Conditions: Urothelial Carcinoma Bladder Cancer
Keywords: Pembrolizumab PD-1 Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.

Detailed description:
OUTLINE: This is a multi-center trial.

Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab (Experimental Arm B). Stratification factors for randomization: presence of visceral metastatic disease (lung, liver, or bone or other organs vs. lymph node only) at the time of initiation of first-line chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD. Subjects who progress on placebo will be assessed to determine if they are eligible to cross over to unblinded treatment with pembrolizumab.

INVESTIGATIONAL TREATMENT:

For Control Arm A, commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline.

For Experimental Arm B, pembrolizumab (or placebo), 200 mg intravenous infusion (IV) every 3 weeks for up to 12 months, or until progressive disease (PD) or unacceptable toxicity.

The following required laboratory values must be obtained within fourteen days prior to registration for protocol therapy:

Hematopoietic:

* Absolute neutrophil count (ANC) ≥1,500 /mcL
* Platelets ≥100,000 / mcL
* Hemoglobin ≥8.5 g/dL

Renal:

* Creatinine ≤1.5x ULN OR
* Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine levels \>1.5x institutional ULN
* GFR can also be used in place of creatinine or CrCl

Hepatic:

* Serum total bilirubin ≤ 1.5 X ULN OR
* Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
* AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subject with liver metastases

Coagulation:

* International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN. If subject is on anticoagulant therapy, PT or PTT must be within therapeutic range of intended use of anticoagulants.

Arms:
arm 1: Commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months. arm 2: Pembrolizumab, 200mg IV every 3 weeks. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.

Interventions: intervention 1: Placebo intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Normal saline intervention 2: Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months

Protocol document:
Prot_SAP_000.pdf: 
GU14-182 
Clinical Study Protocol  
 
A Randomized, Double-Blinded, Phase II Study of Maintenance Pembrolizumab 
versus Placebo after First-line Chemotherapy in Patients with Metastatic Urothelial 
Cancer  
 
 
Hoosier Cancer Research Network 
GU14-182 
 
 
Sponsor-Investigator 
Matthew D. Galsky, MD  
Icahn School of Medicine at Mount Sinai 
 
Statistician 
Menggang Yu, PhD 
 
Funding Support and Pembrolizumab Provided By  
Merck Sharp & Dohme Corp. (“Merck”) 
 
 
Investigational New Drug (IND) ID#: 127340 
 
NCT# NCT02500121 
 
 
Initial Protocol Version: 07AUG2015 
Protocol Amendment Version Date:  
19FEB2016 
13APR2016 
18JUN2016 
02AUG2016 
21MAR2017 
01DEC2017 
12NOV2018 
05NOV2019 
 


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PROTOCOL SIGNATURE PAGE  
 
Protocol title: A Randomized, Double-Blinded, Phase II Study of Maintenance 
Pembrolizumab versus Placebo after First-line Chemotherapy in Patients with Metastatic 
Urothelial Cancer 
 
 
VERSION DATE:  05NOV2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable guidelines for good clinical practices, or the applicable laws and regulations of 
the country of the study site for which I am responsible, whichever provides the greater 
protection of the individual.  I will accept the monitor’s overseeing of the study.  I will 
promptly submit the protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
 ___________________________________  
 _______________________  
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
 ___________________________________  
 Investigator Name (printed) 
 
 
 ___________________________________  
 Investigator Title 
 
 
 ___________________________________  
 Name of Facility 
 
 
 ___________________________________  
 Location of Facility (City and State) 
 
 ___________________________________  
❑ Not Submitting to IRB 
 Expected IRB Approval Date 
 
COMPLETE AND EMAIL COPY TO HCRN  
Instructions to the Investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Cancer Research Network (HCRN) and keep a 
record for your files. 


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SYNOPSIS 
TITLE 
A Randomized, Double-Blinded, Phase II study of Maintenance 
Pembrolizumab versus Placebo after First-line Chemotherapy in Patients 
with Metastatic Urothelial Cancer 
SHORT TITLE 
Testing the PD-1 inhibitor pembrolizumab after initial chemotherapy in 
patients with metastatic bladder cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective 
The primary objective will be to determine the progression-free survival 
(PFS) as per immune-related RECIST (irRECIST) among subjects with 
metastatic urothelial cancer (mUC) treated with pembrolizumab versus 
placebo as maintenance therapy after up to 8 cycles of first-line 
chemotherapy. 
 
Secondary Objectives 
• Determine the 6-month PFS as per irRECIST 
• Determine the 6-month PFS as per irRECIST among the subsets 
of subjects with PD-L1 positive and PD-L1 negative tumors 
treated with pembrolizumab versus placebo. 
• Determine the PFS as per irRECIST among the subsets of 
subjects with PD-L1 positive and PD-L1 negative tumors treated 
with pembrolizumab versus placebo 
• Determine the PFS as per RECIST 1.1 among subjects treated 
with pembrolizumab versus placebo  
• Determine the objective response rate (ORR) by irRECIST and 
RECIST 1.1 in subjects on maintenance pembrolizumab versus 
placebo with measurable disease 
• Determine the ORR by irRECIST and RECIST 1.1 in subjects 
receiving pembrolizumab after progressing on placebo 
• Determine overall survival (OS) in subjects treated with 
pembrolizumab versus placebo 
• Determine the hazard ratios (HRs) with respect to both PFS and 
OS comparing subjects treated with pembrolizumab versus 
placebo  
• Determine the restricted mean survival time (RMST) in subjects 
treated with pembrolizumab versus placebo 
• Determine durations of response in subjects treated with 
pembrolizumab versus placebo 
• Determine the safety of pembrolizumab administration in this 
patient population  
 
Exploratory Objectives 
• Determine the PFS and 6mPFS rate among subjects without 
visceral metastatic disease randomized to pembrolizumab versus 
placebo  


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• Compare PD-L1 expression in primary tumor tissue and 
metastatic post first-line chemotherapy tumor tissue in a subgroup 
of subjects. 
• Correlate immune infiltrates in tumor tissue with response rate, 
progression-free survival, and overall survival in subjects 
receiving pembrolizumab versus placebo 
• Determine the repertoire of humoral responses and correlate with 
response rate, progression-free survival, and overall survival 
• Determine the induction of T cell responses and correlate with 
response rate, progression-free survival, and overall survival 
• Correlate genomic alterations with response rate, progression-free 
survival, and overall survival 
• Correlate tobacco history with PFS in subjects receiving 
pembrolizumab versus placebo 
 
STUDY DESIGN 
This is a multi-institutional, randomized, placebo controlled, double-
blinded phase II trial. 
NUMBER OF 
SUBJECTS  
N = 108 
PARTICIPATING 
CENTERS 
Up to 30 centers in Hoosier Cancer Research Network 
ELIGIBILITY 
CRITERIA  
Inclusion: 
1. Written informed consent and HIPAA authorization for release of 
personal health information. 
NOTE:  HIPAA authorization may be included in the informed 
consent or obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status (PS) of ≤ 1 within 14 days prior to 
registration for protocol therapy. 
4. Histological or cytological evidence of urothelial cancer of the 
bladder, urethra, ureter, or renal pelvis. Differentiation with variant 
histologies (e.g., squamous cell differentiated) will be permitted 
provided that the predominant histology is urothelial carcinoma. 
5. Metastatic and/or unresectable (cT4b) disease 
6. Must have achieved an objective response (CR/PR) or stable 
disease (SD) upon completion of scheduled treatment.   
7. Subjects may have had up to 8 cycles of standard first-line 
platinum-based chemotherapy for mUC (e.g., as per NCCN 
guidelines). Able to commence study treatment within 2 to 6 weeks 
of receiving last dose of first-line chemotherapy. 
8. All subjects must have adequate archival tissue available prior to 
registration (i.e., at least 20 unstained slides or paraffin block). If 
acceptable archival tissue is not available, the subject must be 
willing to consent to providing a core or excisional biopsy for 
research prior to registration for protocol therapy. If archival tissue 


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is not available and there are no sites amenable to biopsy, 
enrollment must be discussed with the sponsor-investigator on a 
case by case basis.  
9. Adequate laboratory values obtained within 14 days prior to 
registration for protocol therapy.  (see protocol for details) 
10. Female subjects of childbearing potential must have a negative 
serum pregnancy within three days of registration for protocol 
therapy.   
11. Sexually active pre-menopausal women of childbearing potential 
must be willing to use an adequate method of contraception or be 
surgically sterile, or abstain from heterosexual activity from the 
point of registration through 120 days after the last dose of study 
drug.  Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for 
> one year. 
12. Male subjects of childbearing potential must agree to use an 
adequate method of contraception starting with the first dose of 
study drug through 120 days after the last dose of study drug. 
 
Exclusion 
13. More than 1 line of prior chemotherapy for metastatic or locally 
advanced disease (prior neoadjuvant/adjuvant chemotherapy is 
allowed). 
14. Current or past participation in a study of an investigational agent or 
using an investigational device within four weeks of registration for 
protocol therapy. 
15. Diagnosis of immunodeficiency or treatment with systemic steroid 
therapy or any other form of immunosuppressive therapy within 
seven days of registration for protocol therapy.  
16. Prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within two weeks prior to registration for protocol therapy. 
Note:  If subjects have undergone major surgery, they must have 
adequately recovered from the toxicity and/or complications from 
the intervention prior to starting protocol therapy.   
17. Known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or in situ cervical cancer that 
has undergone potentially curative therapy.   
18. Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to 
registration for protocol therapy and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least seven days prior to 
registration for protocol therapy.   


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19. Active autoimmune disease requiring systemic treatment within the 
past three months or a documented history of clinically severe 
autoimmune disease, or a syndrome that requires systemic steroids 
or immunosuppressive agents.  Exceptions include: subjects with 
vitiligo or resolved childhood asthma/atopy. Subjects who require 
intermittent use of bronchodilators or local steroid injections, and 
subjects with hypothyroidism who are stable on hormone 
replacement or Sjögren’s syndrome are eligible for the study. 
20. Has a history of (non-infectious) pneumonitis that required steroids 
or current pneumonitis. 
21. Active infection requiring systemic therapy. 
22. History or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere 
with the subject’s participation for the full duration of the trial, or is 
not in the best interest of the subject to participate, in the opinion of 
the site investigator. 
23. Known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
24. Pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
screening period through 120 days after the last dose of protocol 
therapy. 
25. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) antibody (including ipilimumab or any other antibody or 
drug specifically targeting T-cell co-stimulation or checkpoint 
pathways).  Examples include nivolumab, MPDL3280, etc. 
26. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
27. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
28. Recipient of a live vaccine within 30 days prior to registration for 
protocol therapy. 
29. Unresolved toxicity (i.e., > Grade 1 or above baseline) due to 
previously administered agents. Exception includes: Subjects with 
≤ Grade 2 neuropathy are eligible for the study. 
STATISTICAL 
CONSIDERATIONS 
 
Sample size calculation and analysis plan 
 
We assume that the treatment group will experience three phases in terms 
of treatment effect: no effect, partial effect, and full effect. Specifically, 
we assume that before month 2, there is no treatment effect and after 
month 3 there is full treatment effect. In terms of hazard ratio, it is 1 
before month 2, and a target value 𝜃 <1 after month 3. The decrease of 
the hazard ratio from 1 to 𝜃 between month 2 and 3 does not need to be 
specified and can take any pattern. 
 


