Clinical trial NCT02690948
Conditions: Skin Basal Cell Carcinoma
Sponsor: Anne Chang
Start date: 2016-02-01; Completion date: 2018-08-29
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase 1-2 trial studies how well pembrolizumab with or without vismodegib works in treating patients with skin basal cell cancer that has spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, are checkpoint inhibitors that stimulate immune response. Vismodegib may stop the growth of tumor cells by blocking signals needed for cell growth.

Detailed description:
This study is a non-randomized evaluation of pembrolizumab as a treatment for unresectable or metastatic basal cell carcinoma (BCC). Participants are assigned to treatment with pembrolizumab plus vismodegib or pembrolizumab monotherapy on the basis of suitability for treatment with smoothened (SMO) inhibitors such as vismodegib. Prospective participants who have progressed on vismodegib, are intolerant to or have a medical contra-indication to vismodegib may receive pembrolizumab monotherapy. Because treatment is non-randomized, no comparison between treatment groups is conducted.

PRIMARY OBJECTIVE To assess the overall response rate (ORR) of unresectable or metastatic BCC patients to pembrolizumab with or without vismodegib (all evaluable patients) at 18 weeks

SECONDARY OBJECTIVES

* To assess the ORR of unresectable or metastatic BCC patients to pembrolizumab monotherapy at 18 weeks
* To assess the ORR of unresectable or metastatic BCC patients to pembrolizumab monotherapy at 9 weeks
* To assess ORR of unresectable or metastatic BCC patients to pembrolizumab plus vismodegib at 18 weeks
* To assess ORR of unresectable or metastatic BCC patients to pembrolizumab plus vismodegib at 9 weeks
* To assess the safety and tolerability of pembrolizumab (either monotherapy or combination therapy) for unresectable or metastatic BCC.
* To assess the duration of response after pembrolizumab (either monotherapy or combination therapy)
* Incidence and severity of adverse events
* Correlative studies including programmed death-ligand 1 (PD-L1) expression pre-treatment, lymphocytic infiltrates pre- and post-treatment, mutational analysis pre- and post-treatment

Arms: arm 1: Participants who previously received vismodegib and subsequently progressed will receive pembrolizumab IV over 30 minutes on day 1. Cycles are every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. arm 2: Participants who have not progressed while receiving vismodegib will receive pembrolizumab IV over 30 minutes on day 1 and take vismodegib 150 mg by mouth daily. Cycles repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Vismodegib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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A Phase 1b Open-label Study of Pembrolizumab for Unresectable or  
Metastatic Basal Cell Carcinoma 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director  
Anne Lynn S Chang, MD 
Associate Professor of Dermatology 
Stanford University School of Medicine 
450 Broadway Street, MC5334 
Stanford, CA 94305 
alschang@stanford.edu 
 
 
Co-Investigators 
Alexander Dmitrios Colevas, MD 
Professor of Medicine-Oncology 
875 Blake Wilbur Drive 
Stanford, CA 94305 
colevas@stanford.edu 
Sunil Reddy, MD 
Clinical Assistant Professor  
Medical Oncology 
875 Blake Wilbur Drive 
Stanford, CA 94305 
sreddy@stanford.edu  
Biostatistician 
Shufeng Li, MS 
780 Welch Road, Dermatology 2nd floor 
Department of Dermatology 
Stanford University School of Medicine 
shufeng@stanford.edu 
Study Coordinator 
Geliya Kudryavtseva, MD 
geliyak@stanford.edu  
 
 
 
 
 
  NCT # NCT02690948 
 
  Date: April 29, 2018 


 
 
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PROTOCOL HISTORY 
Document History 
Notes 
Date: 15 September 2015 Initial protocol submitted to Stanford Scientific Review Committee (SRC), IRB, 
FDA, and Merck 
Date: 9 November 2015 
Revisions made including the following: 
 Title changed 
 Adjusted from Phase 2 to Phase 1b as a proof of concept study 
 Sample size increased from 12 to 13 subjects 
 Study calendar updated to include the capture of AEs for each visit 
 Serum chemistry added for each visit 
 Pregnancy test added to be collected at screening, End of Treatment, and as 
needed (PRN) 
Date: 12 December 2015 
Revisions made including: 
 Clarification provided regarding the two study arms per SRC 
 Clarification of number of enrolled subjects per arm 
 Definition of “clearly more effective” outlined on page 27 
Date: 15 January 2016 
SRC approval acquired pending some updates regarding outcomes.  Revisions 
include: 
 Clarification to the outcomes to be reported to ClinicalTrials.gov upon 
completion of the study.  All updated in the statistics and analysis section of the 
protocol 
Date: 3 May 2016 
Revisions include: 
 Exclusion Criteria 2 updated to now include exceptions for inhaled and topical 
steroids 
 Addition of Sunil Reddy, MD, as Co-Investigator 
 Removal of blood sampling from protocol procedures 
Date:  20 October 2016 
Revision includes: 
 Addition of Melissa Worman, MPH, CCRC, as primary study coordinator 
 Minor grammatical/typographical error corrections 
 Clarification that intraarticular, inhaled, and intralesional steroids are allowed 
both at screening and during treatment 
 Clarification that Cycle 4 biopsy can be done prior to cycle 4 based on 
investigator discretion as well as clinical judgement after evaluation of tumor 
regression pattern(s). 
 Addition of language regarding allowance of an LAR to provide consent 
Date:  19 January 2017 
Revision includes:  
 Removal of Melissa Worman, MPH, CCRC, as primary study coordinator 
 Clarification of investigational vs commercial/Access Program drug supply 


 
 
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Date: 9 Feb 2017 
Revision includes: 
 Addition of Richard Brotherton RN as study coordinator 
 Clarification that pulse dose systemic steroids are allowed to prophylax against 
contrast allergies prior to and after imaging in patients with prior known 
contrast allergies 
 Removal of the clause “only upon agreement from the Sponsor” for inclusion 
criterion 5 as this is an investigator-initiated study. 
 Removal of the clause “…but will not be included in the formal analysis”, since 
this study does not directly compare ARM 1 versus ARM 2  
 Removal of PT/PTT/INR from protocol after screening as this is not a necessary 
safety monitoring parameter in the package insert 
 Participants may be included for the purposes of overall survival analysis if 
documented by a progress note by the local oncologist or other physician at the 
time of study end 
 Clarification of commercial stock of pembrolizumab after 5 cycles 
 Clarification of “full physical examination” as shown in study calendar 
Date:  9 Mar 2017 
 Reverts pembrolizumab drug supply to investigational product only, as 
originally described by the protocol.  Removes references to pembrolizumab 
“commercial stock.”  
 Change for all study visits after screening to a targeted physical examination, 
when a physical examination is to be performed.  
 Revises eligibility for the overall survival analysis to include those subjects 
whose status is documented by progress notes by the local oncologist or other 
physician at the time of study end and/or up through 2 years from enrollment 
Date: 18 Oct 2017 
 Addition to allow reduction of imaging frequency by 50% if disease is stable for 
1 year or more during the study (in the Study Calendar) 
Date: 11 Jan 2018 
 Modification of protocol to allow for interim analysis 
 Updates study staff 
Date:  22 March 2018 
 
Clarifies that the primary endpoint is the overall response rate (ORR) of 
patients with locally-advanced or metastatic basal cell carcinoma (BCC) 
treated with either pembrolizumab monotherapy or in combination with 
vismodegib.  This clarification further delineates that these 2 groups will not 
be directly compared on the basis of the non-random allocation to treatment 
cohort.  
Date: 26 Apr 2018 
 Corrects verbiage on primary endpoint to be consistent with other locations in 
protocol (page 48) that all evaluable patients regardless of arm are included in 
the primary endpoint of ORR 
 Clarifies secondary endpoint is ORR for pembrolizumab monotherapy group 
 Clarifies additional secondary endpoint is ORR from pembro plus vismodegib 
group 
 Adds detail to the non-comparative prospective statistical design (page 51) 


 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 6 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ............................................. 8 
1. OBJECTIVES & HYPOTHESES ........................................................................................ 9 
1.1. 
PRIMARY OBJECTIVE & HYPOTHESES  ............................................................................... 9 
1.2. 
SECONDARY OBJECTIVES & HYPOTHESES  ........................................................................ 9 
2. BACKGROUND .................................................................................................................. 10 
2.1 
STUDY DISEASE ................................................................................................................ 10 
2.2 
STUDY AGENT .................................................................................................................. 11 
2.3 
RATIONALE ....................................................................................................................... 12 
2.4 
STUDY DESIGN ................................................................................................................. 14 
2.5 
CORRELATIVE STUDIES BACKGROUND ............................................................................. 14 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 15 
3.1 
INCLUSION CRITERIA ........................................................................................................ 15 
3.2 
EXCLUSION CRITERIA ....................................................................................................... 17 
3.3 
INFORMED CONSENT PROCESS .......................................................................................... 18 
3.4 
TREATMENT ASSIGNMENT PROCEDURES .......................................................................... 19 
3.5 
STUDY TIMELINE .............................................................................................................. 19 
4. TREATMENT PLAN .......................................................................................................... 21 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................. 22 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 27 
4.3 
ALTERNATIVES ................................................................................................................. 28 
5. STUDY AGENT INFORMATION .................................................................................... 28 
5.1 
STUDY AGENT PEMBROLIZUMAB  ..................................................................................... 28 
5.2 
AVAILABILITY .................................................................................................................. 29 
5.3 
AGENT ORDERING ............................................................................................................ 29 
5.4 
AGENT ACCOUNTABILITY ................................................................................................. 29 
6. DOSE MODIFICATIONS .................................................................................................. 29 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 31 
7.1 
POTENTIAL ADVERSE EVENTS .......................................................................................... 31 
7.2 
ADVERSE EVENT REPORTING............................................................................................ 33 
8. CORRELATIVE/SPECIAL STUDIES ............................................................................. 39 
8.1 
LABORATORY CORRELATIVE STUDIES .............................................................................. 39 
9. STUDY CALENDAR .......................................................................................................... 40 
10. MEASUREMENT.............................................................................................................. 41 
10.1  
ADVERSE EVENT (AE) MONITORING  ............................................................................... 41 
10.2  
PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 44 
10.3  
SECONDARY OUTCOME  ................................................................................................. 45 
11. REGULATORY CONSIDERATIONS ........................................................................... 45 


