A Phase 2 Study of Palliative Radiation Therapy and Anti-PD-1/PD-L1 Checkpoint Blockade in Patients With Metastatic Merkel Cell Carcinoma
Phase: PHASE2
Conditions: Merkel Cell Carcinoma
Sponsor: Stanford University

 
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A Phase II Study of Palliative Radiation Therapy and Anti-PD-1/PD-L1 Checkpoint 
Blockade in Patients with Metastatic Merkel Cell Carcinoma 
 
NCT03988647 
 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director  
Susan Jane Knox, PhD, MD 
Department of Radiation Oncology 
Stanford Cancer Center 
875 Blake Wilbur Dr., MC5847 
Stanford, CA 94305-5847 
Phone: 1-650-725-2720 
Fax: 1-650-723-7254 
Email: sknox@stanford.edu 
 
Co-Investigators 
Harlan Pinto, MD 
Department of Medical Oncology  
Stanford Cancer Center 
875 Blake Wilbur Dr., MC5820 
Stanford, CA 94305-5820 
Phone: 1-xxx-xxx-xxxx 
Fax: 1- xxx-xxx-xxxx 
 
Email: harlan@stanford.edu 
 
Susan Swetter, MD 
Department of Dermatology 
450 Broadway St., Pavilion C, 2nd Floor 
Redwood City, CA 94063-5334 
Phone: 1- xxx-xxx-xxxx 
Fax: 1- xxx-xxx-xxxx 
Email: sswetter@stanford.edu 
 
Sunil Arani Reddy, MD                                  
Department of Medical Oncology 
875 Blake Wilbur Dr., CC2232 
Stanford, CA 94305-582 
Phone: 1- xxx-xxx-xxxx 
 

 
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Fax: 1- xxx-xxx-xxxx 
 
Email: sreddy@stanford.edu 
 
 
Lisa Zaba, MD 
Stanford Cancer Center South Bay 
2589 Samaritan Dr.  
San Jose, CA 95124 
Phone: xxx-xxx-xxxx 
Fax: xxx-xxx-xxxx 
Email: lisa.zaba@stanford.edu 
 
 
Biostatistician 
Rie von Eyben, M.S. 
Biostatistics, Radiation Oncology 
875 Blake Wilbur Drive 
Stanford, CA 94305 
Phone: 1- xxx-xxx-xxxx  
Fax: 1- xxx-xxx-xxxx  
Email: rieve@stanford.edu 
 
Study Coordinator 
Leanne Stamps-Deanda 
Cancer Clinical Trials Office 
800 Welch Road, FC3C67 
Stanford, CA 94304 
Phone: xxx-xxx-xxxx  
Fax: xxx-xxx-xxxx  
Email: sldeanda@stanford.edu 
 
 
 
Version # 1 / Version Date: (03-28-2019) 
Amendment 1 / Amendment Date: (07-26-2019) 
• Clarification of inclusion/exclusion criteria (3.1.5, 3.1.8, 3.2.4, 3.2.23) 
Amendment 2 / Amendment Date: (09/10/2019) 
• Weight based dosing (2.4) 
• Update inclusion/exclusion criteria (3.1) 
• Clarify TSH w/Reflex FT4 and pregnancy test requirements (4.) 
• SAE reporting time frame (4. And 7.2) 
• Prior therapy clarification (4.1.1) 
• Dose limiting toxicity defined (6.) 

 
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• Study calendar updates, end of treatment visit window (9.) 
• Update tumor measurement windows (10.1) 
• Redesigned Eligibility Checklist (Appendix 2) 
Amendment 3 / Amendment Date: (11/11/2020) 
• The dose change to fixed dose of 200 kg 
• In dose modification section, CTCAE version 4.0 changed to 5.0 
• UA removed from treatment and follow-up schedule in study calendar and  
treatment and follow-up section in protocol. UA is required only at baseline screening.  
 
SRC Approval Date: 04-04-2019 

 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ..............................................................................................................5 
SCHEMA ........................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  .............................................8 
1. OBJECTIVES .........................................................................................................................9 
1.1 
PRIMARY OBJECTIVE ..........................................................................................................9 
1.2 
SECONDARY OBJECTIVES ...................................................................................................9 
1.3 
EXPLORATORY OBJECTIVE .................................................................................................9 
2. BACKGROUND .....................................................................................................................9 
2.1 MERKEL CELL CARCINOMA AND IMMUNOTHERAPY ............................................................9 
2.2 ANTI-PD-L1/PD-1 INHIBITION IN MERKEL CELL CARCINOMA .........................................11 
2.3 RATIONALE .......................................................................................................................10 
2.4 STUDY DESIGN AND DURATION .........................................................................................11 
2.5 CORRELATIVE STUDIES BACKGROUND ..............................................................................12 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................13 
3.1 INCLUSION CRITERIA .........................................................................................................13 
3.2 EXCLUSION CRITERIA ........................................................................................................14 
3.3 INFORMED CONSENT PROCESS ..........................................................................................16 
3.4     RANDOMIZATION PROCEDURES .........................................................................................16 
3.5 STUDY TIMELINE ...............................................................................................................16 
4. TREATMENT PLAN...........................................................................................................16 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ..................19 
4.2 CRITERIA FOR REMOVAL FROM STUDY .............................................................................19 
4.3 ALTERNATIVES ..................................................................................................................20 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION .................20 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ...............................................................20 
5.2 AVAILABILITY ...................................................................................................................22 
5.3 AGENT ORDERING .............................................................................................................22 
5.4 AGENT ACCOUNTABILITY .................................................................................................22 
6. DOSE MODIFICATIONS ...................................................................................................22 
7. ADVERSE EVENTS AND REPORTING PROCEDURES .............................................25 
7.1 POTENTIAL ADVERSE EVENTS ...........................................................................................25 
7.2 ADVERSE EVENT REPORTING ............................................................................................28 
8. CORRELATIVE/SPECIAL STUDIES ..............................................................................28 
8.1 LABORATORY CORRELATIVE STUDIES ..............................................................................28 
9. STUDY CALENDAR ...........................................................................................................29 
10. MEASUREMENT ..............................................................................................................31 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES .........................................................31 
10.2  EXPLORATORY OUTCOME ...............................................................................................38 
11. REGULATORY CONSIDERATIONS ............................................................................38 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ...........................................................................38 
11.2 DATA AND SAFETY MONITORING PLAN ..........................................................................39 

 
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11.3 DATA MANAGEMENT PLAN .............................................................................................39 
12. STATISTICAL CONSIDERATIONS ..............................................................................39 
12.1 STATISTICAL DESIGN .......................................................................................................39 
12.2 INTERIM ANALYSES .........................................................................................................39 
12.3 PRIMARY ANALYSIS ........................................................................................................39 
12.4 SECONDARY ANALYSIS ...................................................................................................39 
12.5  SAMPLE SIZE ..................................................................................................................40 
13. REFERENCES ...................................................................................................................41 
APPENDICES ..............................................................................................................................42 
APPENDIX 1: ECOG PERFORMANCE STATUS ..........................................................................42 
APPENDIX 2: PARTICIPANT ELIGIBILITY CHECKLIST ...............................................................43 

 
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PROTOCOL SYNOPSIS 
In the table below summarize the basic aspects of this research. This is to be used as a quick 
reference guide. Remove any section that is not relevant to the research.  
 
 
TITLE 
A Phase II Study of Palliative Radiation Therapy 
and Anti-PD-1/PD-L1 Blockade in Patients with 
Metastatic Merkel Cell Carcinoma (MCC) 
STUDY PHASE 
2 
INDICATION 
Metastatic Merkel Cell Carcinoma (stage IV) 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Pembrolizumab will be administered at a fixed 
dose of 200 kg iv per standard of care (SOC) 
every 3 weeks for 4 cycles or until disease 
progression or unacceptable toxicity occurs. 
Palliative radiation therapy to 1-2 sites of disease 
will occur between the first and second treatment 
with pembrolizumab. 
PRIMARY OBJECTIVE(S) 
The primary objectives of this study are to assess 
1) the safety and 2) efficacy of combining Anti-
PD-1/PD-L1 blockade with palliative radiation 
therapy in patients with Stage IV Merkel Cell 
Carcinoma.  Efficacy for the primary objective 
will be tumor response rates (CR, PR, SD, irCR, 
irPR, irSD) at both irradiated and unirradiated 
sites. 
SECONDARY OBJECTIVE(S) 
Assessment of Overall Survival and 
disease control rate/duration of response 
(CR, PR, SD, irCR, irPR, irSD). 
EXPLORATORY OBJECTIVE(S) 
Optional exploratory objectives (dependent 
upon funding) will include mutational 
burden/MSI analysis, measurement of 
polyomavirus in the blood, immune response 
assays at baseline, 2 weeks (±1 weeks) and 8 
weeks (±1 weeks) after radiation therapy, and 
possible tumor biopsy studies. 
 
TREATMENT SUMMARY 
Pembrolizumab will be administered ~every 3 
weeks for at least 4 cycles with palliative 
radiation administered between cycle 1 and cycle 
2. Subjects will participate until disease 
progression or unacceptable toxicity. Participants 
will have an end of treatment visit 3 weeks (±1 
week) after the last dose of pembrolizumab and 
then follow up visits every 3 months (±1 month) 
for two years and then every 6 months (±1 
month) for  years 3-4, then again at year 5 (±1 
month) from the last dose of pembrolizumab or 
until disease progression. Follow Up visits will 
then become optional and SOC. After 

 
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discontinuation of treatment, subjects will enter 
survival follow up conducted every 6 months (±2 
weeks) for 5 years from last dose of 
pembrolizumab. 
SAMPLE SIZE  
30 participants over 36 months 
STATISTICAL CONSIDERATIONS 
Data will be summarized using appropriate 
descriptive statistics: proportions with 95% 
confidence intervals, means, standard deviations, 
and ranges. 
 
 
 
 
 
 
 
 
 

 
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SCHEMA 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stage IV MCC, with 
one additional 
measureable target 
lesion outside the 
disease site 
undergoing palliative 
radiation therapy 
Treatment Visit 
Pembrolizumab 
administered  SOC 
Palliative radiation 
therapy administered 
SOC 
Treatment Visit 
Pembrolizumab 
administered  SOC 
~every 3 weeks 
 
At least 3 additional 
cycles   
End of Treatment Visit 
~3 weeks after last dose 
of pembrolizumab 
Tumor response 
If disease 
progression or 
unacceptable 
toxicity 
3 
weeks 
Follow Up visits  
~every 3 months for 2 
years then every 6 
months (± 1 month) for 
years 2-4 then at ~5 
years from last dose of 
pembrolizumab 
Tumor response
Survival Follow Up 
~every six months 
for 5 years from 
last dose of 
pembrolizumab 

 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
APC 
Antigen presenting cell 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FSH 
Follicle stimulating hormone 
GI 
Gastrointestinal 
Gy 
Gray 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HRT 
Hormone replacement therapy 
HTN 
Hypertensions 
IMRT 
Intensity-modulated radiation therapy 
IRB 
Institutional Review Board 
irRECIST 
Immune-related response evaluation criteria in 
solid tumors 
IV 
Intravenous 
LLN 
Lower limit of normal  
MCPyV 
Merkel cell polyomavirus 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SBRT 
Stereotactic body radiation therapy 
SD 
Stable disease 
SOC 
Standard of Care 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 

 
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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
The primary objectives of this study are to assess 1) the safety and 2) efficacy of combining 
Anti-PD-1/PD-L1 blockade with palliative radiation therapy in patients with Stage IV 
Merkel Cell Carcinoma.  Efficacy for the primary objective will be tumor response rates 
(CR, PR, SD, irCR, irPR, irSD) at both irradiated and unirradiated sites. 
 