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We set the target value 𝜃 of the full treatment effect hazard ratio as 
0.462. This target value is determined from the following rationale. The 
12 months PFS is 6.2% for the control arm and 16.8% for the treatment 
arm from the KEYNOTE-045 trial. Assuming a constant hazard for the 
control group, we can obtain the hazard for the control arm is 0.232 for 
PFS from the KEYNOTE-45 trial, we assume the treatment reaches it 
full effect around month 8. This corresponds to a full treatment effect 
hazard ratio of 0.462.  
 
The sample size is determined by inverting the test statistic proposed by 
Zucker and Lakatos (1990). We set the type I error as 0.05 and power as 
80%. Assuming the study duration is 3 years, the required total sample 
size based on one-sided test is at least 104 evaluable subjects (~52 per 
group). Therefore, the sample size is inflated to 108 to account for 
potential non-evaluable patients/early drop out. Censoring is assumed 
uniformly between month 6 and the end of study.  
 
Stratification factors for randomization: Presence of visceral metastatic 
disease (lung, liver, or bone or other organs vs. lymph node only) at the 
time of initiation of first-line chemotherapy, and response to first-line 
chemotherapy (CR/PR vs. SD).  
 
ESTIMATED 
ENROLLMENT 
PERIOD 
24 to 36 months 
ESTIMATED STUDY 
DURATION  
36 to 48 months is the estimated study duration.  However, subjects will 
be followed per guidelines in Section 7.4. 
 


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SCHEMA ............................................................................................................................................. 9 
1. 
BACKGROUND AND RATIONALE ................................................................................. 10 
2. 
STUDY OBJECTIVES ......................................................................................................... 16 
3. 
ELIGIBILITY CRITERIA .................................................................................................. 17 
4. 
SUBJECT REGISTRATION ............................................................................................... 20 
5. 
TREATMENT PLAN ........................................................................................................... 20 
6. 
TREATMENT DISCONTINUATION ............................................................................... 30 
7. 
STUDY SCHEDULE OF EVENTS (FOOTNOTES ON NEXT PAGE) ......................... 31 
8. 
CRITERIA FOR DISEASE EVALUATION ..................................................................... 40 
9. 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES ......................... 44 
10. 
STUDY DRUG INFORMATION ........................................................................................ 46 
11. 
ADVERSE EVENTS ............................................................................................................. 47 
12. 
STATISTICAL CONSIDERATION ................................................................................... 51 
13. 
TRIAL MANAGEMENT ..................................................................................................... 55 
14. 
DATA HANDLING AND RECORD KEEPING ............................................................... 56 
REFERENCES .................................................................................................................................. 59 
APPENDIX ........................................................................................................................................ 62 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Current therapies for metastatic urothelial cancer are inadequate  
Standard first-line treatment for metastatic urothelial (bladder) cancer involves platinum-
based combination therapy.  While urothelial cancer is a relatively chemotherapy sensitive 
malignancy, median survival is only approximately 14 months.1–3 These findings highlight a 
critical need to develop approaches that build on the chemosensitivity of urothelial cancer to 
achieve durable responses. 
 
1.2 
Bladder cancer is an immunogenic malignancy 
Prior studies have shown that bladder cancer specimens harbor tumor infiltrating 
lymphocytes.4,5  Immunohistochemical staining for intratumoral CD8 T cells in tissue 
samples from 69 patients with bladder cancer (pT2-T4) demonstrated that higher numbers of 
CD8 tumor infiltrating lymphocytes correlated with superior disease-free survival 
(P < 0.001) and overall survival (P = 0.018).4  The cancer-testis family of antigens, 
characterized by both potent immunogenicity and a restricted expression pattern in normal 
adults, are overexpressed in bladder cancer. 6–8  In an analysis of a panel of cancer-testis 
antigens, >75% of bladder cancer specimens expressed at least one cancer-testis antigen.8 A 
range of other antigens and neoantigens have been explored (and are currently being 
explored) as therapeutic targets in bladder cancer for protein and peptide vaccines and drug-
immunoconjugates (e.g., HER-2, MUC-1, CEA, HCG, survivin, etc). 
 
1.3 
Despite the immunogenicity of bladder cancer, patients with bladder cancer 
also exhibit tumor-associated immunologic tolerance.9–11  
Bladder cancer specimens have been shown to be infiltrated by T regulatory cells (Tregs) 
and to express high levels of inhibitory cytokines.10 Notably, Tregs have been shown to 
diminish cancer-testis antigen vaccine-induced antigen-specific effector T cell responses in 
patients.12 
 
1.4 
Several lines of evidence support the importance of immune-checkpoint 
blockade as a therapeutic strategy for the treatment of advanced urothelial cancer.  
Blockade of immune checkpoints is among the most promising approaches to activating 
therapeutic antitumour immunity.  Immune checkpoints comprise multiple inhibitory 
pathways that are critical to the immune system’s maintenance of self-tolerance and 
modulation of the duration and amplitude of immune responses.  However, tumors co-opt 
certain immune checkpoints as a major mediator of immune resistance.  The first immune 
checkpoints to achieve clinical translation include anti-CTLA-4 and anti-PD-1 (or anti-
PD-L1) antibodies.  These checkpoints play different roles during the immune 
response-CTLA4 predominantly regulates T cell activation whereas PD-1 predominantly 
regulates effector T cell activity within peripheral tissue and tumors.13  
 
 


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PD-1 and PD-L1 are overexpressed in bladder cancer specimens and correlate with clinical 
outcomes.  In an analysis of 280 bladder cancer specimens, PD-L1 was expressed on 20% of 
pT2 specimens, 30% of pT3-4 specimens, and expression was significantly associated with 
higher tumor grade and stage.14  A larger study of 318 bladder cancer specimens revealed 
that expression of PD-L1 by urothelial cancer cells (P <0.001) and PD-1 by tumor 
infiltrating lymphocytes (p=0.012) were significantly associated with pathologic stage.15   In 
addition, in the subset of patients with organ-
confined disease, PD-L1 expression 
independently predicted all-cause mortality 
after cystectomy (HR 3.18; 95% CI 1.74-5.79; 
P < 0.001; Figure 1).  
 
In a syngeneic (MB49) subcutaneous mouse 
model of bladder cancer, blocking CTLA-4 or 
PD-1 demonstrated anticancer effects.16 
 
1.5 
Combining chemotherapy with 
immune checkpoint blockade may result in 
additive or synergistic effects  
Combining chemotherapy with immune 
checkpoint blockade may result in synergistic activity due to (a) release of tumor antigens as 
a result of tumor cell killing with cytotoxics, resulting in “auto-vaccination” and (b) 
depletion of tumor promoting cellular subsets with cytotoxic chemotherapy (e.g., Tregs, 
myeloid derived suppressor cells).  Indeed, several preclinical models have supported this 
notion.  Jure-Kunkel et al demonstrated synergy with the administration of gemcitabine in 
combination with CTLA-4 blockade in several syngeneic (mouse) xenografts – in a CT-26 
colon cancer model, CTLA-4 blockade alone demonstrated no activity, gemcitabine alone 
demonstrated only modes activity, while the combination resulted in complete regressions in 
5/8 animals.17  Treatment with the combination was shown to increase levels of activated 
CD4 and CD8 T cells while decreasing the number of myeloid derived suppressor cells.  
Furthermore, mice achieving complete regression with the combination rejected subsequent 
tumor rechallenge consistent with the induction of a memory immune response. 
 
1.6 
“Switch maintenance” is an ideal setting for combining immune checkpoint 
blockade and chemotherapy in metastatic urothelial cancer  
The optimal sequence of chemotherapy and immune checkpoint blockade in the 
management of advanced solid tumors remains to be defined.  However, concurrent therapy 
may pose both practical (toxicities) and mechanistic (myelosuppressive and 
lymphodepleting effects of chemotherapy) challenges. The “maintenance” setting, presents 
an ideal clinical setting to further develop a sequential combination approach given: 
 
1. Patients with at least stable disease to initial chemotherapy may be more likely to 
experience tumor cell kill and “auto-vaccination”.  In a contemporary series of patients 
treated with gemcitabine plus cisplatin, approximately 75% of patients achieved at least 
stable disease (at least partial responses in ~40%).18 


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2. In our international outcomes database of patients with urothelial cancer, among 1435 
patients who received first-line chemotherapy for mUC, only 596 (42%) went on to 
receive second-line chemotherapy.19  These data suggest substantial patient “drop off” 
from first to second-line therapy and the potential to impact the course of the disease in a 
more meaningful way with the earlier integration of noncross-resistant therapies. 
 
3. The maintenance setting facilitates enrollment of both “cisplatin-eligible” and “cisplatin-
ineligible” patients, at least partially addressing this accrual barrier to urothelial cancer 
studies.2,20,21 
 
4. While time-to-event endpoints are most appropriate in this setting, objective responses 
are still evaluable for the majority of patients enrolled (excluding the small subset that 
achieved a complete response to first-line chemotherapy). 
 
5. Particularly relevant to the question of timing of chemotherapy and immune checkpoint 
blockade, allowing cross-over to immune checkpoint blockade at progression in patients 
randomized to placebo may facilitate insights into the activity (and immunomodulatory 
effects) of PD-1 blockade in patients with shorter versus longer intervals from receipt of 
cytotoxic therapy. 
 
1.7 
Pembrolizumab is a novel antibody that blocks the interactions between PD-1 
and PD-L1 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Pembrolizumab strongly enhances T-lymphocyte immune 
responses in cultured blood cells from healthy human donors, cancer patients, and primates.  
In T-cell activation assays using human donor blood cells, the EC50 (concentration where 
50% of the maximum effect is achieved) has been ~0.1 to 0.3 nM.  In addition to 
interleukin-2 (IL-2), tumor necrosis factor alpha, interferon gamma, and levels of other 
cytokines were found to be modulated by pembrolizumab.  The antibody potentiates existing 
immune responses only in the presence of antigen and does not nonspecifically activate T-
cells.  Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor models. 
 