 
 
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11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 45 
11.2 
DATA AND SAFETY MONITORING PLAN .......................................................................... 45 
11.3 
DATA MANAGEMENT PLAN ............................................................................................ 45 
12. STATISTICAL CONSIDERATIONS ............................................................................. 46 
12.1 
STATISTICAL DESIGN ...................................................................................................... 46 
12.2 
INTERIM ANALYSES ......................................................................................................... 46 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 46 
12.4 
PRIMARY ANALYSIS ........................................................................................................ 46 
12.5 
SECONDARY ANALYSIS ................................................................................................... 46 
12.6  
SAMPLE SIZE .................................................................................................................. 50 
12.7 
CRITERIA FOR FUTURE STUDIES ...................................................................................... 50 
13. REFERENCES ................................................................................................................... 51 
APPENDICES ............................................................................................................................. 52 
APPENDIX A:  PARTICIPANT ELIGIBILITY CHECKLIST ................................................................. 52 
APPENDIX B:  ECOG PERFORMANCE STATUS ............................................................................ 58 
APPENDIX C:  COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE) ....... 58 
 


 
 
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PROTOCOL SYNOPSIS 
TITLE 
A phase 1b open-label  study of pembrolizumab for 
unresectable or metastatic basal cell carcinoma 
STUDY PHASE 
1b 
INDICATION 
Unresectable or metastatic basal cell carcinoma 
INVESTIGATIONAL PRODUCT  
Pembrolizumab 
PRIMARY OBJECTIVE(S) 
 Primary Objective 1: To assess the overall 
response rate (ORR) of unresectable or metastatic 
BCC patients to pembrolizumab of all evaluable 
patients  
SECONDARY OBJECTIVE(S) 
 Secondary Objective 1A:  To assess the ORR of 
unresectable or metastatic BCC patients to 
pembrolizumab monotherapy  
 Secondary Objective 1B: To assess the ORR of 
unresectable or metastatic BCC patients to 
pembrolizumab plus vismodegib 
 Secondary Objective 2:  To assess the safety and 
tolerability of pembrolizumab (either monotherapy 
or combination therapy) for unresectable or 
metastatic basal cell carcinoma 
 Secondary Objective 3:  To assess the duration of 
response after pembrolizumab (either 
monotherapy or combination therapy) 
 Exploratory Objective 1:  To assess the effect of 
pembrolizumab (either monotherapy or together 
with vismodegib) on the level of PDL1 and CD8 
density by immunostaining 
 Exploratory Objective 2:  To assess if 
pembrolizumab may improve overall survival 
(OS) or progression free survival (PFS) in 
unresectable or metastatic BCC patients (either as 
monotherapy or combination therapy) 
 Exploratory Objective 3:  To assess for biomarkers 
that may predict response to treatment. 
TREATMENT SUMMARY 
Arm 1:  Pembrolizumab 200 mg flat dose every 
3 weeks 
Arm 2:  Pembrolizumab 200 mg flat dose every 
3 weeks + vismodegib 150 mg daily by mouth 
SAMPLE SIZE  
total 26 participants, approx. 13 per arm 
STATISTICAL CONSIDERATIONS 
This is a proof-of-concept study, phase 1b.  Because 
advanced basal cells carcinoma is a rare disease, this 
is a non-comparative study.  The primary and 
secondary endpoints are descriptive and the arms will 
not be compared.  The data from this study will be 
used to power future multi-center studies.  


 
 
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SCHEMA 
 
 
Pembrolizumab  
200 mg IV  
every 3 weeks 
Stable,(par+al(or(
complete(response(by(
RECIST(1.1(
Intolerable(
toxicity(
Unresectable(or(
metasta+c(BCC(
Informed(consent(
Eligibility(Determina+on(
Progressive 
disease 
by RECIST 1.1 
End(of(Treatment(
Pembrolizumab  
200 mg IV  
every 3 weeks 
+ 
Vismodegib  
150 mg daily 
ARM 2: Partial response 
or stable Disease on 
vismodegib 
ARM 1: Progressive 
disease on vismodegib 
Primary	
outcome:	
ORR	of	aBCC	
pa ents	a er	
pembro	
monotherapy	
or	pembro
+vismodegib	
ARM 1: Pembrolizumab  
monotherapy 
ARM 2: Pembrolizumab/  
vismodegib combination  
therapy 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
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 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 
 


 
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1. 
OBJECTIVES & HYPOTHESES 
1.2. 
Primary Objective & Hypotheses  
Primary Objectives 
Primary Hypotheses 
1: To assess the overall response rate 
(ORR) of unresectable or metastatic BCC 
patients to pembrolizumab of all 
evaluable patients 
1: Pembrolizumab will lead to a response 
rate of 10% or greater in patients with 
advanced or metastatic basal cell 
carcinoma 
1.2. 
Secondary Objectives & Hypotheses 
Secondary Objectives 
Secondary Hypotheses 
1A and B: 
To compare the ORR of 
unresectable or metastatic BCC patients 
to pembrolizumab monotherapy  and 
pembrolizumab plus vismodegib.   
1: Pembrolizumab plus vismodegib will 
lead to a response rate of 11% or greater 
in patients with advanced or metastatic 
basal cell carcinoma for each group A)  
pembrolizumab monotherapy and 
B)pembrolizumab plus vismodegib 
1: To assess the safety and tolerability of 
pembrolizumab (either monotherapy or 
combination therapy) for unresectable or 
metastatic basal cell carcinoma.   
1: Pembrolizumab monotherapy or 
combination therapy is safe and 
well-tolerated in subjects with 
unresectable or metastatic basal cell 
carcinoma. 
2. To assess the duration of response after 
pembrolizumab (either monotherapy or 
combination therapy) 
2. Pembrolizumab monotherapy or 
combination therapy will provide a 
clinically-relevant duration of 
response (DOR)  
Exploratory Objectives 
Exploratory Hypotheses 
1. To assess the effect of pembrolizumab 
(either monotherapy or together with 
vismodegib) on the level of PDL1 and 
CD8 density by immunostaining. 
1. PDL1 levels and CD8 density will 
increase by immunostaining after 
pembrolizumab (either by monotherapy 
or together with vismodegib) 
(Topalian, et al, 2012) 
2. To assess if pembrolizumab may improve 
overall survival (OS in unresectable or 
metastatic BCC patients (either as 
monotherapy or combination therapy) 
2. Pembrolizumab plus vismodegib will 
improve OS in unresectable or metastatic 
BCC patients compared to 
pembrolizumab monotherapy. 
3. To assess if possible biomarkers 
associated with response to treatment 
3. There will be different changes in the 
RNA or DNA sequences detected in 
patient that respond to treatment 
compared to those that do not 