1.2. 
Secondary Objectives 
 
Assessment of Overall Survival and disease control rate/duration of response (CR, PR, 
SD, irCR, irPR, irSD) 
 
1.3. Exploratory Objective 
 
Optional exploratory objectives (dependent upon funding) will include mutational burden/MSI 
analysis, measurement of polyomavirus in the blood, immune response assays at baseline, 2 
weeks (±1 weeks) and 8 weeks (±1 weeks) after radiation therapy, and possible tumor biopsy 
studies. 
 
2. 
BACKGROUND 
 
2.1 
Merkel Cell Carcinoma and Immunotherapy 
Merkel Cell Carcinoma is a rare and aggressive skin cancer for which much is written although 
rigorous trials are lacking (1).  In general, many patients still die of advanced stage IV disease 
having a 5 year survival of 13.5%. (2)  Recent approval of the checkpoint inhibitor, avelumab, 
likely improves this dismal outcome, but to some extent increasing awareness and diagnosis of 
this entity may also be contributing to improved outcomes.  Swedish Cancer Registry 
incidence shows a doubling in close to 20 years. (3)  Besides, avelumab other recent 
breakthroughs in knowledge include the association in some cases of the DNA virus, known as 
Merkel Cell Polyomavirus with the disease. (4)  Historically, patients with localized disease 
are treated with surgery with or without radiation.  Although these treatments can be associated 
with good outcomes, the strength of data for the exact delivery of such treatments is still weak 
due to the lack of good controlled studies.  In addition, many patients develop metastatic 
disease with chemotherapy being the major treatment option in previous decades.  Again, the 
data is of low quality, but the lack of long-term responders suggests only minor benefit.   
Further improvements are clearly needed, including controlled studies and increased research 
on new ideas to improve upon current therapy.   
Immunological aspects of Merkel Cell include, in some patients, viral association, and 
increasing incidence in the setting of immune suppression such as with transplant (5).  
Regardless of immunological profile, the recent approval of avelumab, an anti-PDL-1 
monoclonal antibody (6) has led to much renewed interest in systemic therapy in general and 
immunotherapy specifically. Although the trial was not randomized, it did suggest benefit and 
showed long term efficacy in some patients.  Further strengthening the efficacy of avelumab 
was its use after chemotherapy.  Pembrolizumab (Keytruda), an anti-PD1 antibody, has also 
been studied with evidence of long-term clinical benefit. (7), and was approved by the FDA in 
December 2018. 
Given our knowledge of efficacy of radiation (8) for local control and smaller benefits of 
chemotherapy for the treatment of Merkel cell carcinoma, combination therapy with 
checkpoint inhibitors and radiation therapy makes sense.  The immunological nature and 

 
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radiosensitivity of Merkel cell carcinoma and encouraging results to date with PD-1/PD-L1 
axis inhibition, provide a compelling rationale for the study of the combination of checkpoint 
inhibition and radiation therapy as a means of inducing a clinically meaningful anti-Merkel 
cell carcinoma immune response.   We and others have studied this approach in melanoma (9, 
10) and other diseases, with impressive results in a subset of patients.  This continues to be a 
very active and promising area of clinical investigation.  Given the features of Merkel cell 
carcinoma discussed above, we hypothesize that it is likely that this approach will be beneficial 
in Merkel cell carcinoma as well. 
 
2.2 
Anti-PD-L1/PD-1 Inhibition in Merkel Cell Carcinoma 
Avelumab (Bavencio) is a programmed death ligand-1 (PD-L1) blocking antibody approved 
for 1) metastatic Merkel Cell Carcinoma (MCC) and 2) locally advanced and metastatic 
urothelial cancer.  It is dosed at 800 mg IV every 2 weeks. Until progression of disease or 
unacceptable toxicity.  The most common AEs (20% and above) in MCC patients were fatigue, 
musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and 
peripheral edema.  The most common AEs in urothelial carcinoma patients were fatigue, 
infusion reactions, musculoskeletal pain, nausea, decreased appetite and urinary tract 
infections.  In a study of 88 MCC patients, the overall response rate was 33 % with 11.4% 
complete responses, and duration of response ranging from 2.8-23.3+ months.  
 
Pembrolizumab (Keytruda) is a PD-1 blocking antibody, approved for multiple indications, 
and most recently in December 2018, approved for recurrent locally advanced or metastatic 
MCC.  The approval was based on the Phase II CITN-09/KEYNOTE-017 trial in which 
pembrolizumab resulted in an Overall Response Rate (ORR) of 56%, PR rate of 32% and CR 
rate of 24% in patients who had not previously received systemic therapy for their advanced 
disease.  An additional 10% had stable disease.  In this multicenter, single arm trial, 50 
treatment naïve patients were treated with pembrolizumab at 2 mg/kg every 3 weeks.  86% of 
patients had metastatic disease and 64% were positive for Merkel cell polyomavirus (MCPyV).  
At a median follow up of 14.9 months the median duration of response (DOR) was not 
reached.  Among the 28 patients with response, 96% had a DOR of at least 6 months, and 54% 
had a DOR of 12 months or more.  Both Progression Free Survival (PFS) and median Overall 
Survival (OS) with pembrolizumab were higher than historical data for chemotherapy controls.  
The median time to response was 2.8 months, with most responses occurring by 12 weeks.  
Responses were observed regardless of Merkel cell polyomavirus (MCPyV) status, with an 
ORR of 59% in MCPyV-positive patients and 53% among MCPyV-negative patients. The 
most common AEs of pembrolizumab reported in at least 20% of patients who received single-
agent pembrolizumab were fatigue, musculoskeletal pain, decreased appetite, pruritus, 
diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and abdominal pain. 
Overall, 96% of patients experienced all-grade treatment-related AEs, with 14% of patients 
discontinuing treatment dues to treatment-related AEs.  Grade 3 and above treatment-related 
AEs were reported for 28%, and there was one treatment-related death in this study.  
 
Additional information regarding pembrolizumab (e.g. PK, route of elimination, metabolism, 
etc.) can be found in the package insert. 
 
2.3 
Rationale 
The underlying hypothesis for this study is that local radiation therapy (RT) can be safely used 
in combination with PD-1/PD-L1 blockade.  This combination therapy may have the potential 

 
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to enhance the induction of systemic anti-Merkel cell carcinoma immune responses, which will 
inhibit growth and kill Merkel cell tumor cells in sites of established metastases outside of the 
local radiation therapy field. 
 
This is a single institution study of pembrolizumab combined with palliative radiation therapy 
in patients with metastatic Merkel cell carcinoma.  Palliative treatment means treatment to 
shrink a tumor, slow its growth or control symptoms.   Patients must require radiation therapy 
for palliation of symptoms or to prevent local progression of disease and associated 
complications and/or symptoms from metastases. 
 
Radiation therapy (RT) is commonly used to palliate sites of metastatic disease.  Radiation can 
locally kill Merkel carcinoma cells and result in the release of tumor antigens in close 
proximity to antigen presenting cells (APC) in tumors, which could help to initiate an anti- 
tumor immune response.  The combination of RT with PD-1/PD-L1 blockade, which inhibits 
co- inhibitory signaling in between T cells and tumor, may result in enhanced anti-tumor 
responses that result in greater tumor burden reduction systemically. 
 
2.4 
Study Design and Duration 
This is a single institution, single arm, open-label, Phase II treatment study to evaluate the 
safety and efficacy of palliative radiation therapy combined with pembrolizumab as a means of 
providing for PD-1/PD-L1 checkpoint blockade in patients with metastatic Merkel Cell 
Carcinoma as either first line therapy or upon progression on prior therapy. 
 
In this study, pembrolizumab will be administered at 200 kg IV every 3 weeks as standard of 
care as approved by the FDA.   Palliative radiation therapy will be given between the first and 
second cycles of immunotherapy. 
 
Subject participation in this study comprises the following time periods: 
 
•   Screening 
-Screening assesses the subject’s eligibility to participate as determined by the 
inclusion/exclusion criteria. 
- Screening labs and ECOG Performance Status must be completed within 4 
weeks of confirmation of eligibility. Imaging must be completed within 4 weeks 
of confirmation of eligibility and within 6 weeks of starting pembrolizumab 
therapy. 
-Eligibility must be confirmed within 28 days of signing the informed consent 
form. 
 
•   Pembrolizumab 
- Patients will receive pembrolizumab as a single agent administered 200 kg as 
standard of care intravenously every 3 weeks until progression or unacceptable 
toxicity.  
- Laboratory evaluations must be performed and the results examined before 
administration of each dose. 
- As durable disease stabilization and/or objective tumor response can be seen 
after early progression before Week 12, it is recommended that, in the absence of 
dose-limiting toxicities (e.g., serious AEs), immunotherapy be administered over 

 
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the initial 12 weeks even in the setting of apparent clinical progression, providing 
the subject’s performance status remains stable. 
- All subjects, including those who may have discontinued treatment for drug-
related AEs and/or who have evidence of clinical progression, should obtain a 
tumor assessment 3weeks (±1 week) after the last dose of pembrolizumab. 
- Based on clinical experience in ongoing and completed immunotherapy studies, 
the following recommendations apply for subject management in light of the 
tumor assessment taken 3 weeks (±1 week) after the last dose of pembrolizumab: 
• 
The appearance of new lesions in subjects with other stable or shrinking 
baseline tumor burden may be experiencing clinical benefit and should 
continue on treatment before alternative anti-cancer agents are considered. 
These subjects can be seen to have continued tumor shrinkage in subsequent 
imaging. 
• 
As long as overall tumor burden is stable or decreasing, subjects can remain 
in treatment, even in the presence of new lesions, at the discretion of the 
treating physician. 
• 
Clinical progression warranting alternative anti-cancer treatment should be 
considered in subjects whose overall tumor burden appears to be substantially 
increased and/or in subjects whose performance status is decreased. 
 
•   Follow-Up 
- Subjects with SD, PR or CR will continue receiving pembrolizumab every 3 
weeks per standard of care. After the last dose of pembrolizumab, subjects will 
enter Follow-Up. Efficacy assessments for these subjects are per standard of care. 
 