Recent data with anti-PD-1 antibodies, including pembrolizumab and nivolumab (BMS-
936558), have validated PD-1 as an attractive target for clinical intervention and have 
provided proof of concept for anti-PD-1 mAbs in several malignancies.  Nivolumab showed 
an overall response rate of approximately 28% in patients with advanced melanoma and 
27% in patients with renal carcinoma who had failed prior therapy.22 In addition, an 
objective response rate of near 20% was observed in non-small cell carcinoma patients.22–24  
Pembrolizumab has shown an overall response rate of over 40% in patients with melanoma 
and over 20% in patients with NSCLC.  Importantly, responses have been of long duration 
and both MK- 3475 and nivolumab are generally well tolerated. 
 
 


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Data from early phase clinical studies with pembrolizumab (> 700 patients) demonstrate that 
pembrolizumab has been generally been well tolerated at doses up to 10 mg/kg once every 
two to three weeks without dose-limiting toxicities.  The adverse event profile of 
pembrolizumab in a large phase II trial in patients with metastatic melanoma is detailed in 
Table 1 below.25  
 
Table 1 Drug-Related Adverse Events with Pembrolizumab in Patients with Melanoma 
 
Drug-Related Event 
All Grades (n=135) 
number (percent) 
Grade 3 or 4 (n=135) 
number (percent) 
Any 
107 (79) 
17 (13) 
Hypothyroidism 
11 (8) 
1 (1) 
Gastrointestinal disorder 
 
 
  Diarrhea 
27 (20) 
1 (1) 
  Nausea 
13 (10) 
0 
  Abdominal pain 
7 (5) 
1 
Generalized symptom 
 
 
  Fatigue 
41 (30) 
2 (1) 
  Mylagia 
16 (12) 
0 
  Headache 
14 (10) 
0 
  Asthenia 
13 (10) 
0 
  Pyrexia 
10 (7) 
0 
  Chills 
9 (7) 
0 
  Decreased appetite 
6 (4) 
1 (1) 
Increase in aminotransferase level 
 
 
  AST 
13 (10) 
2 (1) 
  ALT 
11 (8) 
0 
Renal failure 
3 (2) 
2 (1) 
Respiratory disorder 
 
 
  Cough 
11 (8) 
0 
  Dyspnea 
6 (4) 
0 
  Pneumonitis 
6 (4) 
0 
Skin disorder 
 
 
  Rash 
28 (21) 
3 (2) 
  Pruritis 
28 (21) 
1 (1) 
  Vitiligo 
12 (9) 
0 
Drug related adverse events occurring in at least 5 patients or drug-related grade 3 or 4 adverse  
events that occurred in at least 2 patients from25 
 
1.8 
Inhibiting PD-1/PD-L1 signaling is associated with clinical activity in metastatic 
urothelial cancer. 
Recently, proof of concept for targeting PD-1/PD-L1 in patients with metastatic urothelial 
cancer has been established. Powles et al demonstrated that in 30 patients with PD-L1-
expressing (by immunohistochemistry) metastatic urothelial cancer refractory to standard 
chemotherapy treated with the anti-PDL1 antibody, MPDL3280A, 43% achieved an 
objective response.26 Plimack et al reported the preliminary results of the urothelial cancer 
expansion cohort of KEYNOTE-012, a Phase Ib Multi-Cohort Study of MK3475 in Patients 
with PD-L1+ Advanced Solid Tumors. Among 33 chemotherapy-refractory patients treated 
with pembrolizumab 10 mg/kg every 2 weeks, 24% achieved an objective response 
including several durable responses.27 In a phase 3 trial of pembrolizumab versus standard 
chemotherapy in patients with metastatic urothelial cancer progressing despite platinum-


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based regimens, pembrolizumab was associated with a significant improvement in overall 
survival leading to approval by the US FDA for this indication.28  
 
1.9 
Rationale for the proposed study 
A randomized phase II study of pembrolizumab versus placebo as maintenance therapy after 
first-line treatment of metastatic urothelial cancer is supported by the following: 
 
1. Metastatic urothelial cancer is a chemosensitive disease though response durations 
are generally short-lived. 
2. Bladder (urothelial) cancer is an immunogenic malignancy but patients with bladder 
cancer exhibit tumor-associated immune tolerance.  
3. PD-L1 expression in bladder (urothelial) cancer correlates with stage and grade and 
is of prognostic significance.  
4. PD-1/PD-L1 blockade may overcome tumor-associated immune tolerance, has 
shown antitumor effects in preclinical models of bladder cancer, and has shown 
preliminary evidence of striking anticancer activity in patients with bladder cancer.  
5. Administration of chemotherapy prior to immune checkpoint blockade may augment 
the effects of immunotherapy, due to “auto-vaccination” and depletion of tumor-
promoting cellular subsets (e.g. myeloid-derived suppressor cells).  
6. Switch maintenance with checkpoint blockade may build on the responses achieved 
with cytotoxic chemotherapy alone to induce durable disease control and serve as a 
platform for curative therapy. 
 
1.10 
Rationale for Dose Selection/Regimen  
In KN001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, while one 
randomized cohort evaluation of 10 mg/kg Q3W versus 10 mg/kg Q2W is ongoing.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.  For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W, with an observed ORR was 26% (21/81) 
in the 2 mg/kg group and 26% (25/79) in the 10 mg/kg group (FAS).  The proportion of 
subjects with drug-related AE, grade 3-5 drug-related AE, serious drug-related AE, death or 
discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg 
group.  
 
In Cohort B3 of KN001, advanced melanoma subjects (irrespective of prior ipilimumab 
therapy) were randomized to receive pembrolizumab at 10 mg/kg Q2W versus 10 mg/kg 
Q3W.  The ORR was 30.9% (38/123) in the 10mg/kg Q2W group and 24.8% (30/121) in the 
10 mg/kg Q3W group (ASaT).  The proportion of subjects with drug-related AE, grade 3-5 
drug-related AE, serious drug-related AE, death or discontinuation due to an AE was 
comparable between groups. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  


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Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days), thus supporting a Q3W dosing schedule.  
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 subjects. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion 
of similar efficacy and safety in melanoma at 10 mg/kg Q3W versus the dose regimen of 2 
mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 
In conclusion, the above data indicates that the 200 mg Q3W fixed dose regimen planned to 
be used in this trial is likely similar, with regard to efficacy and tolerability, to the 10 mg/kg 
Q2W dose regimen used in KN012, and supports its use in this study. No dose reduction is 
allowed for pembrolizumab in this study. 
 
1.11 
Rationale for Endpoints  
In a pooled landmark analysis of patients with metastatic bladder (urothelial) cancer treated 
with cisplatin-based chemotherapy on a series of phase 2 and 3 trials, we have previously 
demonstrated that progression-free survival and overall survival are highly correlated.29  For 
example, the median overall survival for patients who had progressed at 9 months was 5.7 
months compared with 21.4 months for those who had not progressed (p<0.0001).  Using 
the Fleischer model, the estimated correlation between progression-free survival and overall 
survival was 0.86 (bootstrap standard error 0.001, 95% CI 0.82, 0.90).  This finding was 
externally validated in an independent cohort. These findings support the use of progression-
free survival as a practical, and clinically relevant, primary endpoint for the current study. 
 
1.12 
Rationale for Not Limiting Enrollment to Patients with PD-L1 Positive Tumors 
Emerging data suggest that patients with PD-L1 positive tumors are more likely to respond 
to treatment targeting the PD-L1/PD-1 signaling axis. However, this has not been uniformly 
observed, likely due to various assays, tumor tissue (archival primary tumor versus post-
systemic therapy metastatic tissue), and cut-points used to establish “positivity” based on 
this immunohistochemical assay. Furthermore, patients with “PD-L1 negative” tumors have 
experienced responses to treatment. Therefore, in the current study, enrollment will not be 
limited to patients with PD-L1 expressing tumors. However, the outcomes in PD-L1 
“positive” and “negative” patients will be analyzed as a secondary endpoint.   
 
 
 


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1.13 
Rationale for Modification of the Analysis Plan and Sample Size 
During the conduct of the current study, five PD-1/PD-L1 antibodies have been approved by 
the US FDA for the treatment of patients with metastatic urothelial cancer progressing 
despite prior platinum-based chemotherapy and two PD-1/PD-L1 antibodies have been 
approved as first-line treatment for cisplatin-ineligible patients with metastatic urothelial 
cancer. Notably, pembrolizumab has been approved in both of these settings. The 
commercial availability of immune checkpoint inhibitors in the first-line and second-line 
settings, coupled with the large number of studies seeking to integrate these therapies earlier 
in the course of treatment (i.e., adjuvant setting or in combination with chemotherapy as 
first-line treatment for metastatic disease) has dramatically changed the treatment landscape 
and undoubtedly impacted enrollment. Further, results from several studies across tumor 
types exploring PD-1/PD-L1 inhibitors have revealed that while improvements in 
progression-free survival likely occur, such improvements are often not apparent using 
traditional survival analysis approaches due to “delayed separation of the curves” 
highlighting the need for novel analytic approaches.30 To address both the slower than 
anticipated accrual to this randomized phase II study, and the need to develop approaches 
that better capture the potential benefits of immune checkpoint inhibitors particularly in the 
setting of progression-free survival endpoints, we have developed a novel approach as 
described in the Statistical Considerations (section 12).  
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
The primary objective will be to determine the progression-free survival (PFS) as per 
immune-related RECIST (irRECIST) among subjects with metastatic urothelial cancer 
(mUC) treated with pembrolizumab versus placebo as maintenance therapy after up to 8 
cycles of first-line chemotherapy. 
 