 
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2. 
BACKGROUND 
2.1 
Study Disease 
Basal cell carcinomas (BCCs) are the most common cancers in humans worldwide with an 
estimated 77% increase over the past two decades (Mohan and Chang, 2014).  Despite the 
staggering number of cases with over 2 million new cases per year in the United States, BCCs 
are understudied in large part because they are not included in the Surveillance, Epidemiology 
and End Results program database (Mohan and Chang, 2014).   
The first-line therapy for BCCs is excision, however the five-year recurrence rate for BCC is 3% 
(Jarkowski, et al, 2014; Mohan and Chang, 2014).  About 1% of BCCs are unresectable, with 
28,000 cases yearly of locally advanced or metastatic disease (Mohan and Chang, 2014). 
Effective therapy for unresectable BCC is a current unmet medical need.  For patients with 
unresectable BCC, the prognosis is poor, despite recent advances in targeted therapy 
(Sekulic, et al, 2012), with >50% of patients unresponsive to Smoothened inhibitor treatment 
and >20% recurrence within 1 year (Chang and Oro, 2012).  These patients are often referred to 
academic centers such as Stanford for care.   
Recent advances in cancer immunotherapy open a much-needed window of opportunity to gain 
traction for treating unresectable BCCs.  In particular, checkpoint blockade utilizing antibodies 
that impede immune inhibitory pathways, such as PD1/PD-L1, represent a novel strategy.  The 
important role of the immune system in suppressing BCCs can be inferred from 
immunosuppressed patients who develop high rates of these cancers.  One rapidly growing class 
of cancer immunotherapy drugs leveraging adaptive immunity is the immune checkpoint 
inhibitors targeting the PD1/PDL1 interaction between tumor and T cells.  New emerging lines 
of evidence suggest that this adaptive immunotherapy for BCCs is highly likely to be effective: 
(1) PDL1 (also known as B7H1) overexpression in keratinocytes, which are derived from basal 
cells, accelerates carcinogenesis in a mouse model of CSCC (Cao, et al, 2011) (2) monoclonal 
antibodies that block PDL1 can reverse the anergic state of tumor-specific T cells leading to 
enhanced antitumor immunity (Lyford-Pike, et al, 2013) and (4) data presented at European 
Society for Medical Oncology 2014 revealed that an anti-PDL1 antibody (MEDI4736) for head 
and neck SCC (HNSCC) led to a 20% overall response rate (ORR), with a 46% response rate in 
PDL1 positive tumors versus 11.4% in PD-L1 negative tumors, using a cut point of 1% staining 
of tumor cells or stroma (Fury, et al, 2014; Segal, et al, 2014).  Indeed, we have recently found 
that about 20-30% of advanced basal cell carcinomas stain positive for PDL1 (unpublished 
results), suggesting potential response of BCCs to PD1 inhibitors. 
Pembrolizumab has demonstrated efficacy in melanoma and small cell lung cancer (Garon, et al, 
2015), two cancers that are the result of environmental carcinogens, leading to a high mutational 
load.  Similarly, BCC has been shown to be among the most mutated of human cancers, 
suggesting favorable response of these cancers to immunotherapy with pembrolizumab 
(Jayaraman, et al, 2014).  This study is noncomparative, but there will be 2 arms, both using 
pembrolizumab.  Because current standard of care for advanced BCC is vismodegib, a 
Smoothened inhibitor, despite its response rate of < 50% (Sekulic, et al, 2012), one of the arms 
in this study will be patients on vismodegib plus pembrolizumab to assess if overall response can 
be improved with combination therapy.  In fact,  in the melanoma literature, emerging data 


 
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suggests that combination chemotherapy results in improved outcomes compared to each alone 
(Larkin, et al, 2015). 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on pembrolizumab (Keytruda, MK-3475). 
2.2 
Study Agent 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ;  PKCθ;  
and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted 
T-cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 


 
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Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
For clinicaltrials.gov compliance 
Pembrolizumab is FDA-approved for metastatic melanoma.  This study requires an 
Investigational New Drug application (IND).   
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
2.3 
Rationale 
 
Effective therapy for unresectable BCC is a current unmet medical need.  For patients with 
unresectable BCC, the prognosis is poor, despite recent advances in targeted therapy 
(Sekulic, et al, 2012), with >50% of patients unresponsive to Smoothened inhibitor treatment 
and >20% recurrence within 1 year (Chang and Oro, 2012).  These patients are often referred to 
academic centers such as Stanford for care.   
Recent advances in cancer immunotherapy open a much-needed window of opportunity to gain 
traction for treating unresectable NMSCs. 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475 (pembrolizumab).  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of MK-3475 showed evidence 
of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10 mg/kg Q2W, the highest 
dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this 
protocol to test for initial tumor activity.  Recent data from other clinical studies within the 
MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity.   
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (> 21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients.  Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight.  The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 to 5.0 for MK-3475 in the melanoma indication.  The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs.  the 


 
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proposed dose regimen of 2 mg/kg Q3W (ie, 5-fold higher dose and exposure).  The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure.  In 
addition, exposure was similar between the NSCLC and melanoma indications.  Therefore, there 
are no anticipated changes in exposure between different indication settings.   
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on:  1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.   
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 
3) will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
The primary endpoint will consist of evaluation of the Overall Response Rate (ORR) of all 
evaluable patients with unresectable or metastatic BCC including those in the pembrolizumab 
monotherapy group and pembrolizumab plus vismodegib combination therapy  group .   
Primary efficacy endpoints: 
1: Overall response rate (ORR) of unresectable or metastatic BCC patients to 
pembrolizumab including all evaluable patients regardless of whether in 
pembrolizumab monotherapy or pembrolizumab vismodegib group, assessed as the 
percentage of patients with partial or complete response after 18 weeks of treatment (as 
well as 9 weeks).   
Secondary endpoints): 
1: ORRs of evaluable unresectable or metastatic BCC patients to A) pembrolizumab 
monotherapy and B) pembrolizumab plus vismodegib combination therapy, separately 
but not compared, as the percentage of patients with partial or complete response after 
9 and 18 weeks of treatment  
2. Safety and tolerability of pembrolizumab (both monotherapy or combination therapy) 
for unresectable or metastatic basal cell carcinoma, assessed as the percentage of 
treated patients experiencing adverse events of any grade, or related adverse events 
Grade 3 or higher, in each of the two study arms.  
3. Duration of response after pembrolizumab as monotherapy and in combination with 
vismodegib, assessed as the median value after 9 and 18 weeks of treatment.  


 
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Exploratory endpoints: 
1. Level of PDL1 and CD8 density by immunostaining in each arm of the study and 
overall 
2. OS for each study arm and overall 
3. Sequence differences in DNA and RNA of tumors responding to treatment compared to 
those that do not respond 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
This is an exploratory open label, two-arm study of efficacy and safety of pembrolizumab in 
unresectable and/or metastatic basal cell carcinomas (BCCs.  One arm will comprise individuals 
with unresectable or metastatic BCC who are intolerant of Smo inhibitor due to side effects, 
cannot use Smo inhibitor for medical cause or decline to use smoothened inhibitor monotherapy 
such as vismodegib.  These patients will be treated with pembrolizumab until disease progression 
or intolerable toxicity.  The second arm will comprise individuals with unresectable or metastatic 
BCC who are willing and able to take vismodegib together with pembrolizumab; these 
individuals will be treated with pembrolizumab plus vismodegib until disease progression or 
intolerable toxicity.  Each arm will be analyzed separately. 
Primary Outcome:  “Overall Response Rate (ORR)” as the overall response rate (ORR) of all 
evaluable unresectable or metastatic BCC patients to pembrolizumab, assessed as the percentage 
of patients with partial or complete response after 9 and 18 weeks of treatment.  This represents 
3 and 6 cycles of treatment, with a cycle considered to be 3 weeks (21 days).  
Secondary Outcome 1:  “Overall Response Rate (ORR)” as the overall response rate (ORR) of 
unresectable or metastatic BCC patients to A) pembrolizumab monotherapy and B) 
pembrolizumab in combination with vismodegib, assessed as the percentage of patients with 
partial or complete response after 9 and 18 weeks of treatment.  
Secondary Outcome 2:  “Incidence of Adverse Events” as the percentage of treated patients by 
treatment cohort experiencing adverse events of any grade, or related adverse events Grade 3 or 
higher, in each of the two study arms 
Secondary Outcome 3:  “Duration of Response (DOR)” as the duration of response (DUR) to 
pembrolizumab as monotherapy or in combination with vismodegib, assessed as the median 
value (with 1st and 3rd quartiles) for subjects who complete 9 and 18 weeks of treatment.  
2.5 
Correlative Studies Background 
Biomarkers explored will include PDL-1 levels and be performed by QualTek (Santa Barbara, 
CA), using formalin fixed, paraffin embedded tissue and subjected to immunohistochemistry.   
Correlatives assessed include: 
 intratumoral lymphocytic infiltration pre and post treatment in each arm, including CD8+ cell 
density 
 PDL-1 immunostaining levels pre and post treatment for each arm 
 PDL-1 immunostaining levels and correlation with treatment response for each arm 


 
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Preliminary Results:  
For unresectable or metastatic BCC, there are currently no clinical trials of immune checkpoint 
inhibitors.  However, the likely response of BCCs to checkpoint inhibitors is derived from 
patients whose BCCs have been incidentally exposed to checkpoint inhibitors while getting 
treatment for metastatic melanoma.  We have a patient in our clinical practice with metastatic 
melanoma whose advanced BCC (bracket) shrank while on a checkpoint inhibitor, but his 
melanoma did not (data not shown).  Figure 1 shows histology of a BCC with an immune 
infiltrate staining for PDL1 (arrow), courtesy of J Taube).  We also have unpublished results 
demonstrating that advanced BCCs (n = 25) show 20 to 30% positivity for PDL1 
immunostaining.  Correlation of this marker with clinical outcomes is currently under 
investigation. 
1 
 
The results of our proposed study will be foundational and provide critical data to better 
understand the efficacy and safety of immunotherapies for unresectable or metastatic BCCs. 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Participants wishing to enter the study must be able and willing to sign written informed consent, 
in compliance with Stanford Human Subjects Panel and the Declaration of Helsinki principles.  
If a patient has a designated legally-authorized representative (LAR), the LAR can provide 
consent.  They must fulfill the inclusion and exclusion criteria as outline below. 