•   Survival Follow-Up (Post Study Follow-Up) 
- Subjects who are no longer receiving pembrolizumab due to unacceptable 
toxicity (e.g., refractory Grade > 3 AEs), disease progression, investigator 
judgment, or study closure are managed in survival follow-up.  
- If possible, subjects will be contacted or medical records reviewed every 6 
months (±2 weeks) for 5 years after the last dose of pembrolizumab to evaluate 
survival status. 
 
2.5 
Correlative Studies Background 
Correlative studies will be performed if/when funding for them becomes available.  
• Mutational burden/MSI - has been associated with response to checkpoint inhibitors in 
other solid tumor types (e.g. melanoma), and we would look at this to see if there is an 
association between this endpoint and response in MCC in our study 
• Measurement of MC polyomavirus - to look for an association between this endpoint and 
response 
• Immune Response Assays - to look for potential immune response biomarkers associated 
with response - e.g. may include Luminex for 51 cytokines testing in serum or plasma, 
ELISA for MHC class 1 polypeptide-related sequence A (MYCA) and MHC class 1 
polypeptide-related sequence B (MYCB) in serum or plasma, immunophenotyping 
including myeloid-derived suppressor cells (MDSC) and gamma/delta T cells, mass 
cytometry or CyTOF ICS with phorbol 12-myristate 13-acetate (PMA) + ionomycin 
stimulation (global immunocompetence assay) 

 
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Because of relatively small patient numbers we will be looking for trends/correlations with 
response. 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
 
3.1.1 Histologically confirmed metastatic or locally advanced Merkel Cell Carcinoma 
(includes in-transit or bilateral bulky disease) with at least two distinct sites of 
disease. 
 
3.1.2 Subjects with brain metastases and/or carcinomatous meningitis are eligible providing 
they are neurologically stable (if systemic steroids are required, subjects should be stable 
on the lowest clinically effective dose, as steroids may interfere with the activity of 
immunotherapy if administered at the time of the first Anti-PD-1/PD-L1 dose.) 
 
 
 
  
 
3.1.3 Must be at least 14 days since treatment for MCC, and recovered (baseline or residual 
non ir Grade 1 toxicity or ir Grade 2 toxicity at the investigator’s discretion, see section 
4.1.1) from any clinically significant toxicity experienced during treatment before the 
first dose of on study pembrolizumab therapy. 
 
 
3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
 
3.1.5 Life expectancy of ≥ 16 weeks. 
 
 
3.1.6  Subjects must have measurable disease according to RECIST v1.1, and have baseline 
(screening/baseline) radiographic images, (e.g. CT, PET CT or MRI brain, chest, 
abdomen, pelvis, to be determined by the attending physician) within 4 weeks of 
confirmation of eligibility and within 6 weeks before the initiation of on study 
pembrolizumab therapy. 
 
 
3.1.7 Required values for initial laboratory tests: 
  
 
 
 
-WBC: ≥ 2000/µL (~ 2 x 109/L) 
 
 
 
 
-ANC: ≥ 1000/µL (~ 1 x 109/L)  
 
 
 
 
-Platelets: ≥ 50 x 103/µL (~ 50 x 109/L) 
 
 
 
 
-Hemoglobin:  ≥ 8 g/dL 
 
 
 
 
-Calculated creatinine clearance (eGFR) greater than 30mL/min 
 
 
-AST/ALT: Less than 2.5 x ULN for subjects without liver metastasis, less than 5 
times ULN for liver metastases 
 
 
-Bilirubin: less than 3.0 x ULN (except for subjects with Gilbert’s Syndrome, who 
must have a total bilirubin of less than 3.0 mg/dL) 
 
 
-Non-clinically significant laboratory abnormalities such as lipase elevation would 
not be an exclusion. 
 
3.1.8 No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C, or active 
infection requiring systemic antibiotics. Testing for the above is not required unless 
clinically suspected. 

 
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3.1.9  At least one measurable site of disease (≥ 10 mm as per RECIST v1.1 except for lymph 
nodes that must be 15 mm or greater on the short axis) outside of the planned palliative 
radiation therapy field. 
 
3.1.10 Require radiation therapy for palliation of symptoms or to prevent local progression of 
disease and associated complications and/or symptoms from metastases.   
 
3.1.11 Men and women, at least 18 years of age. 
 
3.1.12 Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study [and for up to 26 weeks after the 
last dose of investigational product] in such a manner that the risk of pregnancy is 
minimized. 
 
 
 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal. Post-menopausal is defined as: 
 
 
 
 
•     Amenorrhea ≥ 12 consecutive months without another cause, or 
 
 
 
• 
For women with irregular menstrual periods and on hormone replacement therapy 
(HRT), a documented serum follicle stimulating hormone (FSH) level > 35 
mIU/mL 
 
 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products such 
as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to 
prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., 
vasectomy) should be considered to be of childbearing potential. WOCBP must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG) within 1 week prior to the start of investigational product. 
 
3.1.13 Men of fathering potential must be using an adequate method of contraception to avoid 
conception throughout the study [and for up to 26 weeks after the last dose of 
investigational product] in such a manner that the risk of pregnancy is minimized. 
 
3.2 
Exclusion Criteria 
 
3.2.1 WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for 
the entire study and for up to 26 weeks after the last dose of investigational product. 
 
3.2.2 Women who are breastfeeding. 
 
3.2.3 WOCBP with a positive pregnancy test within 6 weeks before enrollment. 
 
3.2.4  
Autoimmune disease: Poorly controlled autoimmune disease is excluded.  Well 
controlled autoimmune disease (e.g. well controlled RA) will be assessed by the study 
team and a decision made regarding eligibility based on the degree of 
immunosuppression and severity of symptoms. 

 
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3.2.5 Any subject who has a life-threatening condition that requires high-dose 
immunosuppressant(s).  Steroid doses greater than 20 mg/day will exclude the patient 
from participation in the trial. 
 
3.2.6 Presence of known hepatitis B or hepatitis C infection, regardless of control on antiviral 
therapy. 
 
3.2.7 Subjects who have another active, concurrent, malignant disease are not eligible, with the 
exception of subjects with adequately treated basal or squamous cell skin cancer, 
superficial bladder cancer, carcinoma in situ of the cervix, or other cancers that are in 
remission/not measurable. Patients will be excluded if they have any known additional 
malignancy that requires active treatment while on treatment for Merkel Cell Carcinoma. 
 
 
3.2.8 Evidence of symptomatic interstitial lung disease or symptomatic active, noninfectious 
pneumonitis. 
 
3.2.9 Participants with impaired cardiac function or clinically significant cardiac disease such 
as unstable angina/uncompensated heart failure, uncontrolled symptomatic arrhythmia. 
 
 
3.2.10 Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or 
antiviral treatment.  This exclusion does not include prophylactic antibiotics or topical 
antibiotics. 
 
3.2.11 Known hypersensitivity to another monoclonal antibody, which cannot be controlled 
with standard measures (e.g. antihistamines and corticosteroids). 
 
3.2.12 Any condition that would, in the investigator’s judgment, interfere with full participation 
in the study. 
 
3.2.13 Prisoners or subjects who are involuntarily incarcerated. 
 
3.2.14 Subjects with acute or poorly controlled psychiatric illness or subjects who are 
compulsorily detained for physical (e.g., infectious disease) illness, with the exception of 
patients that are well supported and able to participate (e.g. paraplegia from a motor 
vehicle accident). 
 
3.2.15 Any underlying medical or psychiatric condition that, in the opinion of the investigator, 
could make the administration of anti-PD-1/PD-L1 hazardous or could obscure the 
interpretation of adverse events. 
 
3.2.16 Any live vaccine therapy for up to 4 weeks before or after any dose of immunotherapy on 
this trial. 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  

 
Protocol Amendment # 3 
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November 11, 2020 
Participants must sign the IRB approved informed consent prior to participation in any study 
specific procedure. The participant must receive a copy of the signed and dated consent 
document.  The original signed copy of the consent document must be retained in the medical 
record or research file.  
 
3.4       Randomization Procedures 
Randomization is not used for this open label single arm study. 
 
 
3.5 
Study Timeline 
Primary Completion: 
 
The study will reach primary completion  7 ½ years  from the time the study opens to accrual. 
 
Study Completion: 
 
The study will reach study completion 7 ½ years from the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
Screening/Baseline Visit 
 
The following tests and examinations must be performed and the eligibility criteria 
satisfied before treatment may begin: 
 
•  Histologic diagnosis of Merkel Cell Carcinoma 
•  Demographics and medical history 
• Measurements of weight, height, temperature, pulse, respiratory rate, and resting 
systolic and diastolic blood pressure 
•  Complete physical examination 
•  ECOG Performance Status 
•   Clinical laboratory tests: 
- Hematology: hemoglobin, hematocrit, CBC counts with differential (including       
absolute lymphocyte count) and direct platelet count 
  - Serum Chemistry: albumin, serum alkaline phosphatase, SGOT (AST)/SGPT 
(ALT), total bilirubin, calcium, creatinine, glucose, lactate dehydrogenase (LDH), 
total protein, urea nitrogen (BUN), electrolytes (including sodium, potassium, 
chloride, and bicarbonate), TSH w/Reflex FT4 
- Urinalysis: 
o Gross examination including specific gravity, protein, glucose, and blood 
o Optional microscopic examination including WBC/HPF, RBC/HPF and any 
additional findings 
•  Optional Blood sample obtained for investigational immune response assays  
•  Chest radiography unless baseline CT scan was performed 
•  Electrocardiogram 
 
•    Relevant baseline radiographic images (e.g. brain, chest, abdomen, pelvis, and 
bone scans with the exact imaging studies utilized determined by the attending 
physician) within 6 weeks of initiation of anti-PD-1/PD-L1 

 
Protocol Amendment # 3 
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November 11, 2020 
•  Current medications 
•  Baseline review of symptoms 
•  Pregnancy test 
•  Optional Tumor biopsy 
 
Treatment Visits  
The day subjects receive the first dose of pembrolizumab therapy will define Day 1. 
Subjects are required to have blood collected and chemistry labs analyzed up to 1 
week prior to each dose of pembrolizumab. Investigators or an assigned medical 
professional must review liver function tests from the predosing labs and ensure the 
results meet dosing requirements prior to authorizing administration of each dose of 
pembrolizumab. 
 
Subjects will receive a single dose of pembrolizumab as standard of care with 200kg 
IV every 3 weeks (with a -3 and +7-days window) until disease progression or 
unacceptable toxicity occurs. 
 