2.2 
Secondary Objectives 
• Determine the 6-month PFS as per irRECIST 
• Determine the 6-month PFS as per irRECIST among the subsets of subjects with PD-
L1 positive and PD-L1 negative tumors treated with pembrolizumab versus placebo. 
• Determine the PFS as per irRECIST among the subsets of subjects with PD-L1 
positive and PD-L1 negative tumors treated with pembrolizumab versus placebo 
• Determine the PFS as per RECIST 1.1 among subjects treated with pembrolizumab 
versus placebo  
• Determine the objective response rate (ORR) by irRECIST and RECIST 1.1 in 
subjects on maintenance pembrolizumab versus placebo with measurable disease 
• Determine the ORR by irRECIST and RECIST 1.1 in subjects receiving 
pembrolizumab after progressing on placebo 
• Determine overall survival (OS) in subjects treated with pembrolizumab versus 
placebo 
• Determine the hazard ratios (HRs) with respect to both PFS and OS comparing 
subjects treated with pembrolizumab versus placebo  
• Determine the restricted mean survival time (RMST) in subjects treated with 
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• Determine durations of response in subjects treated with pembrolizumab versus 
placebo 
• Determine the safety of pembrolizumab administration in this patient population  
 
2.3 
Exploratory Objectives 
• Determine the PFS and 6mPFS rate among subjects without visceral metastatic 
disease randomized to pembrolizumab versus placebo  
• Compare PD-L1 expression in primary tumor tissue and metastatic post first-line 
chemotherapy tumor tissue in a subgroup of subjects. 
• Correlate immune infiltrates in tumor tissue with response rate, progression-free 
survival, and overall survival in subjects receiving pembrolizumab versus placebo 
• Determine the repertoire of humoral responses and correlate with response rate, 
progression-free survival, and overall survival 
• Determine the induction of T cell responses and correlate with response rate, 
progression-free survival, and overall survival 
• Correlate genomic alterations with response rate, progression-free survival, and 
overall survival 
• Correlate tobacco history with PFS in subjects receiving pembrolizumab versus 
placebo 
 
3 ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
1. Written informed consent and HIPAA authorization for release of personal health 
information.  NOTE:  HIPAA authorization may be included in the informed 
consent or obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for 
protocol therapy. 
4. Histological or cytological evidence of urothelial cancer of the bladder, urethra, 
ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell 
differentiated) will be permitted provided that the predominant histology is urothelial 
carcinoma. 
5. Metastatic and/or unresectable (cT4b) disease 
6. Must have achieved an objective response (CR/PR) or stable disease (SD) upon 
completion of scheduled treatment.   
7. Subjects may have had up to 8 cycles of standard first-line platinum-based 
chemotherapy for mUC (e.g., as per NCCN guidelines). Able to commence study 
treatment within 2 to 6 weeks of receiving last dose of first-line chemotherapy. 
8. All subjects must have adequate archival tissue available prior to registration (i.e., at 
least 20 unstained slides or paraffin block). If acceptable archival tissue is not 
available, the subject must be willing to consent to providing a core or excisional 
biopsy for research prior to registration for protocol therapy. If archival tissue is not 
available and there are no sites amenable to biopsy, enrollment must be discussed 
with the sponsor-investigator on a case by case basis.  


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9. Required laboratory values, as outlined in Table 2, must be obtained within 14 days 
prior to registration for protocol therapy.  
Table 2 Required Lab Values 
System 
Lab Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8.5 g/dL 
Renal 
Creatinine OR 
Measured or calculated a creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5xULN OR 
≥30 mL/min for subject with  
creatinine levels >1.5x institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy.  If subject on anticoagulant 
therapy, PT or PTT must within therapeutic range of 
intended use of anticoagulants 
 
a Creatinine clearance should be calculated per institutional standard 
 
10. Female subjects of childbearing potential must have a negative serum pregnancy 
within three days prior to registration for protocol therapy  
11. Sexually active, pre-menopausal women of childbearing potential must be willing to 
use an adequate method of contraception or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after the last dose 
of study drug.  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > one year. 
12. Male subjects of childbearing potential must agree to use an adequate method of 
contraception starting with the first dose of study drug through 120 days after the last 
dose of study drug. 
 
3.2 
Exclusion Criteria 
1. More than one line of prior chemotherapy for metastatic or locally advanced disease 
with the following exception: 
• 
prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if 
completed greater than 12 months prior to initiation of chemotherapy regimen 
for metastatic or unresectable disease. 
2. Current or past participation in a study of an investigational agent or using an 
investigational device within four weeks of registration for protocol therapy. 


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3. Diagnosis of immunodeficiency or is receiving treatment with systemic steroid 
therapy or any other form of immunosuppressive therapy within seven days prior to 
registration for protocol therapy. 
4. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two 
weeks prior to registration for protocol therapy. Note:  If the subjects have 
undergone major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting protocol therapy. 
5. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy. 
6. Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to registration for protocol therapy and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least seven days prior to registration for protocol therapy. 
7. Active autoimmune disease requiring systemic treatment within the past three 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Exceptions 
include: subjects with vitiligo or resolved childhood asthma/atopy. Subjects who 
require intermittent use of bronchodilators or local steroid injections, and subjects 
with hypothyroidism who are stable on hormone replacement or Sjögren’s syndrome 
are eligible for the study. 
8. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
9. Active infection requiring systemic therapy. 
10. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, 
in the opinion of the site investigator. 
11. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening period through 120 days 
after the last dose of protocol therapy. 
13. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways).  Examples include nivolumab, MPDL3280, etc. 
14. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
16. Receipt of a live vaccine within 30 days prior to registration for protocol therapy. 
(See Section 5.1.3 for an example list of live vaccines) 


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17. Unresolved toxicity (i.e., > Grade 1 or above baseline) due to previously 
administered agents. Exception includes: subjects with ≤ Grade 2 neuropathy are 
eligible for the study. 
 
4 
SUBJECT REGISTRATION 
Sites must register all subjects through Hoosier Cancer Research Network’s electronic data 
(EDC) capture system.  A subject is considered registered to the protocol when an “on 
study” date has been entered into the EDC system.  Randomization will occur after 
registering a subject in the EDC system. Subjects must begin protocol therapy within five 
business days of randomization.  
 
4.1 
Stratification 
Stratification factors for randomization: Presence of visceral metastatic disease (lung, liver, 
or bone or other organs vs. lymph node only) at the time of initiation of first-line 
chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD).  
 
5 
TREATMENT PLAN 
 
5.1 
Treatment Schedule/Administration 
 
Table 3 Treatment Schedule 
Arm 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration 
 
A 
Placebo 
NA 
Every 3 weeks 
Intravenous (IV) 
infusion  
Up to  
24 months 
 
B 
Pembrolizumab  200 mg 
Every 3 weeks 
IV infusion  
Up to 
24 months 
 
Protocol therapy will be administered on Day 1 (± 3 days) of each three-week cycle. 
Pembrolizumab (Experimental Arm B) or placebo (Control Arm A) will be administered as 
a 30 minute IV infusion. 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 -five minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min). 
 
For Control Arm A, commercially available normal saline will be used as the placebo.  No 
active placebo drug will be mixed with the normal saline.   
 
Treatment will continue, in the absence of prohibitive toxicities or disease progression, for 
up to 24 months.  Upon progression, subjects who are randomized to placebo will have an 
option to cross over to receive pembrolizumab treatment.  See section 7.3.2.  Subjects who 
randomize to placebo but come off study treatment due to toxicity may cross over to receive 
treatment with pembrolizumab provided their toxicities resolve to baseline.  
 


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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the sponsor-investigator. The 
reason for interruption should be documented in the subject's study record. 
 
5.1.1. Dose Calculations 
The dose amount required to prepare the pembrolizumab infusion solution is a fixed dose 
(i.e., not based on the subject’s weight) as per Table 3.  
 
5.1.2. Pre-medications 
No premedications are required prior to protocol therapy administration. 
 
5.1.3. Concurrent Therapy and Dose Modifications 
 
5.1.3.1 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 any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The site investigator should discuss any questions regarding this with the 
sponsor-investigator.  The final decision on any supportive therapy or vaccination rests with 
the site investigator and/or the subject's primary physician.  However, the decision to 
continue the subject on trial therapy or vaccination schedule requires the mutual agreement 
of the site investigator, the sponsor-investigator and the subject. 
 
5.1.3.2 Acceptable Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site investigator in keeping with the community 
standards of medical care.  All concomitant medication will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 30 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. 
 
5.1.3.3 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy; NOTE:  Radiation therapy to a symptomatic solitary lesion or to the 


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brain may be considered on an exceptional case by case basis after consultation with 
sponsor-investigator.  The subject must have clear measurable disease outside the 
radiated field.  Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu - 
Mist®) 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.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the sponsor-
investigator.  NOTE:  Inhaled steroids are allowed for management of asthma. 
 
Subjects who, in the assessment by the site investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the site investigator deems to be medically 
necessary.  The Exclusion Criteria describes other medications that are prohibited in this 
trial. There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 


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


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
 
 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
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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5.1.3.5 Timing of Dose Administration 
Trial treatment of pembrolizumab may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle due to administrative reasons (up to 5 days after randomization is 
permitted). 
 
5.2 
Rescue Medications & Supportive Care 
 
5.2.1 Supportive Care Guidelines for Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the site 
investigator determines the events to be related to pembrolizumab.  
 
Pneumonitis:  
• For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
• For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed. 
• Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).   
• All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
• For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
• For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
 


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Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
• For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis: 
• For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
• For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
Hepatic: 
• For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
o Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 events, treat with systemic corticosteroids. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  


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Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
Table 5 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of pembrolizumab (MK-3475). 
 
Table 5 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the site investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the site investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the site investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
5.3 
Diet/Activity/Other Considerations 
 
5.3.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
5.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Therefore, non-
pregnant, non-breast-feeding women may only be enrolled if they are willing to use an adequate 
form of contraception or are considered highly unlikely to conceive.  Highly unlikely to conceive 
is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and 
has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be either 
two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects 
should start using birth control from study Visit 1 throughout the study period up to 120 days 
after the last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
 
5.3.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
site 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 HCRN.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to HCRN and followed as described above. 


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5.3.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.  
 
6 
TREATMENT DISCONTINUATION 
 
6.1 
Reasons for Discontinuing Protocol Therapy 
A subject will be discontinued from protocol therapy under the following circumstances: 
 
• If there is evidence of progressive disease. However, subjects randomized to placebo will 
be eligible to cross over to pembrolizumab treatment at the time of progression. 
• If the site investigator thinks a change of therapy would be in the best interest of the 
subject. 
• If the drug(s) exhibit(s) an unacceptable adverse event. 
• If a subject becomes pregnant or is unwilling to use appropriate birth control techniques 
as outlined in the inclusion criteria. 
• If there is a treatment interruption for greater than 12 weeks due to treatment related 
adverse event. 
• Subjects can stop participating at any time. However, if they decide to stop participating 
in the study, subjects will continue to be followed for disease progression and survival. 
• Twenty-four months of uninterrupted protocol therapy and no evidence of progressive 
disease. 
 