 
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3.1 
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial.  Consent may be 
obtained by LAR according to the protocol. 
2. Have a histologically-proven BCC in which curative resection is unlikely without significant 
morbidity, or have nodal or distantly metastatic disease which has progressed on smoothened 
inhibitor monotherapy (ARM 1) or has undergone partial response or stable disease on 
smoothened inhibitor monotherapy (ARM  2).  Individuals who are intolerant or have a 
medical contra-indication to smoothened inhibitor may be enrolled into ARM 1. 
3. Be  18 years of age on day of informed consent signing. 
4. Have measurable disease based on RECIST v1.1.   
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1.  Subjects for whom newly-obtained samples cannot be 
provided (eg, inaccessible or subject safety concern) may submit an archived specimen . 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1.   


 
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Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥ 1,500/mcL 
Platelets 
≥ 100,000/mcL 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine  
OR 
Measured or calculated a creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤ 1.5 x upper limit of normal (ULN)  
     OR 
≥ 60 mL/min for subject with creatinine levels > 1.5 x 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 x ULN  
     OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 x ULN  
     OR 
≤ 5 x ULN for subjects with liver metastases 
Albumin 
> 2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) OR 
Prothrombin Time (PT) 
≤ 1.5 x ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
Activated Partial Thromboplastin Time 
(aPTT) 
≤ 1.5 X ULN unless subject is receiving anticoagulant 
therapy, as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the 1st dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
9. Female subjects of childbearing potential should be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 120 days after the last dose of study medication (Section 5.7.2).  Subjects of 
childbearing potential are those who have not been surgically sterilized or have not been free 
from menses for > 1 year.   
10. Male subjects should agree to use an adequate method of contraception starting with the 
1st dose of study therapy through 120 days after the last dose of study therapy. 


 
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11. Female is not breastfeeding, is postmenopausal or surgically sterile; demonstrates 
non-pregnant state, and agrees to use 2 acceptable methods of birth control throughout the 
trial, until 120 days after the last dose of treatment 
12. Male with female partner of childbearing potential agrees to use adequate method of 
contraception throughout study, until 120 days after last dose of treatment or last blood draw. 
3.2 
Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the 1st dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the 1st dose of trial treatment.  
Exceptions include topical, intralesional intra-articular and inhaled steroids.  A pulse steroid 
dose prior to and after imaging to prevent contrast allergy in patients with known allergy to 
contrast is allowed. 
3. Has a known history of active TB  (Bacillus Tuberculosis) 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Study Day 1 
or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to Study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis 
unless they are stable without new neurological symptoms for 1 month.  Subjects with 
previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least 4 weeks prior to the 1st dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment.  
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (ie, 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic 
treatment.  Intraarticular, inhaled and intralesional doses of steroids are allowed at screening 
and during the study.  


 
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10. Has known history of, or any evidence of active, non-infectious pneumonitis that required 
steroids or current pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after 
the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1-2 antibodies). 
17. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
3.3 
Informed Consent Process 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.  
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.   
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 


 
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3.4 
Treatment Assignment Procedures: All subjects will receive study treatment.  There 
will be no randomization.  Patients will be assigned to Arm 2 pembrolizumab + vismodegib only 
if vismodegib is a suitable treatment, otherwise they will be assigned to Arm 1 pembrolizumab 
only.  
3.5 
Study Timeline 
Visit requirements are outlined in Section 6.0 Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 Trial Procedures. 
3.5.1 Screening Period 
The screening period will be within 28 days of Cycle 1, Day 1.  Potential participants who screen 
fail may be rescreened, if the medical circumstances have changed. 
3.5.2 Treatment Period 
The treatment period will consist of 21-day cycles until disease progression as determined by 
RECIST 1.1 or intolerable toxicity.  The treatment period is planned to be eight 21-day cycles, 
but treatment may be extended beyond 8 cycles if the patient has documented clinical response 
and treatment has been adequately tolerated.  Treatment period may be interrupted for up to 
21 days if there is a Grade 3 or 4 adverse event.  Restarting treatment may be allowed if patient 
has stable disease, partial response or complete response.  See also Section 3.5.7 Second Course 
Phase (Retreatment Period).  
3.5.3 Post-Treatment Visits 
There will be one post-treatment visit (end of treatment visit) will occur.  If the post treatment 
visit occurs 30 days after the last study agent administration, it can be done on the same day as 
the safety follow up visit (see below).  If the subject has an adverse event that is not resolved at 
the post-treatment visit, they will be asked to return for additional safety follow up visits until 
resolution of adverse events.  Additional safety follow ups beyond 3 months of the end of 
treatment will be considered standard of care. 
3.5.4 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with 
an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0 to 1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 
90 days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab (as 
described in Section 7.1.5.5) may have up to two safety follow-up visits, one after the Treatment 
Period and one after the Second Course Phase. 
3.5.5 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks 
(± 7 days).  Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject 


 
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begins retreatment with pembrolizumab as detailed in Section 7.1.5.5.  Information regarding 
post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria in 
Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 Trial Flow Chart for 
Retreatment.  
3.5.6 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone 12 weeks 
after end of treatment to assess for resolution of adverse events and survival status.  Participants 
who are followed by local oncologists or other physician may be included for the purposes of 
overall survival analysis if documented by a progress note at the time of study completion. 
3.5.7 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to 1 year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
 Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-determined 
confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy 
 Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 5.1.2 
 Female subject of childbearing potential should have a negative serum or urine pregnancy 
test within 72 hours prior to receiving retreatment with study medication.   
 Female subject of childbearing potential should be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 120 days after the last dose of study medication (Section 5.7.2).  Subjects of child 
bearing potential are those who have not been surgically sterilized or have been free from 
menses for > 1 year.   


 
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 Male subject should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.   
 Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of the 
trial or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 
last received pembrolizumab.  Treatment will be administered for up to one additional year. 
Visit requirements are outlined in Section 6.0 Trial Flow Chart. 
Primary Completion: 
The study will reach primary completion 24 months from the time the study opens to accrual. 
Study Completion: 
The study will reach study completion 36 months from the time the study opens to accrual. 
4. 
TREATMENT PLAN 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2.  Trial Treatment 
Arm 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen /  
Treatment Period 
Use 
1 
Pembrolizumab 
200 mg flat 
dose 
Q3 wks* 
IV infusion 
Day 1 of each 3-week cycle 
Experimental 
2 
Pembrolizumab 
plus 
vismodegib 
(latter to be 
supplied as 
standard of 
care (SOC) 
200 mg flat 
dose  
pembrolizumab  
Q3 wks* 
IV infusion 
Day 1 of each 3-week cycle 
Experimental 
150 mg 
vismodegib 
Daily 
Oral 
Every day starting with 
Cycle 1, Day 1 
Standard of Care 
 
Dose alterations for immune toxicities will be followed as per Merck guidelines. 
*until disease progression or intolerable toxicity.   
Dose selection is as described above.  In the case of an adverse event deemed related to the study 
drug that is Grade 3 or 4, study drug may be held for up to 6 weeks; if the subject had been 
deriving clinical benefit from the study agent, that is, stable, partial or complete response, the 
subject may be allowed to resume study drug after adverse event returns to Grade 1, with 
reduction in dosage by 50% or as recommended by the sponsor.   
The rationale for selection of doses to be used in this trial is provided in Section 4.0 Background 
and Rationale.   
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.   
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 


 
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administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (ie, infusion time is 30 minutes: -5 minute/+10 minute). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.   
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs. 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.   


 
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 Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
 Intraarticular, inhaled, topical, and intralesional steroid treatments are allowed.  A pulse 
steroid dose prior to and after imaging to prevent contrast allergy in patients with known 
allergy to contrast is allowed. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
There are no rescue medications for this study.  Supportive care is as outlined as follows.  
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below and in greater detail in the ECI guidance 
document.  Where appropriate, these guidelines include the use of oral or intravenous treatment 
with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to pembrolizumab.   
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document).  Refer to Section 5.2.1 for dose 
modification.   
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3 or 4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 


 
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 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.   
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3 or 4 hyperglycemia associated with metabolic acidosis or ketonuria.   
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.   
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids.  When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3 or 4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks.  Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment.  Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2 to 4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g.  propranolol) are suggested as 
initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3 or 4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 


 
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over no less than 4 weeks.  Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3 to 4 events, treat with intravenous corticosteroids for 24 to 48 hours.   
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3 to 4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.   
 Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
Table 3.  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(eg, antihistamines, 
NSAIDS, narcotics, 
IV fluids); prophylactic 
medications indicated for 
≤ 24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve 
and the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be 
premedicated 1.5 hr 
(± 30 minutes) prior to 
infusion of 
pembrolizumab 
(MK-3475) with: 
 Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
 Acetaminophen 
500 to 1000 mg po (or 
equivalent dose of 
antipyretic). 