During this treatment phase, the following procedures will be performed within 1 week 
of each scheduled visit: 
 
•  Pregnancy test for WOCBP, required within 6 weeks before first dose of 
pembrolizumab, then optional as clinically indicated for ongoing doses 
• Vital sign measurements will include weight, temperature, pulse, and resting 
systolic and diastolic blood pressure. Vital sign measurements of pulse, and systolic 
and diastolic blood pressure will be collected prior to the infusion of anti-PD-1/PD-
L1. 
•  Physical examination  
•  ECOG Performance Status 
 
•   Clinical laboratory tests (as outlined in the screening phase) (taken and            
results reviewed prior to study drug administration): 
-  Hematology 
-  Serum chemistry 
-  TSH w/Reflex FT4- week 13 only (for patients who continue pembrolizumab past 
week 10) 
 
•  Blood (optional) for investigational immune response assays at 2 weeks (±1 weeks) 
and 8 weeks (±1 weeks) after completion of radiation therapy. 
•  Concomitant medications 
•  Adverse event assessment 
•  Optional Tumor biopsy 
 
Follow-up 
 
Patients will be seen for an end of treatment visit 3 weeks (±1 week) after the last 
pembrolizumab dose and again for follow up visits every 3 months (±1 month) for 2 years 
and then every 6 months (± 1 month) for years 3-4 and again at year 5 (±1 month) per SOC 
thereafter until progression of disease by imaging criteria or increased symptomatology 
that requires another therapy. Follow up visits will be performed until 5 years from the last 
dose of pembrolizumab and will then become optional and SOC. 

 
Protocol Amendment # 3 
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November 11, 2020 
 
The following procedures will be performed at each scheduled follow-up visit ±1 month 
during the first 2 years. During years 3-5 the clinical laboratory tests will be performed 
only once per year. 
 
• Measurements of vital signs (resting systolic and diastolic blood pressure, pulse, 
respiratory rate, and temperature) and weight 
•  Physical examination 
•  ECOG Performance Status 
•  Clinical laboratory tests 
-  Hematology 
-  Serum chemistry 
-  TSH w/Reflex FT4  
 
•  Concomitant medications (for the first 2 years) 
•  Adverse event assessment (for the first 2 years) 
• Status of new and continuing AEs and SAEs (at minimum, collected up to 60 days 
following last dose of pembrolizumab, 6 months for irSAEs definitely related) 
•  Relevant imaging studies for tumor measurements 
•  Optional Tumor biopsy 
 
Survival Follow-Up Assessment for all Subjects 
 
After a subject progresses or changes therapy due to symptomatology, they will enter 
survival follow-up. In the event a subject withdraws from the treatment phase of the 
study or discontinues from all other study procedures, the investigators may continue to 
contact the subject (with his/her agreement) for the collection of survival follow-up 
data. The subject’s decision should be documented in the source records. If possible, 
contact will be made for all subjects enrolled in the study, regardless of enrollment date. 
If possible subjects or their caregivers will be contacted every 6 months (±2 weeks) for 
5 years from the last dose of pembrolizumab and inquiries will be made about survival 
data and/or death date. 
 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Concomitant medications/supportive care will be administered per SOC. 
 
4.1.1 Prohibited and/or Restricted Treatments 
Subjects in this study may not use live vaccines for the treatment of cancer or prevention of 
disease (including those for common medical conditions) for up to 4 weeks before and after 
dosing with Anti-PD-1/PD-L1. Concomitant anti-cancer medications or treatments are 
prohibited in this study while subjects are receiving Anti-PD-1/PD-L1. 
 
Subjects may not use any of the following therapies during the study: 
 
•    Any non-study anti-cancer agent (investigational or non-investigational) 
 
•    Any other investigational agents 
 
•    Immunosuppressive agents (unless required for treating potential AEs) 

 
Protocol Amendment # 3 
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November 11, 2020 
 
• 
 Chronic systemic corticosteroids greater than 20 mg/day (unless required for treating 
treatment emergent AEs or required for management of signs or symptoms due to 
brain metastases) 
 
• 
 Any non-oncology live vaccine therapies used for the prevention of infectious diseases 
(for up to 4 weeks before or after any dose of study drug). 
 
Subjects may be allowed with the following prior therapies: 
 
• Prior treatment with an anti-PD-1/PD-L1 antibody does not exclude patients from this 
study. Each case will be considered individually and a decision made by the study team. 
 The team will consider if a subject was discontinued from the prior anti-PD-1/PD-L1 
treatment due to an AE or SAE. For example, non-clinically significant immune-related 
laboratory abnormalities – may not automatically exclude patients from participating in 
this study – e.g. asymptomatic elevated amylase; responsiveness to steroids.  
 
•  A history of AEs with prior IL-2 or Interferon will not preclude subjects from entering the 
current study. 
 
 
4.2 
Criteria for Removal from Study 
Subjects MUST discontinue study treatment for any of the following reasons: 
•    Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best 
interest of the subject. 
•    Progressive disease, based on the investigator’s judgment, at or after the end of 
treatment visit. Progression before the end of treatment visit can be followed by 
objective response and does not require discontinuation. Small new lesions, by 
themselves, are not defined as progression.  
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
All subjects who discontinue study treatment should comply with protocol-specified 
follow-up procedures as outlined in Section 4. The only exception to this requirement is 
when a subject withdraws consent for all study procedures or loses the ability to consent 
freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). 
 
If a subject was withdrawn before completing the study, the reason for withdrawal must 
be entered on the appropriate case report form (CRF) page. 
4.3 
Alternatives 
Alternatives to participation in this study include: 
   • 
Getting treatment without being in a study which may include other Merkel cell 
carcinoma therapy such as: 
 
 
o 
Immunotherapy without radiotherapy 

 
Protocol Amendment # 3 
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November 11, 2020 
 
 
o 
Chemotherapy 
 
 
o 
Targeted therapy  
 
 
o 
Radiotherapy alone without immunotherapy 
 
• 
Taking part in another study 
 
• 
Getting no treatment 
 
• 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the Merkel cell carcinoma. It 
does not treat the cancer directly but instead tries to improve how you feel. Comfort care 
tries to keep you as active and comfortable as possible. 
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
 Investigational Agent/Device/Procedure   
5.1.1 Pembrolizumab 
 
 
 
Unit:     Pembrolizumab 200 kg; comes in 100 mg/4mL solution vials 
 
 
Route:   Intravenous infusion  
 
 
Source: Stanford Hospital Pharmacy 
 
5.1.1.1 Handling and Dispensing 
 
Pembrolizumab must be stored refrigerated (2ºC - 8ºC) with protection from light. In 
preparation of infusion, pembrolizumab may be stored in IV infusion bags (PVC, non-
PVC/non-DEHP) or glass infusion containers at room temperature for up to 6 hours or 
refrigerated (2ºC - 8ºC) for up to 24 hours. Drug must be completely delivered to the 
subject within 24 hours of preparation. This includes any time in transit plus the total 
time for the infusion. 
 
As with all injectable drugs, care should be taken when handling and preparing 
pembrolizumab. Whenever possible, it should be prepared in a laminar flow hood or 
safety cabinet using standard precautions for the safe handling of intravenous agents, 
applying aseptic technique. Latex gloves are required. If pembrolizumab concentrate or 
solution comes in contact with skin or mucosa, immediately and thoroughly wash with 
soap and water.  
 
5.1.1.2 Preparation and Administration of Pembrolizumab 
 
Pembrolizumab will be prepared according to standard of care and administered 
intravenous at a dose of 200 /kg according to standard of care. See the current package 
insert for additional details. 
 
Pembrolizumab should be administered under the supervision of a physician experienced 
in the use of intravenous agents. Pembrolizumab is administered as an intravenous 
infusion only. Patients may be premedicated as per standard of care as needed. Infusions 
will be interrupted, or the rate slowed as needed for mild or moderate (grade 1 or 2) 
infusion-related reactions.  Infusions will be permanently stopped for severe or life-
threatening (grade 3 or 4) infusion reactions. 
 
 

 
Protocol Amendment # 3 
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November 11, 2020 
5.1.1.3 Criteria that Require Permanent Discontinuation of Pembrolizumab 
 
Subjects MUST discontinue study treatment for any of the following reasons that are not 
related to a related adverse event: 
 
•  Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
•  Pregnancy 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
 
Exceptions to Permanent Discontinuation of pembrolizumab dosing under the following 
situations: 
 
• Potentially reversible inflammation (< Grade 4), attributable to a local antitumor 
reaction and a potential therapeutic response. This includes inflammatory reactions at 
sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but not 
diagnostic of metastasis. 
• Hospitalization for < Grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up. 
• Subjects with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified: 
 
 
- Ocular toxicity that has responded to topical therapy 
 
 
 - Endocrinopathies where clinical symptoms are controlled with appropriate 
hormone replacement therapy. 
 
Note: Pembrolizumab may not be restarted while the subject is being treated with 
systemic corticosteroids except for subjects on stable doses of hormone replacement 
therapy such as hydrocortisone. 
 
All subjects who discontinue treatment prematurely due to a drug-related AE or 
symptomatic progression prior to disease assessment at the end of treatment visit are 
required to return for the 3 weeks (±1 week) after the last dose of pembrolizumab visit, 
unless they are switched to an alternate anti-neoplastic medication. 
 
 
5.1.2 Radiation Therapy 
Patients will receive palliative radiation therapy to 1-2 sites of disease.  Radiation therapy will be 
delivered between the first and second cycles of anti-PD-1/PD-L1 therapy.  The total dose and 
fractionation regimen of radiation will be determined by the attending physician by such factors 
as the location and size of the lesion that requires radiation, volume of radiosensitive normal 
tissue in the field, and clinical status of the patient.  Patients will be treated with either 9 Gy X 3 
(27 Gy in 3 fractions), or 4-6 Gy X 5 (20-30 Gy in 5 fractions). Radiation therapy will be 
planned in 3 or 4 D, and may be delivered using conventional, IMRT/ rapid arc or SBRT.  
Portal imaging for QC will occur according to SOC.  All patients will be seen at least weekly by 
the attending physician while on treatment. 
 

 
Protocol Amendment # 3 
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November 11, 2020 
5.2 
Availability 
Both pembrolizumab and palliative radiation therapy are SOC. 
 
5.3 
Agent Ordering 
Pembrolizumab will be obtained through the Stanford Hospital Pharmacy as SOC. 
 
5.4 
Agent Accountability 
Pembrolizumab is FDA approved SOC therapy for Merkel cell carcinoma being dispensed from 
the Stanford Hospital Pharmacy and will not require accountability tracking. 
 
6. 
DOSE MODIFICATIONS 
Decisions to skip or modify a pembrolizumab dose will be made based on specified safety 
criteria as shown in the table below.  
 