6.2 
Reasons for Withdrawal from Study 
• Subject withdraws consent for participation 
• Termination of the study 
• Lost to follow-up 
• 
Death 


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7 STUDY SCHEDULE OF EVENTS  
 
Screening 
RANDOMIZATION 
On Treatment 
Cycle = 3 weeks 
(up to 24 months) 
Progression/Unblinding 
EOT15 
Cross-over to 
pembrolizumab 
 
Follow-
up 
-28 days 
-14 days 
Cycles 1+ 
Day 1 (±3) 
30 days (±7)  
after last dose 
Cycle 1+ 
Day 1 (±3) 
 
 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
Eligibility evaluation (review of inclusion and 
exclusion criteria)1 
X 
X 
 
X 
 
 
Medical history 
 
X 
 
 
 
 
Physical examination 
 
X 
X 
X 
X 
 
Vitals and ECOG performance status2 
 
X 
X 
X 
X 
 
Charlson Comorbidity Index  
 
X 
 
 
 
 
 Smoking History Questionnaire3 
 
X 
 
 
 
 
AEs & concomitant medications  
 
X 
X 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
CMP4 
 
X 
X10 
X 
X10 
 
CBC4 
 
X 
X10 
X 
X10 
 
PT/INR and aPTT5 
 
X 
  
 
X5 
 
Thyroid Function (TSH, T3 and T4)6 
 
X 
X6 
 
X6 
 
Serum pregnancy test7 
 
X7 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
CT or MRI of chest, abdomen, and pelvis  
X12 
 
X11 
[X]12 
X11 
[X]13 
TREATMENT EXPOSURE 
 
 
 
 
 
 
pembrolizumab or placebo (IV) 
 
 
X 
 
X 
 
CORRELATIVE STUDIES 
 
 
 
 
 
 
Archival tumor tissue for research8 
X 
 
 
 
 
 
Tumor Biopsy if archival tissue not available8 
X 
 
 
 
 
 
Tumor Biopsy for sub-study analysis8 
X 
 
 
 
 
 
Blood samples for research9 
 
 
X 
X 
X 
 
FOLLOW-UP 
 
 
 
 
 
 
For progression, start date of additional cancer 
treatment, and survival14 
 
 
 
 
 
X14 


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1. Subjects should undergo informed consent prior to any research specific testing being performed.  Subjects randomized to Arm A (placebo) 
who discontinue treatment due to progression or unacceptable toxicity will be eligible to cross over to pembrolizumab provided eligibility 
outlined in section 3 is met.  (NOTE: inclusion criteria #6 regarding initiation of study treatment within 2 to 6 weeks of completing first line 
chemotherapy only applies to initial randomization to placebo).  Cross over treatment should be initiated within 4 weeks of confirming 
eligibility.  Subjects initiating treatment with pembrolizumab from placebo will follow the same schedule outlined in the calendar above and 
receive up to 24 months of treatment unless progression or unacceptable toxicity is experienced. 
2. Vital signs (blood pressure, weight [kg] and height [cm] SCREENING ONLY and ECOG performance status. 
3. Smoking Questionnaire in Appendix A 
4. CMP includes: serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total 
bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, 
potassium, sodium).  CBC includes: platelets, ANC & HGB. 
5. Repeat PT/INR and aPTT tests for subjects being screened for eligibility to cross over to pembrolizumab. 
6. TSH, T3 and T4 tests are done on Day 1 of even numbered cycles only (i.e., Cycle 2, 4, 6, etc.). For T3 and T4, free versus total is at the site 
investigator’s discretion 
7. Obtain a negative serum pregnancy test for females of childbearing potential within three days of registration for protocol therapy. 
8. Request from all subjects, archived tumor tissue (primary or metastatic based on availability) for research. If archival tissue is unavailable, 
obtain an excisional or percutaneous core biopsy (only) for research.  If no sites are amendable to biopsy, enrollment must be discussed with 
the sponsor-investigator on a case by case basis.  NOTE for biopsy for sub-study analysis: If the subject has archived primary tissue 
available and has agreed to the optional exploratory sub-study analysis, collect archived primary tumor tissue at baseline, and obtain an 
excisional or percutaneous core biopsy (only) for research.  
9. Blood samples for research will be collected prior to treatment on Cycle 1 Day 1, Cycle 4 Day 1, and at Progression (if subject’s disease 
progressed) or End of Treatment (if for a reason other than progression). Samples will be obtained during the randomized portion of the trial 
and at these same time points for subjects who cross over from placebo to unblinded treatment with pembrolizumab.  Subjects crossing over 
from placebo to unblinded treatment with pembrolizumab will have their initial progression samples count as their cross over Cycle 1 Day 1 
samples.  Blood samples are not to be shipped so that they are received on a weekend or holiday.  Samples leftover after initial protocol testing 
is complete may be stored for unspecified future cancer related research. Consent will be obtained from subjects. 
10. Cycle 1 Day 1 only, required tests do not need to be repeated if done within seven days prior. 
11. Restaging CT or MRI of the chest, abdomen, and pelvis is performed after every four cycles of treatment (i.e., approximately every 12 weeks).  
Make every effort to perform the same imaging modality throughout the study. After the first documentation of progression per RECIST 1.1, 
if the subject is clinically stable, confirmatory scans should be performed 4-6 weeks later (see Section 7.6 for details). 
12. Repeat imaging tests if it has been > 28 days since the last radiological assessment. 
13. Subjects who discontinue treatment without evidence of progression will be followed with imaging studies performed every three months (± 7 
days), or until new anticancer treatment is initiated. Make every effort to perform the same imaging modality throughout the follow up period. 
14. After the EOT visit, make every possible attempt to contact the subject or family to information on start date of additional anticancer treatment 
and survival, every three months (±7 days) during the first two years, every six months (±7 days) during years 3-5, and annually (±2 weeks) 
thereafter. 


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15. Treatment will be discontinued if evidence of disease progression, unacceptable toxicity, subject withdraws or after 24 months, whichever 
comes first.  Please see Section 7.3.2 for unblinding and Section 7.3.3 for cross over information. 


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Table 6 Schedule for correlative blood sample collections* 
Time point 
Correlative blood samples 
Pre-Treatment Cycle 1 Day 1 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
Pre-Treatment Cycle 4 Day 1 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
Time of progression** 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
End of treatment*** 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
Cross-over Cycle 1 Day 1** 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
Cross-over Cycle 4 Day 1 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
Cross-over Time of progression 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
End of treatment*** 
1 red top tube (10 ml total) 
1 Tempus tubes (3 ml total) 
6 ACD tubes (51 ml total) 
 
*Samples will be obtained during the randomized portion of the trial and at these same time points for subjects 
who cross over from placebo to unblinded treatment with pembrolizumab 
 
**Subjects crossing over from placebo to unblinded treatment with pembrolizumab will have their initial 
progression samples count as their cross over Cycle 1 Day 1 samples 
 
***Subjects discontinuing treatment for reasons other than progression will have correlative samples drawn at 
the end of treatment visit. 
 
 


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7.1 
Screening 
 
7.1.1 Within 28 days prior to registration for protocol therapy: 
• 
Informed consent prior to research specific testing 
• 
Radiological assessment (CT or MRI of chest, abdomen, and pelvis) with tumor 
measurements 
• 
Identification of available paraffin embedded block or adequate unstained slides of 
archived tumor tissue (primary or metastatic based on availability).  
o NOTE: if adequate archived tissue is unavailable, excisional or percutaneous core 
tumor biopsy is required for research purposes. 
• 
OPTIONAL SUB-STUDY ANALYSIS: For subjects who have archival tissue from 
primary site, and who agree to the exploratory sub-study analysis comparing PD-L1 
expression in primary tumor tissue versus metastatic post first-line chemotherapy tumor 
tissue, perform excisional or percutaneous core tumor biopsy for research. 
 
7.1.2 Within 14 days prior to registration for protocol therapy unless otherwise noted: 
• 
Eligibility evaluation (review of inclusion and exclusion criteria) 
• 
Medical history 
• 
Physical examination 
• 
Vital signs including Blood pressure, Weight [kg] Height [cm] (SCREEN ONLY) and 
ECOG PS  
• 
Laboratory testing: 
o Complete metabolic profile (CMP) will include: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and 
alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, 
sodium). 
o CBC (including platelets, ANC & HGB) 
o PT/INR and aPTT 
o TSH, T3 and T4 tests are done. For T3 and T4, free versus total is at the site 
investigator’s discretion 
o Serum pregnancy test for female subjects of childbearing potential (within three days 
of registration for protocol therapy). 
• 
Smoking History Questionnaire (Appendix A)  
• 
Charlson Comorbidity Index assessment (See SPM for form) 
• 
Record Adverse Events and concomitant medications 
 
 


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7.2 
On Treatment: Day 1 of each Cycle (± 3 days) unless otherwise noted: 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will 
occur: (NOTE: For Cycle 1 Day 1 ONLY, required tests do not need to be repeated if done 
within 7 days prior) 
• 
Physical examination 
• 
Vital signs including Blood pressure and Weight [kg] and ECOG PS  
• 
Laboratory testing: 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, total 
CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium) 
o CBC (including platelets, ANC & HGB) 
o TSH, T3 and T4 tests are done on Day 1 of even numbered cycles only (i.e., Cycle 2, 
4, 6, etc.). For T3 and T4, free versus total is at the site investigator’s discretion 
o Correlative studies: Blood sample collection (See Table 7 above for correlative 
sample schedule) 
• 
Record Adverse Events and any changes to concomitant medications 
• 
Restaging CT or MRI of the chest, abdomen, and pelvis is performed after every four 
cycles of treatment (i.e., approximately every 12 weeks).  Make every effort to perform 
the same imaging modality throughout the study.  
• 
Pembrolizumab or placebo administration (IV) 
 
7.3 
Progression/Unblinding/End of Treatment (EOT)  
Treatment will be discontinued if there is evidence of disease progression or unacceptable 
toxicity or if the subject stops participating or withdraws from the study.  After the first 
documentation of progression per RECIST 1.1, if the subject is clinically stable, confirmatory 
scans should be performed 4-6 weeks later (see Section 7.3.2 for details). 
  
7.3.1 End of Treatment Visit: 30 days after last dose of study drug (± 7 days) 
• 
Physical examination 
• 
Blood pressure 
• 
Weight [kg] 
• 
ECOG PS 
• 
Laboratory testing: 
o CMP will include: serum chemistries (creatinine, glucose, total protein, BUN, total 
CO2, albumin, total bilirubin, alkaline phosphatase, and AST and ALT) and 
electrolytes (total calcium, chloride, potassium, sodium)  
o CBC (including platelets, ANC & HGB) 
o Correlative studies: Blood sample collection (see Table 7 above for correlative 
sample schedule) 
• 
Record Adverse Events and changes to concomitant medications 
• 
Subjects will continue to be followed until resolution or stabilization of any treatment-
related toxicities.  
• 
Radiological assessments (only if >28 days since last assessment). 
 