 
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Table 3.  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but 
is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
 
Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth control 
or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 
1) surgically sterilized, or 2) postmenopausal (a woman who is ≥ 45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either 2 barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy.  Subjects should start 
using birth control from study Visit 1 throughout the study period up to 120 days after the last 
dose of study therapy.   
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progesterone agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 


 
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and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.  If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck.  
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.  
4.2 
Criteria for Removal from Study 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  A subject must be 
discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
 Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved. 
 Unacceptable adverse experiences  
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations 
of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose.  Subjects who stop 
pembrolizumab after 24 months may be eligible for up to 1 year of additional study treatment if 
they progress after stopping study treatment provided they meet the requirements  
 
Administrative reasons 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment).  
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression each 


 
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subject will be followed by telephone for overall survival until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.  Subjects who then 
experience radiographic disease progression may be eligible for up to 1 year of additional 
treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator 
if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.   
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
5. There are 2 or more responders in one arm  
     AND  
There are no responders in the other arm (after 10 patients have been enrolled in 
this latter arm). 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in 
Section 7.1.5.4). 
4.3 
Alternatives 
All study subjects will discuss their treatment alternatives with their primary care physician or 
medical oncologist prior to enrollment in the study as well as with the investigator of this study.   
5. 
STUDY AGENT INFORMATION 
5.1 
Study Agent Pembrolizumab  
Clinical Supplies, as investigational pembrolizumab, will be provided by Merck as summarized 
in Table 4. 


 
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Table 4.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
This trial is open-label;  therefore, the subject;  the trial site personnel;  and the Sponsor and/or 
designee are not blinded to treatment.  Drug identity (name, strength) is included in the 
label text;  random code/disclosure envelopes or lists are not provided.  
5.2 
Availability 
Investigational pembrolizumab will be provided by Merck. 
5.3 
Study Agent Ordering 
Investigational pembrolizumab will be requested from Merck by principal investigator and drug 
will be shipped to the Stanford Investigational Pharmacy, Attention:  Martha Hamilton, PharmD. 
5.4 
Study Agent Accountability 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical supplies must be stored in a secure, limited-access locations under the storage conditions 
specified on the label.   
Receipt and dispensing of investigational drug supply must be recorded by an authorized person 
at the trial site. 
The clinical trial drug supply assigned to this study may not be used for any purpose other than 
that stated in the protocol. 
The investigator is responsible for keeping accurate records of the investigational clinical 
supplies received from Merck or designee,  the amount dispensed to by the subjects;  and the 
amount remaining at the conclusion of the trial.   
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy.  It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
6. 
DOSE MODIFICATIONS 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment.  Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 4 below.   


 
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Table 5.  Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea / Colitis 
2 to 3 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose. 
3 to 4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3 to 4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3 to 4 
hyperglycemia associated with evidence of 
beta cell failure.   
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2 to 3 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2 to 4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3 to 4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3 to 4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3 to 4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-Related 
Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0 to 1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1  For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2  Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0 to 1 within 12 weeks of the last dose.   
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for interruption 
should be documented in the patient's study record. 
Dose reductions are not allowed in this study. 


 
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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Known or potential risks associated with pembrolizumab include immune mediated adverse 
reactions, including pneumonitis, diarrhea/colitis.  Reported adverse reactions in 20% or greater 
of patients included fatigue, cough, nausea, pruritus, rash, decreased appetite constipation, 
arthralgia and diarrhea.  Additional details of the adverse reactions are as follows: 
Immune-Mediated Pneumonitis 
Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 
8 (1.9%) and 1 (0.2%) patients, respectively, receiving pembrolizumab in Trial 1.  The median 
time to development of pneumonitis was 5 months (range 0.3 weeks to 9.9 months).  The median 
duration was 4.9 months (range 1 week to 14.4 months).  Five of eight patients with Grade 2 and 
the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic 
corticosteroids (greater than or equal to 40 mg Prednisone or equivalent per day) followed by a 
corticosteroid taper.  The median initial dose of high-dose corticosteroid treatment was 
63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 
1 to 34) followed by a corticosteroid taper.  Pneumonitis led to discontinuation of 
pembrolizumab in 3 (0.7%) patients.  Pneumonitis completely resolved in seven of the nine 
patients with Grade 2 to 3 pneumonitis. 
Monitor patients for signs and symptoms of pneumonitis.  Evaluate patients with suspected 
pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater 
pneumonitis.  Withhold pembrolizumab for moderate (Grade 2) pneumonitis, and permanently 
discontinue pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) pneumonitis 
[see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 
Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 
cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving pembrolizumab in Trial 1.  The 
median time to onset of colitis was 6.5 months (range 2.3 to .8).  The median duration was 
2.6 months (range 0.6 weeks to 3.6 months).  All three patients with Grade 2 or 3 colitis were 
treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent 
per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median 
duration of initial treatment was 7 days (range 4 to 41), followed by a corticosteroid taper.  
One patient (0.2%) required permanent discontinuation of pembrolizumab due to colitis.  All 
4 patients with colitis experienced complete resolution of the event. 
Monitor patients for signs and symptoms of colitis.  Administer corticosteroids for Grade 2 or 
greater colitis.  Withhold pembrolizumab for moderate (Grade 2) or severe (Grade 3) colitis, and 
permanently discontinue pembrolizumab for life-threatening (Grade 4) colitis [see Dosage and 
Administration (2.2) and Adverse Reactions (6.1)]. 
Immune-Mediated Hepatitis 
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a 
Grade 4 case in 1 (0.2%) patient, receiving pembrolizumab in Trial 1.  The time to onset was 
22 days for the case of Grade 4 hepatitis which lasted 1.1 months.  The patient with Grade 4 
hepatitis permanently discontinued pembrolizumab and was treated with high-dose (greater than 


 
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or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a 
corticosteroid taper.  Both patients with hepatitis experienced complete resolution of the event. 
Monitor patients for changes in liver function.  Administer corticosteroids for Grade 2 or greater 
hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue 
pembrolizumab. 
Immune-Mediated Hypophysitis 
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 
case (0.2% each), in patients receiving pembrolizumab in Trial 1.  The time to onset was 
1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 
hypophysitis.  Both patients were treated with high-dose (greater than or equal to 40 mg 
prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained 
on a physiologic replacement dose. 
Monitor for signs and symptoms of hypophysitis.  Administer corticosteroids for Grade 2 or 
greater hypophysitis.  Withhold pembrolizumab for moderate (Grade 2) hypophysitis, withhold 
or discontinue pembrolizumab for severe (Grade 3) hypophysitis, and permanently discontinue 
pembrolizumab for life- threatening (Grade 4) hypophysitis  
Renal Failure and Immune-Mediated Nephritis 
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune 
nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and 
one Grade 4.  The time to onset of autoimmune nephritis was 11.6 months after the first dose of 
pembrolizumab (5 months after the last dose) and lasted 3.2 months; this patient did not have a 
biopsy.  Acute interstitial nephritis was confirmed by renal biopsy in 2 patients with Grade 3 to 4 
renal failure.  All three patients fully recovered renal function with treatment with high-dose 
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a 
corticosteroid taper. 
Monitor patients for changes in renal function.  Administer corticosteroids for Grade 2 or greater 
nephritis.  Withhold pembrolizumab for moderate (Grade 2) nephritis, and permanently 
discontinue pembrolizumab for severe (Grade 3), or life-threatening (Grade 4) nephritis  
Immune-Mediated Hyperthyroidism and Hypothyroidism 
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) 
and 1 (0.2%) patients, respectively, receiving pembrolizumab in Trial 1.  The median time to 
onset was 1.5 months (range 0.5 to 2.1).  The median duration was 2.8 months (range 0.9 to 6.1).  
One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required 
initial treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or 
equivalent per day) followed by a corticosteroid taper.  One patient (0.2%) required permanent 
discontinuation of pembrolizumab due to hyperthyroidism.  All five patients with 
hyperthyroidism experienced complete resolution of the event. 
Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) 
patient, receiving pembrolizumab in Trial 1.  The median time to onset of hypothyroidism was 
3.5 months (range 0.7 weeks to 19 months).  All but two of the patients with hypothyroidism 
were treated with long-term thyroid hormone replacement therapy.  The other two patients only 


 
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required short-term thyroid hormone replacement therapy.  No patient received corticosteroids or 
discontinued pembrolizumab for management of hypothyroidism..   
Thyroid disorders can occur at any time during treatment.  Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold pembrolizumab for 
severe (Grade 3) hyperthyroidism, and permanently discontinue pembrolizumab for 
life-threatening (Grade 4) hyperthyroidism.  Isolated hypothyroidism may be managed with 
replacement therapy without treatment interruption and without corticosteroids.   
Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated adverse reactions can occur. 
The following clinically significant, immune-mediated adverse reactions occurred in less than 
1% of patients treated with pembrolizumab in Trial 1: exfoliative dermatitis, uveitis, arthritis, 
myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory 
foci in brain parenchyma, and adrenal insufficiency. 
Across clinical studies with pembrolizumab in approximately 2000 patients, the following 
additional clinically significant, immune-mediated adverse reactions were reported in less than 
1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. 
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm 
etiology or exclude other causes.  Based on the severity of the adverse reaction, withhold 
pembrolizumab and administer corticosteroids.  Upon improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month.  Restart pembrolizumab if the 
adverse reaction remains at Grade 1 or less.  Permanently discontinue pembrolizumab for any 
severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening 
immune-mediated adverse reaction  
Embryofetal Toxicity 
Based on its mechanism of action, pembrolizumab may cause fetal harm when administered to a 
pregnant woman.  Animal models link the PD-1/PDL-1 signaling pathway with maintenance of 
pregnancy through induction of maternal immune tolerance to fetal tissue.  If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient 
of the potential hazard to a fetus. 
Advise females of reproductive potential to use highly effective contraception during treatment 
with pembrolizumab and for 4 months after the last dose of KEYTRUDA  
7.2 
Adverse Event Reporting 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or 
protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (ie, any clinically significant adverse change in 