Recommended Dose Modifications of Pembrolizumab for Adverse Reactions  
Treatment-Related 
Adverse Reaction  
Severity of Adverse 
Reactions*  
Dose Modification  
Immune-Mediated 
Pneumonitis  
Grade 2 pneumonitis  
Withhold (a)  
Grade 3 or 4 pneumonitis or 
recurrent Grade 2 pneumonitis  Permanently discontinue.  
Immune-Mediated 
Hepatitis  
Aspartate aminotransferase 
(AST)/or alanine 
aminotransferase (ALT) more 
than 3 and up to 5 times the 
upper limit of normal or total 
bilirubin more than 1.5 and up 
to 3 times the upper limit of 
normal  
Withhold Pembrolizumab.  
Resume Pembrolizumab in patients 
with complete or partial resolution 
(Grade 0 to 1) of hepatitis after 
corticosteroid taper.  
If no liver mets, AST or ALT 
more than 5 times the upper 
limit of normal or total 
bilirubin more than 3 times the 
upper limit of normal; if liver 
mets and grade 2 AST or ALT 
at baseline with at least 50% 
increase that persist for one 
week or more  
Permanently discontinue.  
Immune-Mediated 
Colitis  
Grade 2 or 3 diarrhea or colitis  
Withhold.  
Resume in patients with complete 
or partial resolution (Grade 0 to 1) 

 
Protocol Amendment # 3 
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November 11, 2020 
of colitis or diarrhea after 
corticosteroid taper.  
 
Grade 4 diarrhea or colitis or 
recurrent Grade 3 diarrhea or 
colitis  
Permanently discontinue.  
Immune-Mediated 
Endocrinopathies 
(including but not limited 
to hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, 
hyperglycemia)  
Grade 3 or 4  
 
Withhold until clinically stable.  
 
Immune-Mediated 
Nephritis and Renal 
Dysfunction  
Grade 2 
Withhold.  
Resume in patients with complete 
or partial resolution (Grade 0 to 1) 
of nephritis and renal dysfunction 
after corticosteroid taper.  
Grade 3 or 4 
Permanently discontinue.  
Other immune-mediated 
adverse reactions 
(including but not limited 
to myocarditis, myositis, 
psoriasis, arthritis,  
hypopituitarism, uveitis, 
Guillain-Barré 
syndrome, pancreatitis, 
rhabdomyolysis, 
myasthenia gravis, 
histiocytic necrotizing 
lymphadenitis, 
demyelination, vasculitis, 
hemolytic anemia, 
hypophysitis, iritis, and 
encephalitis) 
 
For Immune-mediated 
For any of the following:  
 
 
Grade  2 or 3 based on severity 
and type 
Grade 3 based on severity and 
type or grade 4  
 
  
Grade 3 or suspected Stevens-
Johnson syndrome (SJS) or 
toxic epidermal necrolysis 
 
 
 
Withhold (a) 
 
Permanently discontinue.  
 
 
Withhold 
 

 
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November 11, 2020 
skin AEs  
 
(TEN) 
Grade 4 or confirmed SJS or 
TEN 
Permanently discontinue. 
 
For any of the following:  
Life-threatening adverse 
reaction (excluding 
endocrinopathies)  
Recurrent severe immune-
mediated adverse reaction  
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks  
Persistent Grade 2 or 3 
immune-mediate adverse 
reactions lasting 12 weeks or 
longer  
 
Permanently discontinue.  
Infusion-related reaction  Grade 1 or 2  
Interrupt or slow the rate of 
infusion.  
Grade 3 or 4  
Permanently discontinue.  
*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events. Version 5.0 (NCI CTCAE V5) 
(a) Resume if complete or partial resolution (Grade 0, 1) after corticosteroid taper. 
 
 
Dose Limiting Toxicity (DLT) Definition: 
Dose limiting toxicity is when therapy is permanently discontinued due to toxicity as defined in 
the dose modification table above or when the patient withdraws from treatment due to toxicity 
that the patient finds unacceptable. 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
7.1.1 Pembrolizumab alone: 
Pembrolizumab may cause one or more of the side effects listed below. This information is 

 
Protocol Amendment # 3 
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November 11, 2020 
based on data from cancer subjects in other clinical trials with pembrolizumab. 
 
The most common side effects (greater than 5% chance of happening) of pembrolizumab are: 
• Fatigue  
• Skin reactions: including rash, itching, hives, redness, blisters, and dry skin. Stevens Johnson 
Syndrome and toxic epidermal necrolysis, are rare and potentially life threatening diseases 
characterized by blistering and peeling of the top layer of skin resembling that of a severe 
burn.  
• Diarrhea 
• Nausea 
• Abdominal pain 
• Decreased appetite 
• Joint pain or stiffness 
• Thyroid gland abnormalities 
• Dehydration 
  
Less common side effects of pembrolizumab (between 2-5% chance of happening) include:  
• Liver function blood test abnormalities 
• Dry mouth 
• Vomiting 
• Low electrolyte counts in your blood, for example sodium 
• Lung inflammation (pneumonitis - see details below) 
• Cough 
• Headache 
• Fever 
• Muscle soreness, weakness, stiffness spasms or paralysis 
• Pain in back, arms or legs 
• Shortness of breath 
• Constipation 
• Swelling of the face, arms, or legs 
• Increase in inflammatory blood proteins (e.g., lipase) 
• Liver injury 
 
Rare but potentially serious side effects (less than 2% chance of this happening but potentially 
serious) of pembrolizumab include: 
• Low blood oxygen level 
• Acute lung injury or failure 
• Collection of fluid around the lungs 
• Adrenal gland abnormalities 
• Pituitary gland inflammation 
• Changes in vision (including decreased or blurry vision), dry eye, inflammation of the eye, or 
bleeding into the eye 
• Tingling, burning, or numbness in hands and feet 
• Hepatitis 
• Changes in kidney function tests and acute kidney injury or failure  
• Inflammation of the mouth and lining of the digestive tract  
• Inflammation of the pancreas 
• Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis)  

 
Protocol Amendment # 3 
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November 11, 2020 
• Chest discomfort 
• Heart palpitations 
• Inflammation of the heart or its lining or blood vessels 
• Chills 
• Dry skin 
• Diabetes 
• Increased level of blood acid called ketones 
• Dizziness 
• Infections: including sepsis, lung infections, and skin infections.  
• Hair loss 
• Changes in blood pressure 
• Inflammation or loss of brain nerves supplying vision and spinal cord, abnormal brain 
function 
• Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal organ 
involvement (including liver, kidney, and lung); known as Drug Reaction with Eosinophilia 
and Systemic Symptoms (DRESS) 
• Myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, and 
swallowing muscles. One death in a patient who received nivolumab combined with 
ipilimumab was considered due to myasthenia gravis and severe infection (sepsis). 
• Rhabdomyolysis (muscle fiber released into the blood stream which could damage your 
kidney) and polymyositis (chronic muscle inflammation with muscle weakness)  
• Colitis: Inflammation of intestine. It may cause abdominal pain and diarrhea with or without 
blood. Fever may be present. It may require you to receive additional fluids. If left untreated, 
this may lead to a tear in the wall of the intestine which can be serious and life threatening. 
Tell your study doctor right away if you have any of these symptoms. 
• Guillain-Barre syndrome: A disorder characterized by progressive symmetrical paralysis and 
loss of reflexes, usually beginning in the legs. The paralysis characteristically involves more 
than one limb (most commonly the legs), is progressive, and usually proceeds from the end of 
an extremity toward the torso. 
• Sarcoidosis: growth of tiny collections of inflammatory cells (granulomas) in different parts 
of your body — most commonly the lungs, lymph nodes, eyes and skin. 
• Loss of color (pigment) from areas of skin  
• Allergic reaction  
• Rejection of organ or tissue transplant 
• Graft versus host disease (GVHD): In patients who have received a transplant containing 
blood cells from another person (allogenic transplant), the donor’s immune cells attack the 
normal cells. Symptoms can be rapid and severe and can occur in any organ of the body. This 
has resulted in death when nivolumab, an antibody similar to pembrolizumab, or nivolumab 
and ipilimumab were given after allogenic transplant. 
 
Lung Inflammation (pneumonitis): It is possible that pembrolizumab may cause inflammation 
of the tissues of the lung. This adverse effect has been reported infrequently in patients treated 
with pembrolizumab. While many patients with x-ray or CT abnormalities have not developed 
any symptoms, some patients have developed mild to severe symptoms and in rare cases, death 
has occurred as a result of their lung inflammation. Signs and symptoms of lung inflammation 
may include difficulty breathing, pain or discomfort while breathing, chest pain, cough, 
shortness of breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.  
  
Your study doctor and nurse will watch you closely for changes in your ability to breathe and 

 
Protocol Amendment # 3 
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November 11, 2020 
for other signs or symptoms that might show you are developing this type of lung 
inflammation and will perform regular tests including physical exams, measurement of oxygen 
levels through non-invasive testing (i.e., pulse oximeter), blood tests, chest x-rays and/or CT 
scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
• Any new or increased shortness of breath; 
• Any new or increased chest pain; 
• Any new or increased pain/difficulty while breathing; 
• Any new or increased cough or any significant change in your type of cough; for example any 
new or increased mucous or blood in your cough;  
• Any change in the amount of oxygen you require; 
• Any fever, fatigue, or other symptoms that occur at the same time as any changes to your 
breathing or other lung symptoms.  
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, blood 
tests, chest x-rays, and/or CT scans. You will be monitored very closely for changes in your 
overall lung symptoms, monitoring may require hospitalization. You may require specific 
treatment in order to control pneumonitis. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work. 
 
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage 
the side effects of pembrolizumab treatment, may lower your body’s ability to fight off certain 
infections (i.e., opportunistic infections). These infections may require treatment with 
antibiotic or antifungal medications and may be fatal. 
 
7.1.2 Radiotherapy alone: 
 
Radiotherapy will be delivered by standard of care palliative radiotherapy. 
Radiotherapy will be administered in 3-5 treatments to 1-2 sites of disease. This will occur 
between the first and second dose of pembrolizumab. 
 