 


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7.3.2 Unblinding 
Blinding of the treatment assignment is critical to the integrity of this clinical study.  There are 
situations, however, in which unblinding is necessary.  The patient’s safety takes priority over 
any other considerations in determining if the treatment assignment should be unblinded.  Before 
breaking the blind of an individual patient’s treatment, the site investigator should determine that 
the unblinded information is necessary. The decision to unblind the treatment assignment will 
be discussed with the sponsor-investigator, but the site investigator always has ultimate 
authority for the decision to unblind. 
 
Situations in which unblinding is necessary include but are not limited to: 
• Time of treatment discontinuation due to disease progression 
• Time of treatment discontinuation due to unacceptable toxicity 
• A medical event in an individual subject in which knowledge of the investigational 
product is critical to the subject’s clinical management.   
 
Because of the various situations that can lead to unblinding, and the potential impact of 
unblinding on the primary endpoint, the following approach will be utilized: 
 
• Patients who are unblinded for toxicity and confirmed to be on pembrolizumab, but who 
meet criteria for continued treatment with pembrolizumab due to effective management 
of the toxicity as per 5.1, may continue pembrolizumab and will be followed for the 
primary endpoint of progression as per section 7.6. 
• Patients who are unblinded for a first progression event and confirmed to be on 
pembrolizumab, but who are considered clinically stable and suitable by the treating 
investigator for ongoing treatment while awaiting confirmatory scans 4-6 weeks later as 
per 7.6 may continue pembrolizumab until progression is confirmed. If progression is 
confirmed at the follow-up scan as outlined in 7.6, the initial date of progression will be 
considered the progression date. If progression is not confirmed, patients may continue 
treatment with pembrolizumab.  
 
7.3.3 Cross Over 
Subjects receiving placebo will be eligible for cross over to treatment with pembrolizumab 
provided that eligibility outlined in section 3 is still met. (NOTE: Inclusion criteria #6 regarding 
initiation of study treatment within 2 to 6 weeks of completing first line chemotherapy only 
applies to initial randomization to placebo). 
 
Cross over treatment should be initiated within 4 weeks of confirming eligibility.  Subjects 
initiating treatment with pembrolizumab from placebo will follow the same schedule outlined in 
the study schedule of events in section 7 and receive up to 24 months of treatment unless 
progression or unacceptable toxicity is experienced. 
 
Subjects initially randomized to placebo, who discontinue treatment due to unacceptable toxicity 
rather than progression, may be eligible for cross over to treatment with pembrolizumab 
provided resolution of the toxicity (or improvement to baseline), the eligibility outlined in 
section 3 is still met, and after discussion with the sponsor-investigator. 


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Subjects who cross over to pembrolizumab and discontinue treatment for any reason will follow 
the same study procedures as outlined above for the EOT visit. 
 
7.4 
Follow-up 
Subjects who discontinue treatment without evidence of tumor progression will be followed for 
progression with imaging studies performed every three months (±7 days), or until new treatment 
is initiated. Every effort should be made to perform the same imaging modality (e.g., CT or 
MRI) throughout the follow-up period. The site investigator or designees will make every 
possible attempt every three months (±7 days), for two years from completion of protocol 
therapy, every six months (±7 days) for years 3-5, and annually thereafter (±2 weeks), to contact 
the subject or family to obtain the survival information of the subject and start date of additional 
anticancer treatment. 
 
7.5 
Restaging Evaluations 
A restaging CT or MRI of the chest, abdomen, and pelvis will be performed after every four 
cycles of treatment (i.e., approximately every 12 weeks).  For subjects on an increased dosing 
interval (every four weeks) due to pneumonitis, the frequency of restaging imaging studies 
should be discussed with the sponsor-investigator. Every effort should be made to perform the 
same imaging modality (e.g., CT or MRI) throughout the study.  After the first documentation of 
progression per RECIST 1.1, if the subject is clinically stable, confirmatory scans should be 
performed 4-6 weeks later (see Section 7.6 for details). 
 
7.6 
Determination of Progression/Post-progression imaging 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.  
  
If radiologic imaging shows PD, tumor assessment should be repeated 4-6 weeks later in order to 
confirm PD with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression.  If repeat imaging shows a reduction in the tumor burden compared 
to the initial scan demonstrating PD, treatment may be continued as per treatment calendar.  If 
repeat imaging confirms progressive disease, subjects will be discontinued from study therapy 
(exception noted Table 8) and the date of the original scan documenting progression will be 
considered the progression date.  In determining whether or not the tumor burden has increased 
or decreased, site investigators should consider all target lesions as well as non-target lesions. 
 
When feasible, subjects should not be discontinued until progression is confirmed; however, the 
decision to continue study treatment after the 1st evidence of disease progression is at the site 
investigator’s discretion based on the clinical status of the subject as described in Table 7. 
 
 
 


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Subjects may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
Table 7: Imaging and Treatment after Site-Assessed 1st Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
Site based 
assessment 
indicates PD  
Repeat imaging 
4-6 weeks later to 
confirm PD 
May continue 
study treatment at 
the site 
investigator’s 
discretion while 
awaiting 
confirmatory scan 
by site 
Repeat imaging 
4-6 weeks later to 
confirm PD per 
physician 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Exceptions as per 
note* 
Discontinue 
treatment 
Exceptions as per 
note* 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR or 
CR 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study 
treatment at the 
site investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments  
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per site 
investigator’s 
discretion 
 
Following PD by RECIST 1.1, sites will assess tumor response and progression per immune-
related RECIST (irRECIST) for treatment decisions in order to determine if PD is confirmed at 
the follow up time point ≥ 4weeks later. 
 
If the repeat scan documents an unconfirmed progressive disease, the subject remains clinically 
stable, treatment may continue and imaging should shift to the per protocol frequency. 
 
If the subject is deemed clinically unstable, repeat imaging is not required.  If the subject is 
clinically stable and repeat imaging in ≥4 weeks confirms PD, it is recommended that the subject 
be discontinued from trial treatment.   
 
*NOTE:  If progression is confirmed per irRECIST, the subject remains clinically stable and per 
the site investigator is achieving extraordinary clinical benefit, the site investigator may discuss 
with the sponsor-investigator to consider a potential exception. 
 
 
 


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7.7 
End of Study 
Subjects will be considered off study if any of the following occur: 
• Termination of the study 
• Withdrawal of consent (subject will not be contacted and no further information will be 
collected). If the subject withdraws consent, then no additional data will be collected 
without his/her explicit consent; all data collected prior to withdrawal of consent may be 
used in the data analysis. The collection of date of death and cause of death (if available) 
will be collected in the study since survival is an endpoint.  
• Lost to follow-up; three attempts should be documented in the subject’s source document 
before the site considers the subject as lost to follow-up. 
• Death 
 
8 
CRITERIA FOR DISEASE EVALUATION 
For the current study, response assessments will be made both using both RECIST v1.1, and the 
irRECIST allowing additional comparisons among these criteria for disease response assessment. 
The primary endpoint (PFS at 6 months) will utilize the irRECIST for documenting progression 
as outlined in 7.6. The first date of progression, confirmed on the subsequent imaging study, will 
be considered the date of progression.  
 
8.1 
Definitions Associated with RECIST 1.1 
 
8.1.1 Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
8.1.1.1 Measurable lesions 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
8.1.1.2 Non Measurable lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 


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8.1.1.3 Malignant lymph nodes  
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
8.1.1.4 Baseline documentation of Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
8.1.1.5 Baseline documentation of Non-target lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
8.2 
Response Criteria 
 
8.2.1 Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline 
sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study 
 
 
 


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8.2.2 Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 
mm short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level 
above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase. 
 
*Although a clear progression of “non target” lesions only is exceptional, in such circumstances, 
the opinion of the site physician should prevail. 
 
8.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
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Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
8.4 
Definitions for Response Evaluation – RECIST 1.1 
 
8.4.1 First documentation of response 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.4.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
8.4.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded since treatment started. 
 
8.4.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
8.4.5 Objective response rate 
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST, from the start of treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the start of treatment). 
 
8.4.6 Progression Free Survival 
A measurement from the start of the treatment until the criteria for disease progression is met or 
death occurs, taking as reference the smallest measurements recorded since the treatment started.   
 
Progression free survival will be measured from the date of initial treatment to the earliest date of 
disease progression, resection of measurable tumor or death for subjects who fail; and to the date 
of last contact for subjects who remain at risk for failure. 
 
 
 


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8.5 
Immune Related RECIST (irRECIST) 
PFS, ORR and duration of response per irRECIST are defined as specified for the respective 
endpoints using RECIST 1.1 above, with the exception that a confirmation assessment of PD (4-
6 weeks after the initial PD assessment) is required for subjects who remain on treatment 
following a documented PD per RECIST 1.1 (as detailed in section 7.6).  The first date of 
progression, confirmed on the subsequent imaging study, will be considered the date of 
progression. Subjects who discontinue treatment following a documented PD assessment per 
RECIST 1.1 will be counted as having disease progression on the date of the documented PD 
assessment.   
 
9 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES 
 
9.1 
Source of Study Specimens  
Correlative studies will be performed using peripheral blood samples and serum samples 
obtained at baseline and during protocol treatment (as outlined in Section 7). All subjects are 
required to have archival tumor tissue (primary or metastatic based on availability) identified at 
screening.  
 
If adequate archival tumor tissue is unavailable at registration, a mandatory excisional or 
percutaneous core biopsy for research is required.  If archival tissue is not available and there are 
no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a 
case by case basis. 
 
For subjects agreeing to the OPTIONAL exploratory sub-study analysis comparing PD-L1 
expression in primary tumor tissue versus metastatic post first-line chemotherapy tumor tissue, 
archived primary tumor tissue must be available.  Once availability of this tumor tissue is 
confirmed, an excisional or percutaneous core metastatic tumor biopsy for research will be 
collected prior to registration and only after eligibility criteria are verified. 
 
9.2 
Correlative studies 
The immune cell infiltrate in tumor specimens will be correlated with the response rate, 
progression-free survival, and overall survival for subjects randomized to placebo versus 
pembrolizumab.  The systemic immunomodulatory activity of pembrolizumab will be measured 
by the functional and phenotypic characterization of peripheral immune cells and soluble factors. 
 