 
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frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as 
a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets.  The reporting timeframe for adverse events meeting any serious criteria is 
described in Section 7.2.3.1. 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥ 5-fold the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab.  Appropriate supportive treatment should be provided if clinically 
indicated.  In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety.  (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 


 
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cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety.  (Attn: Worldwide Product Safety; FAX 215 993-1220) 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.   
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.   
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15-Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators.  Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc.  
(Attn:  Worldwide Product Safety; FAX 215-993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
Non-serious and serious adverse events must be recorded as such on the Adverse Event case 
report forms/worksheets.  For this study, additional adverse events termed (events of clinical 


 
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interest) will include overdose of the study drug, elevation of liver enzymes greater than 
3X ULN, an elevated total bilirubin lab value that is greater than or equal to 2X ULN and, at the 
same time, an alkaline phosphatase lab value that is less than 2X ULN.   
Serious adverse events will be reported within 24 hours to the Sponsor and within 
2 working days to Merck Global Safety.  (Attn: Worldwide Product Safety; FAX 215-993-1220)  
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.  Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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


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


 
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8. 
CORRELATIVE/SPECIAL STUDIES  
Archival specimens will be used when tumor is not accessible for biopsy prior to enrollment.  
Otherwise, tumor biopsy will be performed prior to enrollment as well as at the end of treatment 
time point.   
8.1 
Laboratory Correlative Studies 
8.1.1 
Immunohistochemistry will be performed by Merck. 
8.1.1.1 Tissue will be collected by standard Keyes punch or shave biopsy technique as used in 
Dermatology clinic.  In cases where tumor tissue is not accessible on the skin, archival 
specimens which are formalin fixed paraffin embedded will be obtained for correlative 
studies. 
8.1.1.2 Specimens will be collected by the study coordinator or protocol director. 
8.1.1.3 Specimens will be shipped in padded envelopes in plastic containers. 
8.1.1.4  Merck will perform correlative studies except for the DNA and RNA studies.  DNA 
and RNA studies will be performed at Stanford and at the Stanford Human Immune 
Monitoring Core to identify sequence changes that might predict tumor response. 
8.1.1.5  Specimens will be coded by study name and number only prior to sending.  The code 
will be kept in a locked cabinet accessible by research staff only at Stanford.  


 
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9. 
STUDY CALENDAR 
Trial Period: 
Screening 
Phase 
Treatment Cycles (if Arm 2, vismodegib or other FDA approved smoothened 
inhibitor will be given concurrently) (One cycle is defined as 21 days) 
End of Treatment 
Post-Treatment 
Treatment Cycle / Title 
Screening 
(Visit 1) 
1 
2  
3 
4 
5 
6 
7 
8 plus 
At time of 
Discontinuation 
Follow-up 30 days 
post-discontinuation 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Administrative Procedures 
Informed Consent 
X * 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
Survival Status ** 
 
 
 
 
 
 
 
 
 
 
X (and 90-day call) 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (full or targeted) *** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG if 
female of childbearing potential 
X 
X 
 
 
 
 
 
 
 
X 
PRN 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Measurements 
Tumor Imaging (within 28 days of 
Cycle 1, Day 1) 
X 
 
 
 
X (C4D1) 
 
 
X (C7 D1) 
See 
below 
If not performed within  
3 months of EOT visit 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue Collection 
X 
 
 
 
X, if accessible to biopsy 
 
 
 
 
X, if accessible to biopsy 
 


 
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Trial Period: 
Screening 
Phase 
Treatment Cycles (if Arm 2, vismodegib or other FDA approved smoothened 
inhibitor will be given concurrently) (One cycle is defined as 21 days) 
End of Treatment 
Post-Treatment 
Treatment Cycle / Title 
Screening 
(Visit 1) 
1 
2  
3 
4 
5 
6 
7 
8 plus 
At time of 
Discontinuation 
Follow-up 30 days 
post-discontinuation 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Correlative Studies Blood Collection 
X 
 
 
 
X 
 
 
 
 
X 
 
Note that post-treatment visits may occur every 30 days up until 90 days total as needed to follow resolution of adverse event.   
Tumor biopsies to be collected at Cycle 4 and End of Treatment are based on investigator discretion and clinical judgement, timing is flexible based on tumor regression pattern(s). 
Tumor imaging to be performed at Screening;  Cycle 4;  Cycle 7;  and then every 3 cycles after as necessary for the duration of study treatment; at the discretion of the investigator, imaging frequency can 
by reduced by 50% if patient has stable disease for greater than 1 year 
*   Within 28 days of enrollment not required 
** Survival status clarification:  Participants who are followed by local oncologists and continue to receive pembrolizumab and/or vismodegib may be included for the purposes of overall survival 
analysis if documented by a progress note by the local oncologist or other physician, followed for a maximum of two years after enrollment 
***  Full physical examination at screening constitutes of examination according to physician clinical judgement of at least 12 assessments including but not limited to:  1) general appearance;  
2) conjunctiva;  3) eyelids;  4) ears;  5) scalp;  6) nose;  7) lips;  8) neck;  9) back;  10) chest;  11) abdomen;  12) arms;  13) legs;  14) genital area;  15) lymph nodes of the head and neck;  
16) axillary lymph nodes;  17) inguinal lymph nodes;  18) epitrochlear lymph nodes;  19) popliteal lymph nodes;  20) nails;  21) lung auscultation;  22) heart auscultation;  23) dorsalis pedis pulses;  
24) radial pulses;  25) patient’s mood;  26) affect;  27) orientation to person/place/ time;  28) thyroid palpation and inspection.  Targeted physical examination may be conducted after screening.  


 
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10. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
10.1  Adverse Event (AE) Monitoring  
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE version 4.0 (see Section 11.2).  Toxicities will be characterized in terms 
regarding seriousness;  causality;  toxicity grading;  and action taken with regard to trial treatment.   
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs).   
Please refer to Section 7.2 for detailed information regarding the assessment and recording of AEs.   
10.1.2  Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full physical 
exam should be performed during screening,  
10.1.3  Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration. 
10.1.4  Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
10.1.5  Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in 
the Trial Flow Chart.   
10.1.6 Tumor Imaging and Assessment of Disease 
All participants will be imaged by CT or MRI scanning according to the study calendar.  In cases where 
the disease is superficial and the investigator deems clinical examination is adequate to follow the 
NMSC, no imaging will be performed. 
10.1.7 Tumor Tissue Collection  
Archival specimens will be used when tumor is not accessible for biopsy prior to enrollment.  
Otherwise, tumor biopsy will be performed prior to enrollment, while on treatment (at Cycle 4), as well 
as at the end of treatment time point. However, based on investigator discretion and clinical judgement, 
the required biopsy time point at Cycle 4 can be completed prior to Cycle 4 depending upon tumor 
regression pattern(s) during the first few treatments.   


 
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10.1.8 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   


 
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Table 7.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to the first dose of 
treatment if they are not to be repeated at Cycle 1 Day 1.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 
72 hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of trial treatment


 
 
 
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10.1.9 
Pharmacokinetic/Pharmacodynamic Evaluations 
10.1.9.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
There is no PK sampling in this study. 
10.1.9.2   Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in the 
Laboratory Manual. 
10.2  Primary and Secondary Outcome measures 
RECIST version 1.1* will be used in this study for assessment of tumor response.  While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.  Where the target tumor is visible to clinical inspection, high quality color photographs 
will be taken with a ruler in the plane of tumor, and the longest diameter will be assessed and 
recorded as the measurement. 
* As published in the European Journal of Cancer:  EA Eisenhauer, P Therasse, J Bogaerts, 
et al.  “New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1).”  Eur J Cancer.  Jan 2009;45(2):228-247. 
10.2.1 Relevant Subset 
Only participants who return after Cycle 1, Day 1 will be analyzed.  We anticipate 24 study 
subjects will be analyzable. 
10.2.2 Measurement Definition 
Give a detailed definition of the quantity or categorization to be measured.  For example: 
 Overall response rate will be calculated by dividing the number of subjects with partial or 
complete response by RECIST v1.1 divided by the total number of analyzable subjects.   
10.2.3 Measurement Methods 
Response will be measured by RECIST v1.1.  If tumor is visible on clinical inspection, then the 
tumor will be measured with calipers in centimeters.  If the tumor is not visible on clinical 
inspection then either CT scan or MRI will be used, and the longest diameters will be ascertained 
for the target lesion(s) per RECIST v1.1. 
10.2.4 Measurement Time Points 
Efficacy outcome assessments will be at after 9 and 18 weeks of treatment.  This represents 
3 and 6 cycles of treatment, with a cycle considered to be 3 weeks (21 days).   
Safety assessments will be continuous with follow-up for 30 days after last dose or until 
discontinuation or adverse event.  