Side Effects Related to Radiotherapy: 
Side effects of radiation therapy are determined by the site irradiated, normal tissues in the 
field, and the total dose and number of treatments given. Your radiation oncologist will discuss 
this in detail with you and you will be asked to sign a separate consent form for the radiation 
therapy. In general, side effects from radiation therapy are described below. 
Likely: 
• Rash 
• Skin irritation 
 
Less Likely:  
 
• Feeling tired 
• Lowering of blood counts which may make infection and bleeding more likely 
• Nausea 
 
Rare, but serious: 

 
Protocol Amendment # 3 
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November 11, 2020 
 
• Development of a second cancer 
• Increase in pressure in an arm or leg from inflammation that requires surgical intervention 
 
7.2 
Adverse Event Reporting 
 
Adverse events will be graded according to CTCAE v5.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director or designee will assess each Adverse Event (AE) 
to determine whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation. All Serious Adverse Events (SAEs) will 
be tracked until resolution or until 60 days after the last dose of the study treatment. Immune 
related serious adverse events (irSAEs) definitely related to study treatment will be captured for 
6 months after the last dose of study treatment.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 
Laboratory Correlative Studies 
- 
Optional biopsies will be frozen and fixed as per SOC protocols in the pathology lab 
- 
Immune response assays   
o - blood collection, processing and assays will be performed as per the protocols in 
the Stanford Biobank and Human Immune Monitoring Center where the samples 
will be stored and assays performed, respectively. 
- 
Others will be sent to relevant reference laboratories 
 
 
 
9. 
STUDY CALENDAR 
 
 
 
Visits 
Pre 
Study 
Visit 
Treatment Visits 
End of 
Treatment 
Visit 
Follow Up 
Visit 
Post Study Follow 
Up 
Weeks/Months 
Wk 
0 
Wk 
1h 
Btw
Wk 
1-3 
Wk 
4 
Wk 
 7 
Wk 
10 
3 Wks 
after last 
dose of 
Pembroliz
umab 
Every 3, 
6M, or at yr 
5 from last 
dose of 
Pembrolizu
mab 
Upon progression 
or unacceptable 
symptomatology  
 
Investigational Agenta 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Radiation Therapyb 
 
 
X 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 

 
Protocol Amendment # 3 
30 
November 11, 2020 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
 
Concurrent medsc 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Vital signs 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
ECOG Performance status 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest Radiography 
X 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
 
X 
X 
X 
X 
X 
 
Tumor measurements 
X 
 
 
 
 
 
X 
X 
 
 
CBC w/diff 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Pregnancy Testd 
(Urine or Serum) 
X 
X 
 
X 
X 
X 
 
 
 
Hemoglobin 
X 
X 
 
 
X 
X 
X 
X 
X  
 
 
Hematocrit 
X 
X 
 
X 
X 
X 
X 
X 
 
Metabolic panel, comp 
X 
X 
 
X 
X 
X 
X 
X 
 
LDH total serum plasma 
X 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis Macro (Opt 
Micro) 
X 
 
 
 
 
 
 
 
 
TSH w/Reflex FT4e 
X 
 
 
 
 
 
X 
X 
 
 
Optional Immune Response 
and Polyomavirus Testsf 
X 
 
 
X 
X 
 
X 
X 
 
 
 
Optional Tumor Biopsyf 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Survival Follow Upg 
 
 
 
 
 
 
 
 
X 
a: Investigational Agent- pembrolizumab 200 kg infused SOC every 3 weeks 
b: Radiation Therapy- 1-2 sites of disease, delivered between the first and second cycles of pembrolizumab, 9 Gy X 3 (27 Gy in 
3 fractions), or 4-6 Gy X 5 (20-30 Gy in 5 fractions) 
c: Concurrent meds will be collected until the patient goes off study due to disease progression or change in therapy for Merkel 
cell carcinoma or for 2 years of continuing response 
d: Pregnancy test conducted and negative result confirmed before administration of pembrolizumab in women with the potential 
to become pregnant, pregnancy test is required ≤ 6 weeks before first dose of pembrolizumab and optional as clinically 
indicated for ongoing doses 
e: Assessed at week 13 for patients who continue pembrolizumab past week 10 
f: If funding is available, a variety of optional immune response assays will be performed that may include Luminex for 51 
cytokines testing in serum or plasma, ELISA for MHC class 1 polypeptide-related sequence A (MYCA) and MHC class 1 
polypeptide-related sequence B (MYCB) in serum or plasma, immunophenotyping including myeloid-derived suppressor cells 
(MDSC) and gamma/delta T cells, mass cytometry or CyTOF ICS with phorbol 12-myristate 13-acetate (PMA) + ionomycin 
stimulation (global immunocompetence assay).  These assays will be performed at baseline, 2 weeks (±1 weeks) and 8 weeks 
(±1 weeks) after radiation therapy. Possible tumor biopsies (optional) may be performed before, during/after treatment to 
assess response to therapy and changes in immune cell subsets. Optional tests to assess polyomavirus in the blood may be 
performed at baseline and 3 months ± 1 month.  
g: Applicable to all subjects who discontinued, regardless of enrollment date. During the Survival Follow-Up Phase, telephon 
contact will be made every 6 months (±2 weeks) for 5 years from the last dose of pembrolizumab. The site will inquire about 
overall subject survival status. Subjects that withdraw from the treatment phase of the study but do not return to the site for any 
further assessment will be contacted by the site to inquire about AEs and SAEs up to at least 60 days from the last dose of 
pembrolizumab. Definitely related immune related serious adverse events (irSAEs) will be captured for 6 months after the last 
dose of study treatment. 
h: Required before first dose of pembrolizumab 
1. 
If systemic steroids are required, subjects should be stable on the lowest clinically effective dose (≤ 20 mg/day) 

 
Protocol Amendment # 3 
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November 11, 2020 
2. 
 Must be at least 14 days since treatment for MCC, and recovered (baseline or residual non ir Grade 1 toxicity or ir 
Grade 2 toxicity at the investigator’s discretion, see section 4.1.1) from any clinically significant toxicity experienced 
during treatment before the first dose of on study pembrolizumab therapy. 
3. 
≤ 6 weeks demonstrate measurable disease according to RECIST v1.1, and have baseline (screening/baseline) 
radiographic images, (e.g. CT, PET CT or MRI brain, chest, abdomen, pelvis, to be determined by the attending 
physician) 
4. 
≤ 6 weeks pregnancy test for WOCBP 
5. 
≤ 1 week labs and liver function tests performed and results evaluated 
 

 
Protocol Amendment # 3 
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November 11, 2020 
10. 
MEASUREMENTS 
Title: Tumor response rates (CR, PR, SD, irCR, irPR, irSD) as accessed by RECIST 
v1.1/irRECIST at both irradiated and unirradiated sites 
Time Frame: Response will be accessed at the end of treatment visit and follow up visits 
Safety Issue: This outcome is not measuring a safety issue. Safety will be monitored using AE 
assessment during the trial using the CTCAE v5.0 criteria. 
 
10.1  Primary and Secondary Outcome measures 
The primary and secondary outcomes will be assessed by obtaining relevant tumor images at 
baseline line, end of treatment visit, and then at least every 3 months (±1 month) for two years 
and then every 6 months (±1 month) for  years 3-4, then again at year 5 (±1 month) from the last 
dose of pembrolizumab or until disease progression. Response and progression will be evaluated 
using the new international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1)11 as well as the Immune-related RECIST 
(irRECIST).12 Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. RECIST/irRECIST criteria will be used to score response of both the irradiated and 
unirradiated disease sites. 
 
10.1.1 Relevant Subset 
All patients are in a single arm. 
  
10.1.2 RECIST v1.1  
10.1.2.1 Disease Parameters 
Measurable disease: 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. 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented, or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease: All other lesions (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 

 
Protocol Amendment # 3 
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November 11, 2020 
measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. 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. 
 
Non-target lesions. All other lesions (or sites of disease) including any non-measureable 
as well as 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. 
 
10.1.2.2 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 6 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans), but NOT lung. 
 
FDG-PET: It is sometimes reasonable to incorporate the use of FDG-PET scanning 
to complement CT scanning in assessment of progression (particularly possible 

 
Protocol Amendment # 3 
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November 11, 2020 
'new' disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG- PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG- PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
 
 
10.1.2.3 Response Criteria 
Determination of response should take into consideration all target and non-target 
lesions.  
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 mm diameters while on 
study. 
 
Not Evaluable (NE): When at least one target lesion is not evaluated at a particular 
time point.  
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of excising non-target lesions. Unequivocal progression 
should normally trump target lesions status. It must be representative of overall 
disease status change, not a single lesion increase. 
 

 
Protocol Amendment # 3 
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November 11, 2020 
Not Evaluable (NE): When at least one non-target lesion is not evaluated at a 
particular time point. 
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances. 
 
 
 
10.1.2.4 Evaluation of Best Overall (unconfirmed) Response 
 
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest sum recorded since baseline). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria in some circumstances. 
 
10.1.2.5 Best Overall Confirmed Response 
 
Confirmation of CR and PR for determination of best overall response is required 
for studies with a primary endpoint that includes response. 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time 
point, even disease meeting PR criteria relative to baseline, makes the disease PD at 
that point (since disease must have reappeared after CR). However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR or SD, not CR at the first time point. Under 
these circumstances, the original CR should be changed to PR or SD and the best 
response is PR or SD. PR as best overall response requires ≥4 weeks confirmation. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment or die without objective evidence of disease progression at that time should 
be reported to be off study treatment due to “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of 
Time Point 
Response 
First time 
Time Point Response 
Subsequent time point 
≥4 weeks from first time point 
BEST overall confirmed response 
C
CR 
CR 
C
PR 
SD, PD or PR* 
C
R 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
C
R 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
C
R 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
P
CR 
PR 
P
PR 
PR 
P
SD 
SD 
P
R 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
P
R 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
N
NE 
NE 

 
Protocol Amendment # 3 
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November 11, 2020 
treatment. 
 
10.1.2.6 Duration of Response: 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
 
 
10.1.2.7 Recurrence: 
 
Recurrence is defined as newly evident disease for patients who have no evidence of 
disease at baseline or progressive disease for patients who have strictly non-measurable 
disease at baseline. 
 
10.1.2.8 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression or death, whichever occurs first. 
 
10.1.2.9 Survival 
 
Survival is defined as the duration of time from study entry to time of death or the date 
of last contact. 
 
10.1.3 irRECIST 
 
10.1.3.1 Baseline Assessments in irRECIST 
 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1 
 
10.1.3.2 Follow-up Assessments in irRECIST 
 
A. Follow-up recording of target and new measurable lesions 
 
A key difference in irRECIST is that the appearance new lesions does not automatically 
indicate progression. Instead, all measured lesions (baseline-selected target lesions and 
new measurable lesions) are combined into the total measured tumor burden (TMTB) at 
follow up. Baseline-selected target lesions and new measurable lesions are NOT assessed 
separately. Measurements of those lesions are combined into the TMTB, and one 
combined assessment provided. 
 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 

 
Protocol Amendment # 3 
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November 11, 2020 
per time point), new lesions must meet criteria as defined for baseline target lesion 
selection and meet the same minimum size requirements of 10 mm in long diameter and 
minimum 15 mm in short axis for new measurable lymph nodes. New measurable lesions 
should be prioritized according to size, and the largest lesions elected as new measured 
lesions. 
 
B. Follow-up non-target assessment 
 
RECIST 1.1 definitions for assessment of non-target lesions apply. The response of non-
target lesions primarily contributes to the overall response assessments of irCR and 
irNon-CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD assessments. 
Only a massive and unequivocal worsening of non-target lesions alone, even without 
progress in the TMTB is indicative of irPD. In alignment with RECIST 1.1, baseline 
selected non-target lesions can never convert to measurable lesions, not even if they 
increase in size at subsequent time points and become measurable. Only true new lesions 
can be measured and contribute to the TMTB. 
 
