is locked and released.  Statistical analyses will 
be performed using SAS software or other validated statistical software as required.  
 
The statistical analyses will be primarily descriptive and exploratory.  The proportional data 
(DRR, ORR) will be summarized using 95% 2-sided exact Binomial CIs. Time-to-event data 
(DOR, PFS and OS) will be summarized by cohort using the Kaplan-Meier method.  Kaplan-
Meier estimates of event rates at landmark time points (e.g., 3-,6-, and 12-months) and median 
time to the event will be presented with the corresponding 95% CIs.   
 
8.1.2 Safety Analysis Plan 
The secondary objective for this study is to determine safety and tolerability of pembrolizumab 
in combination with etoposide and cisplatin/carboplatin or docetaxel and carboplatin 
chemotherapy. Safety will be assessed through summaries of adverse events, changes in 
laboratory test results, and changes in selected vital signs. Safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE Version 4.0 criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab. The attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded. Adverse events will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and clinically significant 
laboratory changes.  

 
 
 
 
 
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The mandatory Safety Follow-up Visit will be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-neoplastic treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-up Visit should be recorded. Subjects 
with an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until 
the beginning of a new anti- neoplastic therapy, whichever occurs first. Serious adverse events 
will be collected for 90 days after the trial treatment or 30 days after the end of treatment if the 
subject initiates new anti-cancer therapy, whichever is earlier. 
 
8.1.3 Exploratory Endpoints 
Potential correlations of PD-L1 expression, serum, circulating cell, urine, and tissue molecular 
molecular (genomic, metabolic, proteomic) biomarkers with the safety and clinical response 
of pembrolizumab combined with platinum-based chemotherapy will be explored. 
 
8.2 
Sample Size Consideration  
 
This study is not designed to make explicit power and Type I error considerations for 
hypothesis testing. Instead, this study is designed to obtain preliminary efficacy as measured 
by DRR, ORR, DOR, PFS, and OS and determine safety and tolerability of pembrolizumab in 
combination with platinum-based chemotherapy.  
 
The primary endpoint of the efficacy analyses will be DRR. Only descriptive statistical 
analysis will be performed for this signal finding study. Sample size calculation was not based 
on statistical hypothesis testing. 
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. 
Pembrolizumab will be provided by Merck as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 

 
 
 
 
 
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9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, 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 participants 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. 
 
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11.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
 
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
 
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 5.1.1:  
● 
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 

 
 
 
 
 
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● 
Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 9 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
 
○ 
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration. 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 10 during the protocol-defined time frame in Section 5.1.1.   
 
Table 10 
Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the treatment 
period and for at least [X days, corresponding to time needed to eliminate study treatment plus 30 
days for study treatments with genotoxic potential]  after the last dose of study treatment.   

 
 
 
 
 
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Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements.  When applicable this test should be repeated 
a maximum of 24-hours before the first dose/vaccination. 
Following initiation of treatment additional pregnancy testing will be performed at monthly 
intervals during the treatment period and at 30 days after the last dose of study treatment and 
as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 

 
 
 
 
 
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Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 5 and Figures 1 and 3).  This decision 
by the Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 

 
 
 
 
 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up 
to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline.  All other new lesions will be followed qualitatively as New Lesions 
– Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 

 
 
 
 
 
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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”.  This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 6. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, either 
before or after an instance of pseudo-progression. 
• Non-target lesions 

 
 
 
 
 
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o If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in 
one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan 
the burden of new lesions has increased from its smallest value (for new target lesions, their 
sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. 
It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD 
or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication 55.