 
 
 
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10.2.5 Response Review 
Simultaneous review of the patients’ files and radiological images will be performed.  However, 
we do not have resources for independent review of our data besides the Stanford Data Safety 
Monitoring Committee. 
10.3 
Secondary Outcome 
Adverse event number and grade will be recorded for both arms of the study and reported.   
Biomarker levels will be recorded using both qualitative and quantitative measures. 
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 (eg, 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 
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 
Case Report Forms (CRFs) are printed or electronic documents designed to record all 
protocol-related information on each trial participant.  CRFs should summarize the clinical 
findings and observations necessary to ensure safety of participants on the study, and to 
document the study outcomes.  CRFs are required by the SRC for all Interventional studies.  
CRF design and creation must be completed prior to enrollment of the first participant.  Describe 
your plan for developing CRFs, stating what medium will be used, (eg.  OnCore, REDCap, paper 
documents) and where the CRFs will be stored.  For electronic data capture using OnCore, 
contact the OnCore Team at CCTO-OnCore@stanford.edu; for REDCap, contact 
redcap-help@lists.stanford.edu. 
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 database system and will be maintained by the study coordinator.  
CRFs will be kept in a locked office, only accessible to the research team. 


 
 
 
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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
Open-label;  non-comparative; 2-arm study of efficacy and safety of pembrolizumab in 
unresectable and/or metastatic basal cell carcinomas. 
12.1.1 Randomization 
All subjects will receive the treatment.  There will be no randomization.  
 12.2 Interim analyses 
The study will terminate if all of the first 10 patients who enroll show progressive disease at the 
end of Cycle 3.   
Interim analysis will be performed after 13 patients are enrolled. 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
Descriptive statistics will be used to summarize the participants in each arm, including mean and 
median age, sex, prior treatments, duration on study drug, and location of tumor. 
12.4 
Primary Analysis  
 Primary endpoint 1: To assess the overall response rate (ORR) of unresectable or metastatic 
BCC patients to pembrolizumab, (percentage of all evaluable patients with partial or 
complete response after 9 and 18 weeks of treatment including pembrolizumab and 
pembrolizumab plus vismodegib groups) 
12.4.1 Analysis Population 
Only individuals who enroll and return for one additional study visit will be analyzed.  
Non-adherence will be noted in the patient charts, and those who are non-adherent due to toxicity 
will be recorded and noted as such.  They will be included in the analysis population with the 
new baseline being time of study drug restart if more than 1 month has elapsed since study drug 
pause. 
12.4.2. Analysis Plan 
Overall response rate of the 2 arms will be calculated. 
12.5 
Secondary Analysis 
 Secondary endpoint 1:  To assess the ORRs of unresectable or metastatic BCC patients to A) 
pembrolizumab monotherapy (separately and not directly compared statistically), and B) 
pembrolizumab and vismodegib, as percentage of patients with partial or complete response 
after 9 and 18 weeks of treatment).   
 Secondary endpoint 2:  To assess the safety and tolerability of pembrolizumab (both 
monotherapy or combination therapy) for unresectable or metastatic basal cell carcinoma, 
assessed as the percentage of treated patients experiencing any adverse events, or related 
adverse events Grade 3 or higher, in each of the two study arms  


 
 
 
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 Secondary endpoint 3:  To assess the duration of response after pembrolizumab as 
monotherapy and in combination with vismodegib, assessed as the median value after 9 and 
18 weeks of treatment.   
 Exploratory endpoint 1:  To assess the effect of pembrolizumab (both monotherapy and 
together with vismodegib) on the level of PDL1 and CD8 density by immunostaining 
 Exploratory endpoint 2:  To assess if pembrolizumab may improve overall survival (OS) in 
unresectable or metastatic BCC patients (both as monotherapy and combination therapy) 
12.5.1 Analysis Population 
Only individuals who enroll, take at least one dose of study drug and return for one additional 
study visit will be analyzed.  Non-adherence will be noted in the patient charts, and those who 
are non-adherent due to toxicity will be recorded and noted as such.  They will be included in the 
analysis population with the new baseline being time of study drug restart if more than 1 month 
has elapsed since study drug pause. 
12.5.2.  Analysis Plan 
Endpoints will be tallied for the events or biomarkers of interest and compared between the arms.   
Specifically, outcomes to be reported to ClinicalTrials.gov upon completion of this study 
include 
1 Primary:  ORR on pembrolizumab monotherapy 
Measure title:  Overall Response to pembrolizumab for all evaluable patients on the study, 
regardless of monotherapy or with vismodegib 
Measure description:  Percentage of patients with partial or complete response after 
pembrolizumab  
Time frame 6 cycles (18 weeks), also 3 cycles (9 weeks) 
Safety issue:  No 
Measure summary:  Overall Response Rate to be calculated as the ratio of patients with CR or 
PR as a percentage of patients evaluable for OR  
Population:  all patients who enroll and take at least one dose of study agent and have at least one 
follow up evaluation timepoint  
2 Secondary:  ORR on pembrolizumab plus vismodegib combination therapy 
Measure title:  Overall Response on A) pembrolizumab monotherapy and B) pembrolizumab 
plus vismodegib therapy in noncomparative fashion 
Measure description:  Percentage of patients with partial or complete response after 
pembrolizumab plus vismodegib combination therapy or pembrolizumba monotherapy but not 
directly compared 
Time frame:  after 3 and 6 cycles 
Safety issue:  No 


 
 
 
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Measure summary:  Overall Response Rate to be calculated as the ratio of patients with CR or 
PR as a percentage of patients evaluable for OR for pembrolizumab and vismodegib or 
pembrolizumab monotherapy as separate groups 
Population:  all patients who enroll and take at least one dose of study agents, and have at least 
one follow up evaluation timepoint 
3 Secondary:  safety and tolerability  
Measure title:  safety and tolerability  
Measure description:  Percentage of patients experiencing with adverse events any adverse 
events, or related adverse events Grade 3 or higher, in each of the two study arms (including type 
and grade)  
Time frame:  after 3 and 6 cycles 
Safety issue:  Yes 
Measure summary:  Percentage of treated patients with adverse events of any grade, and 
percentage of patients with related adverse events Grade 3 or higher after pembrolizumab 
monotherapy or pembrolizumab in combination with vismodegib  
Population:  patients who enroll, take at least one dose of study agent and have at least one 
follow-up evaluation 
4 Secondary:  duration of response 
Measure title:  median duration of response  
Measure description:  time from first partial or complete response to disease progression by 
RECIST v1.1 
Time frame:  2 years 
Safety issue:  No 
Measure summary:  Median duration of response (DOR) in months, with 1st and 3rd quartiles, by 
cohort, ie, for all evaluable patients, as well as divided into pembrolizumab monotherapy or 
pembrolizumab in combination with vismodegib  
Population: patients who enroll, take at least one dose of study agent and have at least one follow 
up evaluation 
5A Secondary:  biomarkers before and after treatment 
Measure title:  level of PDL1 and CD8 by immunostaining on pembrolizumab either 
monotherapy or together with vismodegib 
Measure description: percentage of PDL1 positive tumor cells, and percentage of CD8 positive 
tumor and immune infiltrate 
Time frame:  after cycle 3 
Safety issue:  No 
Measure summary:  percentage of total tumor cells, percentage of total tumor immune infiltrate 


 
 
 
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Population:  patients who enroll, take at least one dose of study agent and have at least one 
follow up evaluation 
5B Secondary:  biomarkers before and after treatment for all evaluable patients 
Measure title:  level of PDL1 and CD8 by immunostaining for all evaluable patients 
Measure description:  percentage of PDL1 positive tumor cells, and percentage of CD8 positive 
tumor and immune infiltrate 
Time frame: after cycle 3 
Safety issue:  No 
Measure summary:  percentage of total tumor cells, percentage of total tumor immune infiltrate 
Population:  patients who enroll, take at least one dose of study agents and have at least one 
follow up evaluation 
6A Secondary:  overall survival 
Measure title:  overall survival of all evaluable patients  
Measure description:  number of months from study enrollment to last study visit  
Time frame:  2 years 
Safety issue:  No 
Measure summary:  OS will be reported in months and Kaplan-Meier median will be reported 
Population:  patients who enroll, take at least one dose of study agent and have at least one 
follow up evaluation  
6B Secondary:  overall survival 
Measure title:  overall survival of all evaluable patients  
Measure description:  number of months from study enrollment to last study visit  
Time frame:  2 years 
Safety issue:  No 
Measure summary:  OS will be reported in months and Kaplan-Meier median will be reported 
Population:  patients who enroll, take at least one dose of study agents and have at least one 
follow up evaluation  
12.6  Sample Size 
As this is an exploratory non-comparative study, statistics between the two groups was 
not performed. However, for practical purposes, prospective statistical design was based on a 
minimum ORR of 10% for all evaluable patients, defined as the minimum clinically meaningful 
rate given potential risks of pembrolizumab exposure. Based on an estimated ORR of 30%, with 
two-sided alpha=0.05 (p<0.05) and power=0.84, the pre-determined sample size was 26 
evaluable patients, with pembrolizumab monotherapy group and pembrolizumab plus 
vismodegib group included within this number.  