9.2.1 
PD-L1 expression in tumor tissue 
All subjects will have unstained slides available for submission for PD-L1 expression.  
Specimens will be analyzed by a third party laboratory, as identified by Merck, for determination 
of PD-L1 status using an analytically validated immunohistochemical assay. 
 
 
 


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9.2.2 
Immune infiltrate in tumor tissue 
Several studies have demonstrated that the presence of tumor infiltrating lymphocytes in primary 
tumor specimens, including bladder cancer specimens, correlate with improved long term patient 
outcomes.4  Among the most powerful, yet elegantly simplistic, approach to immune-
classification is the “Immunoscore” developed by Galon and colleagues.  The Immunoscore 
utilizes two simple immunohistochemical stains (CD3 and CD8), assessed in two locations 
(tumor core and invasive margin), coupled with digital pathology to score the degree of T cell 
infiltration (as shown in the Figure).31–33  The Immunoscore is currently being harmonized in a 
Society for Immunotherapy of Cancer-led effort involving 23 centers from 17 countries to 
become the standard approach to characterizing tumor-infiltrating lymphocytes.34 
 
Sections from archival tumor tissue will be incubated with monoclonal antibodies against 
immune markers such as CD3, CD8, and other potential biomarkers. 
 
9.2.3 Genomic alterations in tumor tissue and circulating DNA and RNA 
The precise mechanism of action leading to tumor regression in response to treatment with 
immune checkpoint blockade is not fully understood. There is evidence that these agents may 
unmask the endogenous adaptive response to specific tumor antigens.35–39 However, little is 
known about the identity of the tumor antigens that function as the targets of T cells activated by 
immune checkpoint blockade. Such knowledge may be critical to optimizing use of existing 
immunotherapies. Emerging evidence, both in model systems and in subjects, suggests that 
mutation-derived tumor antigens may be predominate in this regard.40–43 We will use genomic 
sequencing strategies in tumor tissue (DNA and RNA) and circulating DNA and RNA to 
correlate response rate, progression-free survival, and overall survival with mutational burden 
and with specific genomic alterations. 
 
9.2.4 Determine the repertoire of humoral responses  
An array of serological assays will be used to evaluate the repertoire of antibody responses 
induced by treatment.   Specifically antibodies from subject serum collected throughout 
treatment will be analyzed for reactivity to known tumor-associated antigens including but not 
limited to: cancer-testis (NY-ESO-1, MAGE-A3, SSX2, PRAME, etc.) and other tumor antigens 
(TP53, WT1, SOX2, etc.) using high-throughput semi-automated ELISA (BioTek) and may also 
use Seromics, a novel antibody profiling method utilizing protein microarrays with the capacity 
to detect circulating antibodies induced by the treatment against >8000 full-length human 
antigens 
 
9.2.5 Determine the induction and the quality of the T cell responses 
It is acknowledged that the tumors in this trial may not share tumor-associated antigens that can 
be studied across all subjects.  Therefore, an effort will be made to identify tumor antigens for 
each subject using strategies including, but not limited to, collating the “antigenome” using 
seromics and immunohistochemistry data as well as identifying mutation-derived tumor antigens 
through genome sequencing and computational biology approaches to predict epitope: MHC 
binding affinity. Subject HLA typing will be done by sequence specific oligonucleotide probing 
and sequence specific priming of genomic DNA using standard procedures. T-cell responses will 
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9.2.6 Determine the correlation between the PD-L1 expression in primary tumor 
specimens and metastatic tumor specimens 
The rationale for this analysis is that while PD-L1 expression by tumor cells has been correlated 
with response to drugs targeting PD-1/PD-L1 signaling, uncertainties remain regarding the 
optimal assay, optimal cut-point, and optimal source of tissue. For example, many prior analyses 
have correlated outcomes to PD-1 blockade with tumor expression of PD-L1 as assessed from 
primary archival tumor specimens. The correlation between PD-L1 expression in primary tumor 
specimens and metastatic specimens is unknown. Furthermore, the impact of first-line 
chemotherapy on PD-L1 expression is unknown. Therefore, in this exploratory analysis, PD-L1 
expression in archival primary tumor specimens will be correlated with PD-L1 expression in 
metastatic post-chemotherapy tumor biopsies to generate data to refine our understanding of the 
optimal setting, assay, and cut-points, for use of PD-L1 as a predictive biomarker for future 
definitive randomized studies. Subjects agreeing to the sub study must have archival primary 
tumor specimens available for PD-L1 expression analysis in addition to undergoing a biopsy of a 
metastatic site. 
 
9.3 
Preparation and Shipment of Study Specimens 
See Correlative Laboratory Manual for collection, processing and shipping instructions for all 
tissue and blood specimens. 
 
9.4 
Banking of Leftover Specimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN) will manage the banked 
samples. Samples will be de-identified and banked indefinitely in the Hoosier Cancer Research 
Network Biorepository and used for future unspecified cancer-related research.  
 
10 
STUDY DRUG INFORMATION 
 
10.1 
Pembrolizumab  
 
10.1.1 Chemical name and properties 
Humanized X PD-1_mAb (H409A11) IgG4 
 
10.1.2 Availability 
Pembrolizumab is an investigational drug for this disease state and is not available outside of a 
clinical trial.  Merck will supply the pembrolizumab. 
 
The site 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. 
 
10.1.3 Product Descriptions 
 Clinical Supplies will be provided by Merck as summarized below: 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
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All other products will be supplied locally by the trial site. 
 
10.1.4 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
10.1.5 Clinical Supplies Disclosures 
The subject and site investigator are blinded to the protocol therapy assignment.  For purposes of 
protocol therapy distribution, all administrators of the EDC system at HCRN and participating 
site pharmacy personnel will be unblinded to the protocol therapy assignment. 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  Clinical supplies may not be used for any purpose other than that stated in 
the protocol. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
10.1.6 Adverse Events 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse 
events.  
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events (IMAEs) are of primary concern. 
Important identified risks for pembrolizumab are of an immune mediate nature, including 
pneumonitis, colitis, hypophysitis (including hypothryoidism/hyperthyroidism), hepatitis, Type I 
diabetes mellitus, uveitis, and nephritis, myositis, Guillain-Barre syndrome, pancreatitis, and 
severe skin reaction toxic epidermal necrolysis (TEN), some with fatal outcome. A new 
important risk of myocarditis has been identified; cases with fatal outcome have been reported.  
 
The majority of IMAEs was mild to moderate in severity, manageable with appropriate care, and 
rarely required discontinuation of therapy. 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the Study 
Procedure Manual or in the EDC system (Documents and Information Tab). 
 
11.1 
Definition of Adverse Events  
 
11.1.1 Adverse Event  
An adverse event (AE) is any untoward medical occurrence whether or not considered related to 
the study drug that appears to change in intensity during the course of the study. The following 
are examples of AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 


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• An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
11.1.2 Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence resulting in one or more of 
the following: 
 
• Results in death NOTE: Death due to disease progression should not be reported as a SAE, 
unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above).  
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
study drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
11.1.4 
Adverse Reaction 
An adverse reaction means any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event. 
 
11.1.5 
Expected Adverse Event 
Expected AEs are those events that have been previously identified as resulting from 
administration of the agent.  For this study, an AE is considered expected when it appears in the 
current AE list, the Investigator’s Brochure (IB), the package insert or is included in the 
informed consent document as a potential risk.  
 
 
 


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11.1.6 
Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2 
Reporting 
 
11.2.1 AE Reporting 
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s).  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
11.2.2 SAE Reporting 
 
11.2.2.1 Site Requirements for Reporting SAEs to HCRN 
• SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s).  
• SAEs will be reported on the SAE/ECI Submission Form within 24 hours of discovery 
of the event.   
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
• All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
The SAE/ECI Submission Form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE/ECI Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 


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Once the SAE has resolved (see resolution guidelines listed in 11.2.1), sites must submit a 
follow-up SAE/ECI Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting SAEs to Merck 
Hoosier Cancer Research Network will report any possibly related and unexpected SAE to 
Merck within one business day of receipt of the SAE/ECI Submission Form and to regulatory 
authorities (FDA) per federal guidelines.  Follow-up information will be provided to Merck as it 
is received from site.    
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE/ECI Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Merck’s parent IND at the time of submission. Additionally, HCRN will submit a copy of these 
documents to Merck at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally, HCRN will submit a copy of these reports to 
Merck at the time of submission to FDA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
Merck will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via the EDC system.    
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
11.6 
Reporting of Pregnancy and Lactation to the Sponsor-Investigator and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
site investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner that 
occurs during the trial or within 120 days of completing the trial.  All subjects and female 
partners of male subjects who become pregnant must be followed to the completion/termination 
of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
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be reported as serious adverse events.  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
 
Such events must be reported within 24 hours to HCRN. HCRN will report such events to the 
sponsor-investigator and Merck Global Safety within one business day of receiving notification 
of the event. (Attn: Worldwide Product Safety; FAX 215-993-1220) 
 
11.7 
Events of Clinical Interest 
Events of Clinical Interest (ECI) described below must be recorded as such on the SAE/ECI 
Submission Form and reported within 24 hours to safety@hoosiercancer.org at HCRN. HCRN 
will report these events within one business day of receipt to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220). 
 
Events of clinical interest for this trial include: 
1.  an overdose of Funder's product that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this trial, an overdose will be defined as any dose 
exceeding the prescribed dose for pembrolizumab greater than 10mg/kg over the prescribed 
dose. No specific information is available on the treatment of overdose of pembrolizumab. In 
the event of overdose, pembrolizumab should be discontinued and the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated.  If an adverse event(s) is associated with (“results from”) the overdose 
of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. 
 
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. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.   
 
12 
STATISTICAL CONSIDERATION 
 
12.1 
Study design  
This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial. 
Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab 
(Experimental Arm B).  Stratification factors for randomization include: presence of visceral 
metastatic disease (lung, liver, or bone vs. none) at the time of initiation of first-line 
chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD). 
 
 
 


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12.2 
Definition of primary endpoint 
The primary endpoint is progression–free survival (PFS), which is defined as the time from 
randomization to death or progression, depending on which occurs first, as per immune-related 
RECIST (irRECIST).  
 
12.3 
Definitions of secondary endpoints 
• PFS, which is defined as the time from randomization to death or progression, depending 
on which occurs first as defined by RECIST 1.1. 
• PFS as per irRECIST and RECIST 1.1 by PD-L1 expression levels. 
• Six-month PFS rate, which is defined as the percentage of participants that are alive and 
progression-free, as per irRECIST and RECIST 1.1, at six months calculated from the 
date of randomization. 
• Six-month PFS rate as per irRECIST and RECIST 1.1 by PD-L1 expression levels. 
• Safety of pembrolizumab, defined as rates of Grade 1-5 toxicity according to CTCAE 
v4.0. 
• Objective response rate (ORR) in subjects on maintenance pembrolizumab versus 
placebo, which is defined by irRECIST and RECIST 1.1 in subjects with measurable 
disease. 
• ORR in subjects receiving pembrolizumab after progressing on placebo as per irRECIST 
and RECIST 1.1. 
• Overall survival (OS), which is defined as the time from randomization to death. 
 