C. Follow-up for New Non-Measurable Lesions 
 
All new lesions not selected as new measurable lesions are considered new non-
measurable lesions and are followed qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions leads to an overall assessment of irPD for the 
time point. Persisting new non-measurable lesions prevent irCR. 
 
10.1.3.3 Overall Assessments for irRECIST 
The irRECIST overall tumor assessment is based on TMTB of measured target and new 
lesions, non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions 
per organ, up to total 5 lesions) is measured. At each subsequent tumor assessment (TA), 
the SumD of the target lesions and of new, measurable lesions (up to 2 new lesions per 
organ, total 5 new lesions) are added together to provide the total measurable tumor 
burden (TMTB). 
 
 
 
 
Overall Assessments by irRECIST 
Complete Response (irCR) 
Complete disappearance of all 
measurable and non-measurable lesions. 
Lymph nodes must decrease to < 10 mm 
in short axis. 
Partial Response (irPR) 
Decrease of ≥ 30% in TMTB relative to 
baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-
measurable lesions 
• If new measurable lesions appear in 
subjects with no target lesions at 
baseline, irPD will be assessed. That irPD 
time point will be considered a new 

 
Protocol Amendment # 3 
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November 11, 2020 
baseline, and all subsequent time points 
will be compared to it for response 
assessment. irPR is possible if the TMTB 
of new measurable lesions decreases by ≥ 
30% compared to the first irPD 
documentation 
• irRECIST can be used in the adjuvant 
setting, in subjects with no visible disease 
on CT/MRI scans. The appearance of 
new measurable lesion(s) automatically 
leads to an increase in TMTB by 100% 
and leads to irPD. These subjects can 
achieve a response if the TMTB 
decreases at follow-up, as a sign of 
delayed response. 
• Based on the above, sponsors may 
consider enrolling subjects with no 
measurable disease and/or no visible 
disease in studies with response related 
endpoints. 
Stable Disease (irSD) 
Failure to meet criteria for irCR or irPR 
in the absence of irPD 
Progressive Disease (irPD) 
Minimum 20% increase and minimum 5 
mm absolute increase in TMTB 
compared to nadir, or irPD for non-target 
or new non-measurable lesions. 
Confirmation of progression is 
recommended minimum 4 weeks after 
the first irPD assessment. An irPD 
confirmation scan may be recommended 
for subjects with a minimal TMTB %-
increase over 20% and especially during 
the flare time-window of the first 12 
weeks of treatment, depending on the 
compound efficacy expectations, to 
account for expected delayed response. 
• In irRECIST a substantial and 
unequivocal increase of non-target 
lesions is indicative of progression. 
• IrPD may be assigned for a subject with 
multiple new non-measurable lesions if 
they are considered to be a sign of 
unequivocal massive worsening 
Other 
irNE: used in exceptional cases where 
insufficient data exist. 
irND: in adjuvant setting when no disease 
is detected 
irNN: no target disease was identified at 
baseline, and at follow-up the subject 

 
Protocol Amendment # 3 
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November 11, 2020 
fails to meet criteria for irCR or irPD 
 
10.1.4 Measurement Time Points 
Tumor measurements will be taken and RECIST v1.1/irRECIST will be calculated from the 
scans (CT, PET CT or MRI brain, chest, abdomen, pelvis, to be determined by the attending 
physician) performed at baseline, end of treatment visit, and follow up visits. 
 
10.2  Exploratory Outcome 
10.2.1 Relevant Subset 
 
All patients are in a single arm. 
 
10.2.2 Measurement Definition 
 
If funding is available, the exploratory outcomes will be assessed. A variety of optional 
immune response assays will be performed that include Luminex for 51 cytokines testing in 
serum or plasma, ELISA for MHC class 1 polypeptide-related sequence A (MYCA) and 
MHC class 1 polypeptide-related sequence B (MYCB) in serum or plasma, 
immunophenotyping including myeloid-derived suppressor cells (MDSC) and gamma/delta 
T cells, mass cytometry or CyTOF ICS with phorbol 12-myristate 13-acetate (PMA) + 
ionomycin stimulation (global immunocompetence assay). Optional tumor biopsies may also 
be collected to assess response to therapy and changes in immune cell subsets. Optional 
assays to access mutational burden/MSI and to measure polyomavirus in the blood may be 
performed dependent upon funding. 
 
10.2.3 Measurement Methods 
At each blood collection, 3 or 4 of 10cc heparin (green-top) tubes for PBMC will be used for 
intracellular cytokine staining (ICS), immunophenotyping and CyTOF assays, and 1 of 5cc 
SST (red-top) tube for serum will be used for Luminex and MYCA/MYCB assays.  A 
minimum blood volume of 5ml per tube for the 10cc heparin tubes and 2.5ml per tube for the 
5cc SST tube are acceptable for assays. 
 
 
10.2.4 Measurement Time Points 
The optional immune response testing will be performed at baseline, 2 weeks (±1 weeks) and 
8 weeks (±1 weeks) after radiation therapy. Possible tumor biopsies (optional) may be 
performed before, during/after treatment to assess response to therapy and changes in 
immune cell subsets. Optional tests to assess polyomavirus in the blood may be performed at 
baseline and 3 months ± 1 month. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 

 
Protocol Amendment # 3 
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November 11, 2020 
to all participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of 
the following types of documents participating in the study: regulatory binders, case report 
forms, eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.   Case report forms 
will be developed using the OnCore database system and will be maintained by the CCTO 
OnCore team. CRFs will be kept in a locked office, only accessible to the research team.” 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
This is a single arm non-randomized open trial to determine the response rate for patients who 
are treated with both pembrolizumab and palliative radiation therapy.  
 
12.1.1 Randomization 
There is no randomization, as all patients are in a single arm. 
12.2 
Interim Analyses 
An interim analysis for futility will be performed after 15 patients have completed the 
treatment phase. A response rate of 20% is expected, so if one or fewer of 15 patients have 
demonstrated a PR or CR, the study will be stopped for futility.12.3 
Primary Analysis  
Primary Endpoint: The determination of the complete response rate and the 95%CI using 
Wilson’s method 
12.3.1 Analysis Population 
All Treated Subjects: All subjects who received at least 
one dose of pembrolizumab and completed the prescribed course of palliative radiation 
therapy. 
12.3.2 Analysis Plan 
Data will be summarized using appropriate descriptive statistics: proportions 
with Wilson’s 95% confidence intervals, means, standard deviations, ranges, and Kaplan-
Meier estimates for time to event data. The toxicity rates will be monitored continuously and 
a final count of toxicities will be performed. 

 
Protocol Amendment # 3 
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November 11, 2020 
12.4 
Secondary Analysis 
Secondary endpoints: Response rate, overall survival, and duration of response (please see section 
10.1). 
12.4.1 Analysis Population 
All Treated Subjects: All subjects who received at least 
one dose of pembrolizumab and completed the prescribed course of palliative radiation 
therapy. 
12.4.2  Analysis Plan 
Data will be summarized using appropriate descriptive statistics: proportions 
with Wilson’s 95% confidence intervals, means, standard deviations, ranges, and Kaplan-
Meier estimates for time to event data. The toxicity rates will be monitored continuously and 
a final count of toxicities will be performed. 
12.5  Sample Size 
A sample of 30 patients would provide 87% power to ensure a half-width of 15.5% of the 
95% confidence interval using Wilson’s method assuming that the observed rate is 20%.  
If the observed rate is exactly 20% then the 95%CI using Wilson’s method will be [9.5%, 
37.3%]. 
 
 
 
 

 
Protocol Amendment # 3 
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November 11, 2020 
 
13. 
REFERENCES 
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2. Amin MB, et. Al. (Eds.). (2017). AJCC Cancer Staging Manual, Eight Edition. Springer 
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3. Zaar O, Gillstedt M, Lindelöf B, Wennberg-LarköAM, Paoli J. J Eur Acad Dermatol 
Venereol. 2016;30(10):1708.  
4. MacDonald M, You J. Merkel Cell Polyomavirus: A New DNA Virus Associated with 
Human Cancer. Adv Exp Med Biol. 2017;1018:35-56. 
5. Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS, Finch JL, 
Hernandez BY, Fraumeni JF Jr, Madeleine MM, Engels EA. Risk of merkel cell 
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6. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, 
Lebbé C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke 
L, von Heydebreck A, Cuillerot JM, Nghiem P. Avelumab in patients with 
chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-
group, open-label, phase 2 trial. Lancet Oncol. 2016 Oct;17(10):1374-1385. doi: 
10.1016/S1470-2045(16)30364-3. Epub 2016 Sep 1. 
7. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry 
S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, 
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EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube 
JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA. Durable 
tumor regression and overall survival (OS) in patients with advanced Merkel cell 
carcinoma receiving pembrolizumab as first-line therapy. J. Clin Oncol 2018:36 
(suppl. Abstr 9506). 
8. Green MD, Hayman JA. Radiotherapy in the Multidisciplinary Management of Merkel 
Cell Carcinoma. J Natl Compr Canc Netw. 2018 Jun;16(6):776-781. doi: 
10.6004/jnccn.2018.7045. 
9. Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J 
Med. 2012 May 24;366(21):2035; author reply 2035-6. doi: 10.1056/NEJMc1203984. 
10. Barker CA, Postow M, Goldman DA, Panageas KS, Halpenny D, McCabe D, Macri M, 
Schwarzenburger P, Ricciardi R, Ryan A, Venhaus R, Knox SJ. A Phase I Clinical Trial 
of Ipilimumab, Nivolumab and Radiotherapy for Patients with Metastatic Melanoma. 
2018. ASTRO, San Antonio, TX. 
11. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Ca 2009;45: 228-247. 
12. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res. 2009;15(23):7412-20. 
 
 
 
 
 

 
 
Protocol Amendment # 2 
43 
September 10, 2019 
APPENDICES: 
APPENDIX 1:  ECOG PERFORMANCE STATUS 
 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
* Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982; 5:649-655. 
 
 
 

 
 
 
Protocol Amendment # 2 
44 
September 10, 2019 
APPENDIX 2:  PARTICIPANT ELIGIBILITY CHECKLIST 
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration. The completed, signed, and dated checklist must be retained in the patient’s study 
file.  
 
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records. A description of 
the eligibility verification process should be included in the EPIC or other Electronic Medical 
Record progress note.I. Protocol Information: 
 
  Protocol Title: 
A Phase II Study of Palliative Radiation Therapy and Anti-PD-1/PD-
L1 Checkpoint Blockade in Patients with Metastatic Merkel Cell 
Carcinoma, Amendment 2, September 10, 2019 
  Protocol Number: 
OnCore: SKIN0047        IRB: 50888 
  Principal Investigator: Susan J Knox, PhD, MD 
 
II. Subject Information: 
 
Subject ID/Initial: 
Gender:         Male           Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
  
IV. Inclusion/Exclusion Criteria 
 
 
Patient Selection 
Window 
Last 
Date to 
Register 
Supporting 
Documentat
ion 
Location 
of 
Document 
Yes No 
 
Signed and Dated 
Informed Consent Form 
NA 
 
Signed ICF 
date: 
 
 
    
 
 
3.
1.
1 
Histologically confirmed 
metastatic or locally 
advanced Merkel Cell 
Carcinoma (includes in-
transit or bilateral bulky 
disease) with at least two 
distinct sites of disease. 
 