 
 
 
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We plan to enroll 13 subjects per arm for a total of 26 participants.  However, the study 
enrollment will discontinue if the primary endpoint is met at interim analysis.  
12.6.1 Accrual estimates  
Estimates are based on prior studies.  We anticipate 13 patients per year will enroll.  If accrual 
falls short, we will reach out to community physicians for referrals through word of mouth or 
paper advertisements. 
12.6.2 Sample size justification 
Consultation with Alex McMillan, PhD and Shufeng Li, MS, both biostatisticians led to the 
following:  
This is a proof-of-concept study, phase 1b.  Because advanced basal cells carcinoma is a rare 
disease, this is a non-comparative study.  The primary and secondary endpoints are descriptive 
and the arms will not be compared.  The data from this study will be used to power future multi-
center studies.  
12.6.3 Effect size justification 
This study is exploratory and does not include effect size analysis. 
12.7 
Criteria for future studies 
Success will be defined as 20% response rate for pembrolizumab monotherapy arm.  Currently, 
for patients with advanced BCC refractory or resistant to Smoothened monotherapy, there is no 
good treatment and all patients experience disease progression. 


 
 
 
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13. 
REFERENCES 
Brahmer J, et al.  (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer.  NEJM 366(26): 2443-54. 
Chang ALS, Oro AE (2012) Initial assessment of tumor regrowth after vismodegib in advanced 
basal cell carcinoma.  Arch Derm 148(11): 1324-5. 
Fury M, Ou SI, Balmanoukian A, et al.  Clinical activity and safety of MEDI4736, an anti-PD-
L1 antibody in patients with head and neck cancer.  Annals of Oncol, 25:S4, abstract 988PD. 
Garon EB, et al.  (2015) Pembrolizumab for the treatment of non-small cell lung cancer.  NEJM 
372:2018-2028, DOI: 10.1056/NEJMoa1501824 
Hamid O, et al.  (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma.  NEJM 369(2): 134-144. 
Jayaraman R, et al.  (2014) Mutational landscape of basal cell carcinoma by whole-exome 
sequencing.  J of Invest Dermatol 134(1): 213-20.  doi: 10.1038/jid.2013.276.   
Karia P, et al.  (2012) Cutaneous squamous cell carcinoma: Estimated incidence of disease, 
nodal metastasis, and deaths from disease in the US.  J Am Acad Derm 68(6):957-966. 
Kefford R, et al.  (2014) Clinical efficacy and correlation with tumor PD-L1 expression in 
patients with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475.  
ASCO abstr 3005. 
Larkin J, et al.  (2015) Combined nivolumab and ipilimumab or monotherapy in untreated 
melanoma.  NEJM 373: 23-34. 
Lyford-Pike S, et al.  (2013) Evidence for a role of the PD-1: PD-L1 pathway in immune 
resistance for HPV-associated head and neck squamous cell carcinoma.  Cancer Res; 73: 
1733-41. 
Malaspina T, et al.  (2011) Enhanced programmed death 1 (PD-1) and PD-1 ligand (PD-L1) 
expression in patients with actinic cheilitis and oral squamous cell carcinoma.  Cancer 
Immunol Immunother 60(7): 965-74. 
Mohan SV and Chang ALS (2014) Advanced basal cell carcinoma: epidemiology and 
therapeutic innovations.  Curr Derm Rep 3:40-5. 
Segal N, et al.  (2014) Preliminary data from a multi-arm expansion study of MEDI4736, an 
anti-PD-L1 antibody.  J Clin Oncol 32:5s, abstr 3002. 
Sekulic A, Migden M, Oro AE, et al.  Efficacy and safety of vismodegib in advanced basal cell 
carcinoma.  New Eng J Med.  2012; 366: 2171-9. 
Topalian SL, Hodi FS, Brahmer JR, et al.  (2012) Safety, activity, and immune correlates of 
anti–PD-1 antibody in cancer.  NEJM 366: 2443-2454. 
Wolfle SJ, et al.  (2011) PD-L1 expression for tolerogenic APCs is controlled by STAT-3.  Eur J 
Immunol 41(2): 413-24.   


 
 
 
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APPENDICES 
APPENDIX A: 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 and the study’s Regulatory Binder.   
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.   
Protocol Title: 
A phase 1b open-label study of pembrolizumab for 
unresectable or metastatic basal cell carcinoma     
 
Protocol Number: 
IRB-34925  /  SKIN0031 
Principal Investigator: 
Anne Lynn S Chang, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Be willing and able to provide written informed consent/assent for the 
trial.  Consent may be obtained by LAR according to the protocol. 
 
 
      
2. Have a histologically-proven BCC in which curative resection is 
unlikely without significant morbidity, or have nodal or distantly 
metastatic disease which has progressed on smoothened inhibitor 
monotherapy (ARM 1) or has undergone partial response or stable 
disease on smoothened inhibitor monotherapy (ARM  2).  Individuals 
who are intolerant or have a medical contra-indication to smoothened 
inhibitor may be enrolled into ARM 1. 
 
 
      
3. Be  18 years of age on day of informed consent signing . 
 
 
      
4. Have measurable disease based on RECIST 1.1.   
 
 
      
5. Be willing to provide tissue from a newly obtained core or excisional 
biopsy of a tumor lesion.  Newly-obtained is defined as a specimen 
obtained up to 6 weeks (42 days) prior to initiation of treatment on 
Day 1.  Subjects for whom newly-obtained samples cannot be 
provided (eg, inaccessible or subject safety concern) may submit an 
archived specimen. . 
 
 
      


 
 
 
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Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
 
      
7. Demonstrate adequate organ function as defined in Table 3 (repeated 
below);  all screening labs should be performed within 10 days of 
treatment initiation.   
 
 
      
8. Female subject of childbearing potential should have a negative urine 
or serum pregnancy within 72 hours prior to receiving the 1st dose of 
study medication.  If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required.   
 
 
      
9. Female subjects of childbearing potential should be willing to use 
2 methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days 
after the last dose of study medication (Section 5.7.2).  Subjects of 
childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.   
 
 
      
10. Male subjects should agree to use an adequate method of 
contraception starting with the 1st dose of study therapy through 
120 days after the last dose of study therapy.   
 
 
      
11. Female is not breastfeeding, is postmenopausal or surgically sterile; 
demonstrates non-pregnant state, and agrees to use 2 acceptable 
methods of birth control throughout the trial, until 120 days after the 
last dose of treatment 
 
 
      
12. Male with female partner of childbearing potential agrees to use 
adequate method of contraception throughout study, until 120 days 
after last dose of treatment or last blood draw. 
 
 
      
 


 
 
 
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Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥ 1,500/mcL 
Platelets 
≥ 100,000/mcL 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤ 1.5 x upper limit of normal (ULN)  
     OR 
≥ 60 mL/min for subject with creatinine levels > 1.5 x 
institutional ULN 
 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 x ULN  
     OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 x ULN  
     OR 
≤ 5 x ULN for subjects with liver metastases 
Albumin 
> 2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
≤ 1.5 x ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
Activated Partial Thromboplastin Time 
(aPTT) 
≤ 1.5 X ULN unless subject is receiving anticoagulant 
therapy, as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
 
Exclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Is currently participating and receiving study therapy or has 
participated in a study of an investigational agent and received study 
therapy or used an investigational device within 4 weeks of the 1st 
dose of treatment.   
 
 
      


 
 
 
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Exclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 
7 days prior to the 1st dose of trial treatment.  Exceptions include 
topical, intralesional intra-articular and inhaled steroids.  A pulse 
steroid dose prior to and after imaging to prevent contrast allergy in 
patients with known allergy to contrast is allowed. 
 
 
      
3. Has a known history of active TB  (Bacillus Tuberculosis) 
 
 
      
4. Hypersensitivity to pembrolizumab or any of its excipients. 
 
 
      
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 
4 weeks prior to Study Day 1 or who has not recovered (ie, ≤ Grade 1 
or at baseline) from adverse events due to agents administered more 
than 4 weeks earlier. 
 
 
      
6. Has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to Study Day 1 or who has not 
recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. 
a. Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
b. Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting therapy.   
 
 
      
7. Has a known additional malignancy that is progressing or requires 
active treatment.  Exceptions include basal cell carcinoma of the skin 
or squamous cell carcinoma of the skin that has undergone potentially 
curative therapy or in situ cervical cancer. 
 
 
      
8. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without evidence 
of progression by imaging for at least 4 weeks prior to the 1st dose of 
trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids for at least 7 days prior to trial treatment.  This 
exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability.  
 
 
      
9. Has active autoimmune disease that has required systemic treatment 
in the past 2 years (ie, with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).  Replacement therapy 
(eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc) is not considered a 
form of systemic treatment.   
 
 
      


 
 
 
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Exclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
10. Has known history of, or any evidence of active, non-infectious 
pneumonitis. 
 
 
      
11. Has an active infection requiring systemic therapy. 
 
 
      
12. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.  
 
 
      
13.  Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
 
 
      
14. Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 120 days after the last dose 
of trial treatment. 
 
 
      
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or 
anti-PD-L2 agent. 
 
 
      
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 
1-2 antibodies). 
 
 
      
17. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C 
(eg, HCV RNA [qualitative] is detected) 
 
 
      
18. Has received a live vaccine within 30 days of planned start of study 
therapy. 
 
 
      
*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.   


 
 
 
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IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  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: 
 


 
 
 
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APPENDIX B:  ECOG Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
* As published in Am J Clin Oncol:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP.  “Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group.”  Am J Clin Oncol.  1982;5:649-655.  The Eastern Cooperative Oncology Group, 
Robert Comis, MD, Group Chair. 
 
APPENDIX C:  Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html)