12.4 
Exploratory endpoints 
• PFS and 6-month PFS as per irRECIST and RECIST 1.1 without visceral metastatic 
disease randomized to pembrolizumab versus placebo. 
• Compare PD-L1 expression in primary tumor tissue and metastatic post first-line 
chemotherapy tumor tissue in a subgroup of subjects. 
• Correlate immune infiltrates in tumor tissue with response rate, progression-free survival, 
and overall survival in subjects receiving pembrolizumab versus placebo 
• Determine the repertoire of humoral responses and correlate with response rate, 
progression-free survival, and overall survival 
• Determine the induction of T cell responses and correlate with response rate, progression-
free survival, and overall survival 
• Correlate genomic alterations with response rate, progression-free survival, and overall 
survival 
• 
Correlate tobacco history with PFS in subjects receiving pembrolizumab versus placebo 
 
12.5 
Analysis plan for primary objective 
We assume that treatment group will experience three phases in terms of treatment effect: no 
effect, partial effect, and full effect. Specifically, we assume that before month 2, there is no 
treatment effect and after month 3 there is full treatment effect. In terms of hazard ratio, it is 1 
before month 2, and a target value 𝜃 <1 after month 3. The decrease of the hazard ratio from 1 to 
𝜃 between month 2 and 3 does not need to be specified and can take any pattern. 
 
We set the target value 𝜃 of the full treatment effect hazard ratio as 0.462. This target value is 
determined from the following rationale. The 12 months PFS survival is 6.2% for the control arm 


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and 16.8% for the treatment arm from the KEYNOTE-045 trial.28 Assuming a constant hazard 
for the control group, we can obtain the hazard for the control arm is 0.232. From Figure 1B of 
Bellmunt et al 2017, we assume the treatment reaches its full effect around month 8. This 
corresponds to a full treatment effect hazard ratio of 0.462.  
 
The sample size is determined by inverting the test statistic proposed by Zucker and Lakatos.44 
We set the type I error as 0.05 and power as 80%. Assuming the study duration is 3 years, the 
required total sample size based on one-sided test is at least 104 evaluable subjects (~52 per 
group). Therefore, the sample size is inflated to 108 to account for potential non-evaluable 
patients/early drop out.  Censoring is assumed uniformly between month 6 and the end of study.  
 
12.6 
Analysis plan for secondary objectives 
PFS will also be compared between Arms A and B using a weighted logrank test. The weight is 
0 before month 2 and 1 after month 3. The form of the weight between month 2 and 3 will take a 
form specified in Equation (5) of Zucker and Lakatos.44 This weighted log-rank test is used due 
to its maximum efficiency.  The time points (months 2 and 3) are chosen based on our belief that 
that treatment is likely to have minimal effect before month 2 and reach its full effect after month 
3. We will also compare the PFS using the usual constant weight logrank test. PFS will also be 
estimated by the Kaplan-Meier method and the estimated curves will be plotted. Median PFS for 
both groups will be estimated and their two-sided 95% confidence intervals will be constructed. 
 
Comparison of the 6-month PFS between the two arms will be conducted using estimates from 
the Kaplan-Meier method and the Greenwood formula. The resulting test is a Chi-square type of 
test 43. Subjects will be analyzed as they are randomized, regardless of the treatment that they 
actually receive. Data at the end of the 12-month follow-up period of the last treated patient will 
be used for analyses. For the placebo group, data before cross-over will be used for the analyses 
of primary objective. The evaluable set will be used for this analysis. PFS with respect to PD-L1 
expression levels and OS will be estimated by Kaplan-Meier methods and the comparisons will 
be performed by logrank tests. Their medians will be estimated with 95% confidence intervals.  
HRs for both PFS and OS will be estimated using Cox proportional hazard models. Covariate 
effects will be evaluated by Cox proportional hazard models. RMST will be estimated based on 
the Kaplan-Meier estimates of the survival functions.  ORR for pembrolizumab maintenance, 
placebo, and pembrolizumab after progression on placebo will be summarized by frequencies 
and percentages.  Comparisons of rates will be performed by Pearson’s chi-square tests or 
Fisher’s exact tests.  Durations of response will be summarized by median (1st, 3rd quartiles) and 
be compared using Wilcoxon rank sum test. These analyses will be performed using the 
evaluable set.  
 
Adverse events for the safety of pembrolizumab will be summarized using frequencies and 
percentages with respect to grade levels.  The safety set will be used for these analyses. 
 
12.7 
Exploratory analysis 
Cohen’s kappa and its 95% confidence interval will be calculated for PD-L1 expression between 
primary tumor tissue and metastatic post first-line chemotherapy tumor tissue in n=14 subjects.  
This sample size will lead to a power of 0.80 to detect a kappa≥0.70 against the null hypothesis 
kappa=0. Otherwise, the statistical analysis for correlative endpoints will be descriptive and 


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hypothesis generating in nature.  Descriptive statistics, statistical plot, correlations and 
appropriate statistical modeling will be used. 
 
12.8 
Safety stopping rule 
The Data and Safety Monitoring Board will examine the overall safety data regularly and decide 
whether the trial should continue as detailed in Section 13 based on the totality of the data. In 
addition, a stopping rule will be employed after 25 and 50 subjects finish at least one cycle of 
treatment in the Experimental Arm B, respectively. This safety stopping rule will be performed 
with respect to two criteria: definitely treatment-related deaths and grade 4 treatment-related 
AEs. Two-sided 90% exact binomial confidence intervals (CIs) will be constructed. If their 
lower bounds exceed pre-defined levels, the study drug will be considered unacceptably toxic for 
this patient population and the study will be terminated.  
 
The package insert of another monoclonal antibody to PD1 indicates a fatal pneumonitis rate of 
0.3-0.9%44.  In addition, there have been other rare fatal events described with PD1 blockade.  
Consequently, if the lower bounds of the CIs of definitely treatment-related death rate exceed 
0.9%, the study will be terminated. This corresponds to ≥ 2+ (2 or more) out of 25 and ≥ 3+ out 
of 50 subjects in the Experimental Arm B. 
  
Previous studies reported a rate of 12% for grade 3-4 AEs.27 Since the expected median PFSs are 
small for this patient population, we choose to focus on treatment-related grade 4 AEs.  A rate of 
10% is chosen that if the lower bounds of the CIs exceed 10%, enrollment will be halted and the 
study will be reviewed for continuation by the Data and Safety Monitoring Board. This 
corresponds to 6+ out of 25 and 10+ out of 50 subjects in the Experimental Arm B. 
 
There will be no planned interim efficacy assessment. 
 
12.9 
Unblinding plan  
For purposes of protocol therapy distribution, all administrators of the EDC system at HCRN and 
participating site pharmacy personnel will be unblinded to the protocol therapy assignment. For 
the purpose of the interim analyses and the final analysis, the statistician and HCRN analysis 
staff will be unblinded.   
 
Unblinding of the protocol therapy will occur at the time of disease progression or 
discontinuation of protocol therapy due to unacceptable toxicity (see Section 6), which are 
considered as medical emergencies.  Please see Section 7.3.2 for additional information on 
unblinding. 
 
Subjects randomized to treatment with placebo will be eligible to cross over for treatment with 
pembrolizumab provided that eligibility outlined in Section 3 is still met.  
 
12.10 Analysis datasets 
• Enrolled set. This will comprise all subjects who meet the eligibility criteria and are 
registered onto the study. 
• Evaluable set. This will comprise all enrolled subjects who undergo at least one post-
baseline assessment or die before any evaluation. 


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• 
Safety set. This will comprise all subjects that receive at least one dose of study drug. 
 
12.11 Sample size calculation/Accrual/Study duration/Replacement rules  
As described in section 12.5.  
 
12.12 Subject characteristics and significant protocol violations 
Demographic and other baseline data will be summarized descriptively for all subjects in the 
enrolled set. Significant protocol violations will be documented. 
 
12.13 Concomitant medication 
Concomitant medications and significant non-drug therapies prior and after the start of the study 
drug will be summarized for the safety set. 
 
12.14 Disposition 
The number of enrolled subjects will be summarized in a flow chart with frequency of 
completion and discontinuation. The subjects discontinued from study drug and their 
corresponding information will be listed.  Significant protocol violations will be tabulated and/or 
listed. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan 
This study will be conducted in accordance with Tisch Cancer Institute (TCI) at the Icahn School 
of Medicine at, Mount Sinai Medical Center (MSMC) Safety Monitoring Plan.   
 
HCRN oversight activities include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the DSMB for review according to DSMB Charter 
 
13.2 
Data Safety Monitoring Board 
The Data Safety Monitoring Committee (DSMC) at Tisch Cancer Institute (TCI) at the Icahn 
School of Medicine at, Mount Sinai Medical Center (MSMC) will serve as the primary Data and 
Safety Monitoring Board (DSMB) for this trial.  They will review and monitor study progress, 
toxicity, safety and other data from this trial.  Questions about subject safety or protocol 
performance will be addressed with the sponsor-investigator, statistician and study team 
members. Should any major concerns arise; the DSMB will offer recommendations regarding 
whether or not to suspend the trial.  
 
The DSMB will meet quarterly and information provided may include: subject accrual, treatment 
regimen information, adverse events and serious adverse events reported by category, summary 
of any deaths on study, audit and/or monitoring results.  
 
The DSMB will provide a recommendation to the team after all information is reviewed. This 
information should also be provided to the IRB at the time of continuing review for the trial. 


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13.3 
Data Quality Oversight Activities by HCRN 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  A summary report (QC Report) of these checks together with any queries 
resulting from manual review of the eCRFs will be generated for each site and transmitted to the 
site and the site monitor. Corrections will be made by the study site personnel.  
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Additional for cause visits may occur as necessary. Source 
documents will be reviewed for verification of agreement with data entered into the EDC system.  
It is important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Merck or its designee as well as 
inspection by appropriate regulatory agencies. 
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information. 
 
14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for 
quality control assurance and integrity. All data will be collected and entered into the EDC 
system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 


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The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Merck, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 


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15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
 
 


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APPENDIX 
Appendix A Smoking History Questionnaire 
 
 


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