NA 
 
 Bx Date: 
 
     
3.
1.
2 
Subjects with brain 
metastases and/or 
carcinomatous meningitis 
are eligible providing 
they are neurologically 
NA 
 
 
 
     

 
 
 
Protocol Amendment # 2 
45 
September 10, 2019 
stable (if systemic 
steroids are required, 
subjects should be stable 
on the lowest clinically 
effective dose, as steroids 
may interfere with the 
activity of 
immunotherapy if 
administered at the time 
of the first Anti-PD-
1/PD-L1 dose.) 
 
3.
1.
3 
Must be at least 14 days 
since treatment for MCC, 
and recovered (baseline 
or residual non ir Grade 1 
toxicity or ir Grade 2 
toxicity at the 
investigator’s discretion, 
see section 4.1.1) from 
any clinically significant 
toxicity experienced 
during treatment before 
the first dose of on study 
pembrolizumab therapy. 
 
NA 
 
 
 
     
3.
1.
4 
Eastern Cooperative 
Oncology Group 
(ECOG) performance 
status of 0 to 2 
28 days 
 
ECOG Date:  
     
3.
1.
5 
Life expectancy of ≥ 16 
weeks. 
NA 
 
 
 
     
3.
1.
6 
Subjects must have 
measurable disease 
according to RECIST 
v1.1, and have baseline 
(screening/baseline) 
radiographic images, 
(e.g. CT, PET CT or MRI 
brain, chest, abdomen, 
pelvis, to be determined 
by the attending 
physician) within 4 
weeks of confirmation of 
eligibility and within 6 
4 weeks 
 
Imaging 
Type: 
 
Imaging 
Date: 
 
    

 
 
 
Protocol Amendment # 2 
46 
September 10, 2019 
weeks before the 
initiation of on study 
pembrolizumab therapy. 
3.
1.
7 
Required values for 
initial laboratory tests: 
 -WBC: ≥ 2000/µL (~ 2 x 
109/L) 
-ANC: ≥ 1000/µL (~ 1 x 
109/L)  
-Platelets: ≥ 50 x 103/µL 
(~ 50 x 109/L) 
-Hemoglobin:  ≥ 8 g/dL 
-Calculated creatinine 
clearance (eGFR) 
greater than 30mL/min 
-AST/ALT: Less than 2.5 
x ULN for subjects 
without liver 
metastasis, less than 5 
times ULN for liver 
metastases 
-Bilirubin: less than 3.0 x 
ULN (except for 
subjects with Gilbert’s 
Syndrome, who must 
have a total bilirubin of 
less than 3.0 mg/dL) 
-Non-clinically 
significant laboratory 
abnormalities such as 
lipase elevation would 
not be an exclusion. 
4 weeks 
 
 
Lab Date: 
 
WBC: 
 
ANC:  
 
Platelets:  
 
Hemoglobin 
 
Creatinine 
clearance: 
 
AST: 
 
ALT: 
 
Bilirubin: 
 
 
 
    
 
 
3.
1.
8 
No known active or 
chronic infection with 
HIV, Hepatitis B, or 
Hepatitis C, or active 
infection requiring 
systemic antibiotics. 
Testing for the above is 
not required unless 
clinically suspected. 
 
 
NA 
 
 
 
 
    
 
 
3.
1.
9 
At least one measurable 
site of disease (≥ 10 mm 
as per RECIST v1.1 
except for lymph nodes 
4 weeks 
 
 
 
 
    
 
 

 
 
 
Protocol Amendment # 2 
47 
September 10, 2019 
that must be 15 mm or 
greater on the short axis) 
outside of the planned 
palliative radiation 
therapy field. 
3.
1.
1
0 
Require radiation therapy 
for palliation of 
symptoms or to prevent 
local progression of 
disease and associated 
complications and/or 
symptoms from 
metastases. 
4 weeks 
 
 
 
 
    
 
 
3.
1.
1
1 
Men and women, at least 
18 years of age. 
 
NA 
 
 
 
     
3.
1.
1
2 
Women of childbearing 
potential (WOCBP) must 
be using an adequate 
method of contraception 
to avoid pregnancy 
throughout the study [and 
for up to 26 weeks after 
the last dose of 
investigational product] 
in such a manner that the 
risk of pregnancy is 
minimized. 
 
WOCBP include any 
female who has 
experienced menarche 
and who has not 
undergone successful 
surgical sterilization 
(hysterectomy, bilateral 
tubal ligation, or bilateral 
oophorectomy) or is not 
postmenopausal. Post-
menopausal is defined as: 
 
•     Amenorrhea ≥ 12 
consecutive months 
without another 
cause, or 
6 week 
before 
therapy 
 
Preg. Test 
Date: 
 
     

 
 
 
Protocol Amendment # 2 
48 
September 10, 2019 
• 
For women with 
irregular menstrual 
periods and on 
hormone replacement 
therapy (HRT), a 
documented serum 
follicle stimulating 
hormone (FSH) level 
> 35 mIU/mL 
 
Women who are using 
oral contraceptives, other 
hormonal contraceptives 
(vaginal products, skin 
patches, or implanted or 
injectable products), or 
mechanical products such 
as an intrauterine device 
or barrier methods 
(diaphragm, condoms, 
spermicides) to prevent 
pregnancy, or are 
practicing abstinence or 
where their partner is 
sterile (e.g., vasectomy) 
should be considered to 
be of childbearing 
potential. WOCBP must 
have a negative serum or 
urine pregnancy test 
(minimum sensitivity 25 
IU/L or equivalent units 
of HCG) within 6 week 
prior to the start of 
investigational product. 
3.
1.
1
3 
Men of fathering 
potential must be using 
an adequate method of 
contraception to avoid 
conception throughout 
the study [and for up to 
26 weeks after the last 
dose of investigational 
product] in such a 
manner that the risk of 
pregnancy is minimized. 
NA 
 
 
 
 
    
 
 

 
 
 
Protocol Amendment # 2 
49 
September 10, 2019 
 
 
Conditions for Patient 
Ineligibility  
 
 
 
 
 
 
3.
2.
1 
WOCBP who are 
unwilling or unable to 
use an acceptable method 
to avoid pregnancy for 
the entire study and for 
up to 26 weeks after the 
last dose of 
investigational product. 
 
NA 
 
 
 
     
3.
2.
2 
Women who are 
breastfeeding. 
NA 
 
 
 
     
3.
2.
3 
WOCBP with a positive 
pregnancy test within 6 
weeks before enrollment. 
 
6 week 
before 
therapy 
 
Preg. Test 
Date: 
 
     
3.
2.
4 
Autoimmune disease: 
Poorly controlled 
autoimmune disease is 
excluded.  Well 
controlled autoimmune 
disease (e.g. well 
controlled RA) will be 
assessed by the study 
team and a decision made 
regarding eligibility 
based on the degree of 
immunosuppression and 
severity of symptoms. 
 
NA 
 
 
 
 
    
 
 
3.
2.
5 
Any subject who has a 
life-threatening condition 
that requires high-dose 
immunosuppressant(s).  
Steroid doses greater 
than 20 mg/day will 
exclude the patient from 
participation in the trial. 
 
NA 
 
 
 
 
    
 
 
3.
2.
6 
Presence of known 
hepatitis B or hepatitis C 
infection, regardless of 
control on antiviral 
NA 
 
 
 
 
    
 
 

 
 
 
Protocol Amendment # 2 
50 
September 10, 2019 
therapy. 
3.
2.
7 
Subjects who have 
another active, 
concurrent, malignant 
disease are not eligible, 
with the exception of 
subjects with adequately 
treated basal or 
squamous cell skin 
cancer, superficial 
bladder cancer, 
carcinoma in situ of the 
cervix, or other cancers 
that are in remission/not 
measurable. Patients will 
be excluded if they have 
any known additional 
malignancy that requires 
active treatment while on 
treatment for Merkel Cell 
Carcinoma. 
NA 
 
 
 
 
    
 
 
3.
2.
8 
Evidence of symptomatic 
interstitial lung disease or 
symptomatic active, 
noninfectious 
pneumonitis. 
NA 
 
 
 
     
3.
2.
9 
Participants with 
impaired cardiac function 
or clinically significant 
cardiac disease such as 
unstable 
angina/uncompensated 
heart failure, 
uncontrolled 
symptomatic arrhythmia. 
NA 
 
 
 
     
3.
2.
1
0 
Chronic or current active 
infectious disease 
requiring systemic 
antibiotics, antifungal, or 
antiviral treatment.  This 
exclusion does not 
include prophylactic 
antibiotics or topical 
antibiotics. 
 
 
 
 
 
    
 
 
3.
2.
Known hypersensitivity 
to another monoclonal 
NA 
 
 
 
     

 
 
 
Protocol Amendment # 2 
51 
September 10, 2019 
1
1 
antibody, which cannot 
be controlled with 
standard measures (e.g. 
antihistamines and 
corticosteroids). 
3.
2.
1
2 
Any condition that 
would, in the 
investigator’s judgment, 
interfere with full 
participation in the study. 
NA 
 
 
 
     
3.
2.
1
3 
Prisoners or subjects who 
are involuntarily 
incarcerated. 
 
NA 
 
 
 
     
3.
2.
1
4 
Subjects with acute or 
poorly controlled 
psychiatric illness or 
subjects who are 
compulsorily detained for 
physical (e.g., infectious 
disease) illness, with the 
exception of patients that 
are well supported and 
able to participate (e.g. 
paraplegia from a motor 
vehicle accident). 
NA 
 
 
 
     
3.
2.
1
5 
Any underlying medical 
or psychiatric condition 
that, in the opinion of the 
investigator, could make 
the administration of 
anti-PD-1/PD-L1 
hazardous or could 
obscure the interpretation 
of adverse events. 
NA 
 
 
 
 
    
 
 
3.
2.
1
6 
Any live vaccine therapy 
for up to 4 weeks before 
or after any dose of 
immunotherapy on this 
trial. 
NA 
 
 
 
     
 
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology 
test results, subject self-report, and medical record review. 
 
IV.  Statement of Eligibility 

 
 
 
Protocol Amendment # 2 
52 
September 10, 2019 
 
This subject is [      eligible /      ineligible] for participation in the study.  By signing this 
form, I verify the subject’s eligibility.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and contractual 
agreements as required by Stanford School of Medicine’s Research Management Group.   
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: