A Phase 2 Study of MK-3475 in Patients With Metastatic Melanoma and Non-Small Cell Lung Cancer With Untreated Brain Metastases
Phase: PHASE2
Conditions: Melanoma, Non-Small Cell Lung Cancer, Brain Metastases
Sponsor: Yale University

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Yale Protocol #: 1401013290
Merck Protocol #: PN027
IND #: 121,564 
TITLE:  A Phase 2 Study of MK-3475 in patients with metastatic melanoma and non-small cell 
lung cancer with untreated brain metastases
Coordinating Center:
      Yale Cancer Center
Principal Investigator:
Harriet Kluger, M.D. 
                                                           Section of Medical Oncology 
                                                           Yale Cancer Center
333 Cedar Street, WWW-213
New Haven, CT 06520
Tel: (203) 737-2572
Fax: (203) 785-3788
Harriet.Kluger@Yale.edu
Co-Principal Investigators:           Veronica Chiang, M.D.
Department of Neurosurgery
333 Cedar Street, TMP4
New Haven, CT 06520
Tel: (203) 785-2808
Fax: (203) 785-2098
Veronica.Chiang@yale.edu
Sarah Goldberg, M.D., M.P.H.
Section of Medical Oncology
Yale Cancer Center
333 Cedar St., FMP130
New Haven, CT 06520
Tel: (203) 785-7564
Fax: (203) 785-3788
Sarah.Goldberg@yale.edu
Co-Investigators:                           Roy Herbst, M.D., Ph.D.
     Mario Sznol, M.D.
     Scott Gettinger, M.D.
     Michael Hurwitz, M.D.
                                                          Anne Chiang, M.D.
                                                          Rogerio Lilenbaum, M.D.
                                                          
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Statistician:
Study Coordinator: 
Xiaopan Yao, PhD.                                                    Stephanie Speaker
Yale Cancer Center for Analytical Sciences          Clinical Trials Office
Yale School of Public Health                                   Yale Cancer Center
300 George Street, Suite 555                                 300 George Street, Suite 120
       New Haven, CT 06519                                             New Haven, CT 06511
 
Tel: 203-737-4856                                                    Tel: 203-737-4156
       Xiaopan.Yao@yale.edu                                          Fax: 203-785-5792
                                                                                           Stephanie.speaker@yale.edu 
Responsible Research Nurse(s)
Amanda Ralabate, R.N.
Elin Rowen, R.N.
2 Church St. South
300 George Street, Suite 120
      New Haven, CT 06520
New Haven, CT 06511
      203-200-1832
203-200-1856
      Amanda.Ralabate@Yale.edu
elin.rowen@yale.edu
Protocol Revision History:
Amendment Number
Protocol Version Number
Date
Original
Version 2.0
13 August 2013
Amendment 1
Version 3.0
31 May 2014
Amendment 2
Version 4.0
2 June 2015
Amendment 3
Version 5.0
20 Aug 2015
Amendment 4
Version 6.0
08 Aug 2016
Amendment 5
Version 7.0
22 Apr 2017
Amendment 6
Version 8.0
23 Oct 2017
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SCHEMA: 
Evaluate patients with untreated brain metastases for 
eligibility and select surgical and clinically evaluable lesions*
Initiate MK-3475 at 10mg/kg IV q 2 weeks
MRI brain at the end of week 4 for safety 
and week 8 for responseevaluation
Evaluable lesions showing PD or stable
Evaluable lesions PR or CR
Determine biomarkers predictive of treatment benefit
-Patients with NSCLC in Cohort 1 must have tumor PD-L1 expression 
No local therapy
Continue MK-3475
if systemic control achieved
MRI brain and body imaging every 8 weeks
Continue MK-3475 until criteria for removal 
from study is met
Arm A: 
Melanoma
Arm B: 
NSCLC
Consider local therapy to 
evaluable lesion
Local therapy to surgical lesion 
with tissue biopsy
Local therapy to surgical lesion with 
tissue biopsy if clinically indicated
*Patients with NSCLC or those with prior resection of CNS metastases who have 
available tissue for analysis do not require identification or treatment of a surgical lesion. 
Patients with PD-L1 negative tumors or patients without accessible tumors will be eligible 
for Cohort 2 of the NSCLC arm.
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Amendment 4, Version 6.0/August 8, 2016 
TABLE OF CONTENTS
Page
SCHEMA .................................................................................................................................iii
1. OBJECTIVES/ENDPOINTS…………………………………………………………….…………………………………...1
1.1
Primary…………………………………………………………………………………………………………….….1
1.2
Secondary Endpoints…………………………………………………………………………………………….1
2. BACKGROUND…………………………………………………………………………………………………………………1
2.1
Study Diseases .......................................................................................................1
2.2       MK-3475 .................................................................................................................2
2.3       Clinical Development, Efficacy and Safety of MK-3475…………………………………………..4
2.4        Local Surgical Therapy with Laser Interstitial Thermocoagulation……………………….. 4
2.5         Study Rationale .....................................................................................................5
2.6
Correlative Studies Background..............................................................................7
3. PATIENT SELECTION .................................................................................................................8
3.1
Inclusion Criteria ....................................................................................................8
3.2
Exclusion Criteria....................................................................................................9
4. TREATMENT PLAN............................................................................................................11
4.1       Study Design .........................................................................................................11
4.2 
Local Therapy and Tissue Biopsy of Brain Metastases ..........................................12
4.3       MK-3475 Formulation ...........................................................................................12
4.4       MK-3475 Storage...................................................................................................13
      4.5        MK-3475 Dosage and Administration....................................................................13
4.6       Dosing Delays....................................................................................................... 15
4.7       Duration of Therapy ............................................................................................. 15
4.8       Treatment Beyond Disease Progression................................................................ 16
4.9       Duration of Follow Up .......................................................................................... 16
5.   GENERAL CONCOMITANT THERAPY AND SUPPORTIVE CARE GUIDELINES.........................16
5.1       Concomitant Medications .....................................................................................16
5.2       Local Therapy ......................................................................................................  17
      5.3       Supportive Care Guidelines ..................................................................................  17
 
6. STUDY ASSESSMENTS AND PROCEDURES........................................................................ 21
      6.1        Screening Visit ..................................................................................................... 21
      6.2        On-Study Visits .....................................................................................................22
      6.3        Follow-up Visits ....................................................................................................23
      6.4        Study Calendar......................................................................................................23
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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ...............................................25
7.1
Safety Analysis......................................................................................................25
7.2
Definition of Adverse Event Terms........................................................................25
7.3       Toxicity Grading ....................................................................................................27
7.4       Toxicity Attribution ...............................................................................................27
7.5       Yale Principal Investigator Safe Reporting Requirements.......................................28
7.6 Yale Safety Reporting and Monitoring(DSMP) ............................................................30
      7.7        Pregnancies ..........................................................................................................31
7.8       Events of Clinical Interest ....................................................................................  31
      7.9        Warnings and Precautions ....................................................................................32
8. PHARMACEUTICAL INFORMATION...................................................................................32
8.1
Availability..........................................................................................................  32
8.2
Agent Accountability ............................................................................................33
9. LABORATORY CORRELATIVE/SPECIAL STUDIES.................................................................33
9.1
Handling of Tissue ................................................................................................33
      9.2        Correlative Studies............................................................................................... 33
10. MEASUREMENT OF RESPONSE.........................................................................................34
10.1     Brain Metastases Response Assessment ...............................................................35
10.2
Systemic Disease Response Assessment ...............................................................36
10.3     Evaluation of Best Overall Response .....................................................................36
10.4     Duration of Response............................................................................................36
10.5
Progression Free Survival..................................................................................... 37
10.6     Response Review ..................................................................................................37
11. STATISTICAL CONSIDERATIONS ........................................................................................37
      11.1  
Study Design/Sample Size Justification .................................................................37
      11.2     Analytic Plan for Primary Objective....................................................................... 41
      11.3     Analytic Plan for Secondary Objectives..................................................................42
      11.4     Reporting and Exclusions.......................................................................................42
      11.5     Accrual Rate and Study Duration ...........................................................................43
APPENDICES
APPENDIX A
Performance Status Criteria........................................................................................44
REFERENCES ..........................................................................................................................45
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1. OBJECTIVES AND ENDPOINTS
The overall objective of this trial is to determine the efficacy of MK-3475 in patients with 
melanoma or non-small cell lung cancer (NSCLC) and untreated brain metastases.  Efficacy will 
be determined by brain metastasis response rate, overall response rate, median progression free 
survival and overall survival. A secondary objective is to determine the safety of MK-3475 in 
patients with untreated brain metastases and to define the overall toxicity profile. An exploratory 
objective is to attempt to determine B7-H1 (PD-L1) expression and other potential predictive 
biomarkers in CNS and peripheral tumors and blood and their relationship to MK-3475.
1.1.
Primary Endpoint
(1) To determine the brain metastasis response rate (BMRR) in patients with melanoma or NSCLC 
with untreated brain metastases treated systemically with MK-3475
1.2 Secondary Endpoints
(1) To determine the best overall response rate (ORR) in patients with untreated brain metastases 
from melanoma or NSCLC treated with MK-3475
(2) To study B7-H1 expression and other potential predictive biomarkers in CNS and peripheral 
tumors and blood, and their association with response to MK-3475
(3) To evaluate median progression-free survival (PFS) and overall survival (OS) in patients with 
melanoma or NSCLC metastatic to the brain, treated with MK-3475
(4) To determine the safety and toxicity of MK-3475 in patients with untreated brain metastases
2. BACKGROUND
2.1
Study Diseases
2.1.1 Melanoma
The incidence of melanoma has been rising faster than that of any other cancer in the United 
States, and the mortality rate has also been rising.  In 2010, the projected incidence was 68,130 
and the death rate from the disease was projected to rise to 8,700 1.  This represents a sharp 
increase in recent years. For example, in 2006 the incidence was 62,190 and the death rate was 
7,910, representing an increase of 10% in both incidence and death rate in a mere four years 2.
Therapeutic options are limited once melanoma metastasizes3, although recent advances in 
development of novel therapies will likely expand the repertoire of active drugs for this disease.  
Older therapies, such as cytotoxic and cytokine agents, including dacarabazine, temozolomide, 
cisplatin, paclitaxel, interleukin-2 (IL-2), and interferon-alfa (IFNa), produce low objective 
responses in the range of 10-20%. None of these agents appear to have an impact on median 
survival, although responses can be associated with meaningful palliation of disease and 4-5% of 
patients treated with high-dose IL2 achieve long-term complete responses 4. Various 
combinations of the active single-agents have been evaluated in phase II trials and in randomized 
phase III trials. Some of the regimens, such as cisplatin-vinblastine-dacarbazine (CVD), or CVD-
IFNa-IL2 (biochemotherapy), produced high response rates exceeding 40% in single-arm trials. 
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However, in prospective randomized studies, the combinations failed to demonstrate clinically 
meaningful improvements in median survival, and the toxicity was not negligible 5.  Until recently, 
dacarbazine has been the standard of care for treatment of metastatic melanoma, although 
median survival in patients treated with dacarbazine is less than 8 months 6-8. For selected 
patients with good performance status and normal organ function, high-dose IL-2 remains a 
reasonable option, although treatment is associated with substantial acute toxicity and requires 
inpatient administration.  
More recently, in a pivotal phase III study of ipilimumab, a monoclonal antibody against cytotoxic 
T lymphocyte associated antigen (CTLA-4), improved survival was observed9.   This and other 
studies led to the FDA approval of ipilumumab for metastatic melanoma in March of 2011.  Other 
recent clinical trials investigating targeted therapies in melanoma have shown promise.  One 
novel agent, vemurafenib, an inhibitor of mutated B-raf, had a survival benefit when compared 
to dacarbazine10. Based on these studies, vemurafenib was recently FDA approved for metastatic 
melanoma. 
2.1.2
Non-Small Cell Lung Cancer
NSCLC is the leading cause of cancer-related death in the United States and worldwide, and 
results in over 160,000 deaths in the United States per year11.  In patients with advanced or 
metastatic disease, platinum-based chemotherapy had been the mainstay of management with 
a response rate and median overall survival of approximately 30% and 12 months, respectively12.  
In patients who are able to tolerate treatment beyond first line, responses are even lower and 
median survival is only minimally improved with chemotherapy.  Targeted therapies, including 
agents targeting the epidermal growth factor receptor pathway have been shown to be effective 
as first-line therapies for select patients with response rates up to 70% and progression-free 
survival of about 1 year.  However, none of these treatments has been shown to be curative in 
patients with metastatic disease, and despite the development of new and effective therapies, 
the five-year survival rate for patients with advanced NSCLC remains less than 5%.  
Nivolumab, a PD-1 inhibitor, is the first immunotherapy agent to be approved for NSCLC with 
squamous cell carcinoma histology based on a randomized trial of nivolumab versus docetaxel in 
the 2nd line treatment setting.  Nivolumab was approved by the FDA in all patients with squamous 
histology, without regards to PD-L1 status of the tumor.  Further studies with nivolumab as well 
as other PD-1 and PD-L1 inhibitors are ongoing, and the role of PD-L1 as a potential biomarker 
continues to be explored.
2.2
MK-3475
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades 13.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies 14-29.  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 solid malignancies such as ovarian, colorectal and pancreatic cancer, hepatocellular 
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carcinoma, malignant melanoma (MEL) and renal cell carcinoma (RCC).  TILs can be expanded ex 
vivo and re-infused, inducing durable objective tumor responses in cancers such as melanoma. 
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) 25, 30. The structure of murine PD-1 has been 
resolved 31-33.  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 30-32.  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 31, 32, 34, 35.  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 31, 
32, 36.  Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T-cells as well as subsets of macrophages and dendritic cells 27.  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 37-40.  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 38.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor.  High expression of PD-L1 on tumor cells (and to 
a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various 
cancer types, including RCC, pancreatic carcinoma, hepatocellular carcinoma, and ovarian 
carcinoma 39, 41.  Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with MEL 41.
The observed correlation of clinical prognosis with PD-L expression in multiple cancers 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.
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection, either as a mono-therapy or in combination with other treatment modalities.  
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a 
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mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL and colorectal 
carcinoma.  Blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the 
tumor and the presence of IFN-g, granzyme B and perforin, indicating that the mechanism of 
action involved local infiltration and activation of effector T-cell function in vivo 42-47.  In addition, 
the combination of gemcitabine and anti-PD-L1 mAb demonstrated synergy in the rejection of 
pancreatic mouse tumors.  In-house experiments have confirmed the in vivo efficacy of PD-1 
blockade as a mono-therapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the IB).
2.3 Clinical Development, Efficacy and Safety of MK-3475
An open-label Phase I trial (Protocol 001) has been conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  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.  Based on PK data showing a half-life of 21 days, the protocol was amended to 
change the dosing frequency in the expansion cohort to every 3 weeks (Q3W).  Promising 
preliminary anti-cancer activity has been observed.  Of further note, those patients with 
melanoma who were treated with MK-3475 10 mg/kg Q2W had a best objective response rate 
of 29/52 [56%; 95% CI 41%, 69%] , and those treated at 10 mg/kg Q3W had a best objective 
response rate of 16/45 [36%; 95% CI 22%, 51%] .  Updated response rates reported at the annual 
meeting of the American Society of Clinical Oncology in 2014 indicated an overall response rate 
of 34% among 411 treated patients. Based on the promising response rates, MK-3475 
(pembrolizumab) was approved by the FDA in 2014 for patients with unresectable melanoma 
whose disease had progressed after treatment with BRAF inhibitors (for patients with BRAF 
mutant melanoma) and ipilimumab. Of note, nivolumab, also an inhibitor of PD-1, was approved 
for use in the same setting in December 2014.
The most common AEs were fatigue, nausea, rash, diarrhea, cough, pruritus, arthralgia, 
headache, abdominal pain, increased AST, pyrexia, and decreased appetite.  The most common 
drug-related AEs included fatigue, rash, pruritus, diarrhea, and arthralgia.  The incidence of Grade 
3-5 AEs was 27%.  Potentially immune-related AEs have been observed, including pneumonitis in 
both the melanoma and NSCLC cohorts.  Although most cases do not result in death, in one 
instance, a 96-year old man with melanoma who experienced Grade 2 pneumonia/pneumonitis 
suffered a fatal myocardial infarction while being treated for the pneumonia/pneumonitis.  
Please refer to the IB for additional clinical data.48
MK-3475 Protocol 001 (PN001) Part C enrolled 38 previously treated subjects with NSCLC to 
receive monotherapy MK-3475 (internal data).  The preliminary objective response rate was 
21% by RECIST 1.1 criteria.  Clinical responses have been observed in subjects with both 
squamous and non-squamous histologies.  The median duration of response was not yet 
reached at 62 weeks.  The response rate among the patients with PD-L1 positive tumors was 
57%, while response rate among those with PD-L1 negative tumors was 9%.  Given these 
results,the use of PD-L1 as a predictive biomarker is being further explored in subsequent 
NSCLC studies.  More patients with NSCLC are being enrolled to MK-3475 PN001 for single 
agent treatment with MK-3475.  Additionally, a Phase II/III study of MK-3475 vs docetaxel is 
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enrolling patients with NSCLC that has been previously-treated with a platinum-containing 
doublet.  
2.4
Local Surgical Therapy with Laser Interstitial Thermocoagulation Therapy (LITT) 
Surgical management of brain tumors traditionally involves craniotomy with surgical debulking 
or resection of large superficial surgically accessible lesions.  For small or deep lesions, the risk of 
craniotomy in a patient with stage IV cancer has not been justifiable.  More recently, LITT has 
been FDA approved for use in the treatment of brain tumors.  Radiofrequency thermocoagulation 
has been used for over 3 decades in the neurosurgical treatment of movement disorders and has 
been shown to effectively coagulate brain tissue and ultimately result in tissue necrosis at 
temperatures of 80 degrees Celsius and above49.  The limitation of prior treatments with 
thermocoagulation, however, was that lesion volume did not correlate well with radiofrequency 
dose, resulting in a lack of the ability to predict extent of heat diffusion and therefore size of the 
lesion created.  In the treatment of functional disorders, since treatment success was based on 
functional improvement, lesion size was far less important.   With tumors, however, volume of 
thermal injury is critical.  Using intraoperative MR thermometry, the temperature of tissues and 
the direction in which the heat is delivered can be monitored in real time.  This enables the 
surgeon to watch the temperature changes in the tissues by MRI as heat is being delivered, stop 
or change treatment to control the size of thermal injury and to protect adjacent critical neural 
structures. LITT does not always require the administration of general anesthesia and from a 
surgical standpoint is considered a minimally invasive procedure.   The procedure only requires 
a small scalp incision, the creation of a single burrhole in the skull, and the stereotactic passage 
of the laser catheter into the lesion as would be done for lesion biopsy.   Most lesions then only 
require up to one hour of thermocoagulation time and, overall, LITT has been reported to carry 
less risk than a standard brain biopsy.  Many centers have now reported good results using LITT 
in the treatment of deep seated metastatic brain tumors of <30mm diameter where craniotomy 
is not justifiable with obliteration of tumor within the area of thermal injury.   Both LITT and 
craniotomy are currently being used in the surgical management of melanoma brain metastases 
at our institution.
2.5 Study Rationale
While recent advances in the treatment of metastatic melanoma and NSCLC with agents 
targeting PD-1 are striking, there remains a significant need to develop therapies for patients 
with untreated brain metastases who were excluded from prior trials with MK-3475 and the 
majority of other studies in these diseases.  The brain is a common site of disease spread in many 
solid tumors, most notably metastatic melanoma and NSCLC.  10-40% of patients with metastatic 
melanoma develop brain metastases during their lifetime and >75% have brain metastases at 
autopsy 50-54. Overall, historical melanoma patient cohorts have reported a median survival of 
patients with brain metastases in the order of 2.5 – 4 months despite use of whole brain 
radiation therapy (WBRT) and surgery. One older patient series showed a median survival of < 4 
months in melanoma patients with brain metastases and a neurological death rate of >30% 
despite the treatment of intracranial metastases with whole brain radiation therapy (WBRT)55.   
Among those with NSCLC, 10% have brain metastases at presentation and another 30% develop 
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them over the course of their disease.  Survival after the development of brain metastases is as 
dismal in those with NSCLC as it is for melanoma.  Multifocal disease is common in both of these 
diseases, with about half of patients with CNS disease presenting with more than one brain 
lesion56.  
Patients with untreated brain metastases have been excluded from most clinical trials of systemic 
therapy for two reasons: (1) historically their prognosis has been poor (overall survival ≤ 4 
months) and (2) experimental drugs are presumed to not penetrate the blood brain barrier (BBB) 
or BBB penetration is not well studied 52.  In melanoma, for example, one phase III study 
evaluating ipilimumab excluded patients with untreated brain metastases and another study 
evaluating ipilimumab and dacarbazine excluded all patients with a history of brain metastases, 
regardless of prior treatment57.  A subsequent trial with ipilimumab for patients with untreated 
brain metastases indeed showed that the drug had some activity in treating CNS disease. In the 
initial vemurafenib studies, patients with progressing or unstable CNS metastases were excluded.  
The pivotal BRIM-3 trial excluded patients with brain metastases unless metastases had been 
definitively treated more than three months prior to trial enrollment 58.  Both temodar and 
sorafenib cross the BBB.  Initial studies with sorafenib alone and in combination with 
chemotherapy excluded patients with active brain metastases 59, 60. A combination study of 
temodar and sorafenib in patients with or without brain metastases showed modest activity in 
patients without a history of prior temodar, and was thought to be favorable in part due to local 
therapies61.  Although a number of studies have been conducted for melanoma patients with 
untreated brain metastases using established therapies, most initial clinical trials with novel 
agents exclude these patients.  A recent trial with dabrafenib, an inhibitor of mutated B-raf, is an 
exception to the long-standing paradigm. A phase I/II study of this agent included a subset of 
patients with untreated brain metastases 62. At the 2010 meeting of the European Society for 
Medical Oncology, Long et al reported that nine of the ten patients with untreated cerebral 
metastases enrolled in this trial had shrinkage of their brain lesions 62.  This was the basis for a 
recent phase II trial of dabrafenib specific for patients with untreated brain metastases63. In 
NSCLC, a small number of trials have shown that combination chemotherapy regimens can 
induce a response in the CNS with untreated brain metastases with a median PFS up to 4 
months64, 65.  These studies demonstrate that asymptomatic brain metastases, similar to 
asymptomatic metastases in other sites, can be treated systemically on clinical trials, and that 
drug activity in the CNS is not necessarily different than in other metastatic locations.
Current standard of care for brain metastases that require immediate local intervention (based 
on symptoms, location, size, or other concerning features) is craniotomy with resection or 
radiation therapy.  As an adjunct to standard craniotomy, LITT is emerging as a new, minimally 
invasive local therapy to treat previously surgically inaccessible brain metastases.  Not only is cell 
death instantaneous, thus decreasing the risk of delayed intra-tumoral hemorrhage, but another 
theoretical advantage of using LITT as part of management of brain metastases is that the 
hyperthermia breaks down the blood brain barrier at the edge of the coagulation region thereby 
possibly increasing access of chemotherapeutic agents into the lesion 58.  In patients in whom 
either craniotomy or LITT are performed, biopsies of tumor and surrounding normal brain can 
also be obtained at the time of local therapy.   The institutional standard of care at Yale is to 
perform a local therapy (craniotomy, LITT or stereotactic radiosurgery) to patients without 
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overwhelming brain metastases instead of whole brain radiation therapy to minimize toxicity 
and improve disease control.  Patients with overwhelming brain metastases based on number 
or size of lesions will not eligible for this protocol.  
The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases from 
melanoma or NSCLC.  Given the promising initial results of MK-3475 in these diseases but the 
lack of data in patients with untreated brain metastases thus far, this trial will study treatment 
in this patient population.  Additionally, for patients with melanoma this trial requires local 
therapy with craniotomy or LITT to at least 1 brain lesion prior to systemic therapy, thereby 
allowing the acquisition of brain tumor tissue for correlative studies on biomarkers that may be 
predictive of clinical response in the CNS and systemically. We will also require a biopsy of an 
extra-cerebral metastasis when feasible, particularly when tissue from the brain lesion is not 
obtained in patients with NSCLC.
2.6 Correlative Studies Background
The phase I dose escalation studies of MK-3475 in patients with melanoma and NSCLC showed 
that response was not uniform, with response rates of 40% and 20, respectively. In the melanoma 
cohorts the association between response and expression of PD-L1 was unclear66.  In NSCLC there 
appears to be an association between PD-L1 expression and response, although the numbers are 
small. Of the 22 patients with PD-L1 expression, six (27%) responded, while one of the 12 patients 
with expression below this threshold responded (8%). The association between PD-L1 expression 
and response to other PD-1 inhibitors is suggested by phase I trials in solid tumor patients, also 
with small numbers of patients67,68. These studies need to be validated in additional patient 
cohorts. Moreover, not all patients with PD-L1 positive tumors responded to MK-3475. Some of 
the studies used whole tumor resections to determine PD-L1 expression, while others used cores 
from biopsies. In addition, a number of pre-clinical studies have now shown that PD-L1 
expression is inducible with drugs such as interferon and vemurafenib69. Therefore, the timing of 
biopsies prior to treatment has to be reassessed, as inter-current therapies might effect PD-L1 
expression. We propose here to treat NSCLC patients with any PD-L1 expression on biopsies done 
just prior to initiation of MK-3475. Based on our prior experience in the phase I trial, we anticipate 
that 65% of patients screened will be eligible. Given that the response rate in melanoma is higher, 
we will treat all melanoma patients that are otherwise eligible, regardless of PD-L1 status, and 
we will use their matched CNS and peripheral tumors to retrospectively study the association 
between PD-L1 status and other biomarkers and response to therapy, both in the CNS and in 
extra-cranial metastases.
Other studies conducted by Dr. Lieping Chen’s group, that characterized the PD-L1/PD-1 axis a 
number of years ago, suggest that presence of CD4 and CD8 positive cells in tumor deposits might 
also be important for response to PD-1 targeting therapies. 70 They found that the majority of 
PD-L1 positive tumors were associated with CD4 and CD8 tumor infiltrating lymphocytes (TILs), 
while the minority of the PD-L1 negative tumors had associated TILs. Moreover, the staining 
pattern of PD-L1 on melanocytes differed based on proximity to TILs. Interferon-γ, a primary 
inducer of B7-H1 expression, can be detected at the interface of PD-L1 positive melanocytes and 
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TILs, possibly reflecting activation of PD-1 on the TILs. This interaction, therefore, might be 
predictive of antitumor response to PD-1 blockade. Additional mediators of this pathway that 
might be associated with anti-tumor response, and will be studied on pre-treatment specimens 
from patients enrolled in this trial. Expression of other members of the B7 super-family of ligands, 
including PD-L2 and B7-H4 on tumor cells, might be associated with activation of PD-1 on tumor 
cells 71, 72. Galectin-9 (the ligand to TIM-3), has been proposed as a mediator of PD-1 related T-
cell exhaustion 73. A more sophisticated and accurate predictive biomarker model might be built 
by incorporating markers on T cells, in addition to quantification of T cell tumor infiltrate. 
Specifically, co-expression of TIM-3 and PD-1 might be associated with sensitivity to PD-1 
blockade 73.  LAG-3 (lymphocyte-activation gene 3) synergizes with PD-1 to inhibit T cell 
activation. 74 Co-expression of PD-1 and CTLA-4 on T cells is thought to be co-inhibitory, and co-
inhibition of these molecules is the basis of ongoing clinical trials. 75 The T-cell stimulatory role of 
PD-1H (PD-1 Homologue) on T cells was recently described by Dr. Chen’s laboratory; it’s 
association with anti-tumor response in the setting of PD-1 blockade has yet to be determined. 
76 Finally, the CNS environment might have a role in promoting anti-tumor immunity. Expression 
of the SALM family (synaptic-adhesion-like molecules) on neuronal cells might be associated with 
immune privilege (unpublished data) and will be studied as predictors of response to PD-1 
inhibition.
3. PATIENT SELECTION
3.1 Inclusion Criteria
1. Biopsy proven metastatic melanoma or NSCLC as follows:
a. Patients with metastatic melanoma must have untreated brain metastases including:
-At least one cerebral metastasis that requires local intervention and is amenable to 
craniotomy or LITT therapy either due to symptoms, lesion size, location, edema or 
hemorrhage (“surgical lesion”).  Alternatively, a patient may be eligible if a cerebral 
metastasis was resected or biopsied any time prior to enrollment and there is tumor 
tissue available for analysis.  
-At least one cerebral metastasis that is at least 5 mm AND twice the MRI slice 
thickness, but less than 20 mm, that is asymptomatic and does not require local 
therapy at the time of enrollment (“clinically evaluable lesion(s)”). 
OR
b. Patients with stage IV NSCLC with at least one cerebral metastasis that is at least 5 mm 
AND twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does 
not require local therapy at the time of enrollment (“clinically evaluable lesion(s)”).
2. Age ≥18
3. ECOG performance status < 2
4. Any number of previous treatments with the exception of previous inhibitors of PD-1, PD-L1, 
or PD-L2; other prior systemic therapies must have been administered at least 2 weeks before 
administration of MK-3475 with the exception of bevacizumab which must have been 
administered at least 4 weeks prior to MK-3475.  Patients are not required to have had prior 
systemic therapy.  The exception to this is patients with NSCLC who test negative for PD-L1 
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expression or are unevaluable for PD-L1 expression must have received prior platinum-based 
chemotherapy for entry into Cohort 2.
Note: Ipilimumab treatment should have been administered at least 4 weeks prior to the start 
of MK-3475.
5. Life expectancy of at least 3 months
6. A history of previously treated brain metastases is allowed, provided that at least 14 days 
have lapsed between radiation and initiation of MK-3475.  Any lesion present at the time of 
WBRT or included in the stereotactic radiotherapy field (or within 2mm of the treated lesion) 
will NOT be considered evaluable unless it is new or documented to have progressed since 
treatment. 
7. PD-L1 expression in tumor tissue from any site is required for patients with NSCLC for entry 
into Cohort 1.  Tumor tissue must be obtained after the last systemic therapy. PD-L1 
expression will be analyzed by a Merck assay.  For NSCLC Cohort 2, patients may test PD-L1 
negative or may be unevaluable for PD-L1 expression (i.e. insufficient tumor tissue).  PD-L1 
expression is not required for patients with melanoma, but melanoma patients are required 
to submit an extra-cerebral specimen for analysis, unless it is not feasible to obtain one.
8. Patients must have normal organ and marrow function as defined below:
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
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
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
9. For women of childbearing potential, agreement to the use of two acceptable  methods of 
contraception, including one barrier method, during the study and for 6 months after 
discontinuation of MK-3475.
10. For men with female partners of childbearing potential, agreement to use a latex condom, 
and to advise their female partner to use an additional method of contraception during the 
study and for 6 months after discontinuation of MK-3475.
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11. Negative serum or urine pregnancy test within 72 hours of commencement of treatment in 
premenopausal women.  
12. Patients must have the ability to understand and the willingness to sign a written informed 
consent document. 
3.2 Exclusion Criteria
1. Symptomatic brain metastases.  Symptoms may be present from the surgical lesion prior to 
resection or LITT but must have resolved by the time of administration of study drug.
2. Patients with brain metastases for whom complete surgical resection is clinically appropriate.
3. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy to the 
lung or brain within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or 
at baseline) from adverse events due to a previously administered agent. Previous radiation 
to other sites may be completed at any time prior to initiation of MK-3475.
a. Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.  
b. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion 
requirements for laboratory parameters.
4. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent or an antibody 
targeting other immune-regulatory receptors or mechanisms.  Examples of such antibodies 
include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR.  Prior ipilimumab, 
IL2, bevacizumab and adoptive cell therapy is allowed.
5. The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not 
be allowed, and patients who previously required corticosteroids for symptom control must 
be off steroids for at least 2 weeks.  Low-dose steroid use (≤10 mg of prednisone or 
equivalent) as corticosteroid replacement therapy is allowed
6. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
7. Presence of leptomeningeal disease
8. Has an active automimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents.  Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule.  Subjects that require intermittent use of 
inhaled steroids or local steroid injections would not be excluded from the study.  Subjects 
with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be 
excluded from the study.
9. Pregnancy or breast feeding.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician immediately.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with MK-3475, breastfeeding must be discontinued if 
the mother is treated with MK-3475.
10. Patients may not be receiving any other investigational agents and may not have participated 
in a study of an investigational agent or using an investigational device within 4 weeks of the 
first dose of treatment.
11. Either a concurrent condition (including medical illness, such as active infection requiring 
treatment with intravenous antibiotics or the presence of laboratory abnormalities) or history 
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of a prior condition that places the patient at unacceptable risk if he/she were treated with 
the study drug or a medical condition that confounds the ability to interpret data from the 
study. 
12. Concurrent, active malignancies in addition to those being studied (other than cutaneous 
squamous cell carcinoma or basal cell carcinoma)
13. Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical 
devices).  An MRI safety questionnaire is required prior to MR imaging.
14. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis 
15. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) 
infection.
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.  
17. Evidence of interstitial lung disease
4. TREATMENT PLAN
4.1 Study Design
This is a 2-arm phase II study with each of the 2 tumor types (melanoma, NSCLC) will be treated 
on a different arm. After establishing eligibility criteria, for patients with melanoma the 
investigator will determine at least one lesion that requires local therapy (surgical resection or 
LITT) based on size, location, and/or risk of hemorrhage; this will be considered the “surgical 
lesion”.  All other eligible brain lesions will be considered “clinically evaluable lesions” and will be 
followed by modified RECIST (mRECIST) criteria to determine best response. Patients with NSCLC 
are not required to have a “surgical lesion” but must have at least one “clinically evaluable lesion” 
in the CNS. After obtaining informed consent, patients with melanoma will undergo local therapy 
to the study lesion (resection or LITT) and tumor tissue will be studied for B7-H1 (PD-L1) and 
other biomarkers as potential predictors of sensitivity to MK-3475, although it should be noted 
that the presence of a biomarker is not necessary for patients with melanoma to go on trial.  
Expression of PD-L1 will be determined both by Merck and by the Yale team. Patients on the 
NSCLC arm in Cohort 1 are required to have formalin-fixed, paraffin-embedded tumor tissue 
available for biomarker analysis, and those who do not have PD-L1 expression will be ineligible 
for treatment.  Patients with NSCLC who test negative for PD-L1 expression or are unevaluable 
for PD-L1 expression will be eligible for Cohort 2.   PD-L1 expression will be determined by the 
Merck assay. This will be followed by treatment with MK-34753 10mg/kg IV every 2 weeks. Each 
cycle consists of 2 weeks of treatment.  Day 1 of the study will be defined as the first day a patient 
receives MK-3475. 
An MRI of the brain will be obtained after 2 cycles (4 weeks) of systemic therapy for patient safety 
(i.e., to confirm there is no imminent risk in the case of progressing lesion or new/worsening 
edema).  Patients with new symptoms from CNS lesions, progressing lesions or worsening edema 
may be taken off study and treated with local therapy to the brain metastases. An efficacy 
evaluation will then be performed after 4 cycles (8 weeks) including MRI of the brain and CT scans 
of systemic disease.  Brain metastasis response will be determined using modified RECIST 
(mRECIST) criteria.  The next MRI of the brain will be obtained after 8 cycles (week 16) and then 
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every 4 cycles (8 weeks), along with body CT, MRI or PET/CT scans.  Patients will continue on 
study until they have overall disease progression in either their clinically evaluable CNS lesions 
(by mRECIST criteria) or in their systemic metastases (by RECIST 1,1 criteria), toxicities that 
preclude continuing the study drug, withdrawal from study, development of other severe illness, 
neurologic or systemic complications following local therapy to any lesion, termination of study, 
or death. Dose reductions for severe immune-related toxicities will not be allowed.  If a patient 
develops symptoms related to ANY lesion, local therapy may be administered to that lesion.  
The plan is to enroll 74 patients total: 20 with melanoma, 44 with NSCLC in Cohort 1, and 10 with 
NSCLC in Cohort 2.   The first interim analysis will be after 8 patients on the melanoma arm, 18 
with NSCLC on the NSCLC arm.
4.2 Local Therapy and Tissue Biopsy of Brain Metastases 
Definition of surgical lesion(s): The surgical lesion is any lesion that is determined by the 
investigator to benefit from immediate local therapy via craniotomy/resection or LITT due to size, 
location, edema or hemorrhage.   
Definition of clinically evaluable lesion(s): A clinically evaluable lesion is at least one  
asymptomatic, untreated brain metastasis that measures at least 5 mm in minimum cross 
sectional diameter and < 20 mm in maximum cross sectional diameter as determined by brain 
MRI at baseline, and is determined by the investigator to be safe to follow clinically without local 
therapy.  If MRI slice thickness is >2.5mm, the minimum cross sectional diameter must be at least 
twice the MRI slice thickness.
At time of enrollment, the surgical lesion(s) and clinically evaluable lesion(s) will be defined. The 
exception to this is patients who have undergone surgical therapy to one or more lesion prior to 
enrollment on study and have tumor tissue available for analysis and patients with NSCLC who 
do not require surgical intervention.  These patients will have clinically evaluable lesion(s) defined 
only.  
In patients with melanoma, the choice of craniotomy versus LITT will be determined by the 
investigators and will depend on individual patient factors such as location of the brain 
metastasis, patient comorbidities, and patient preference.  Only LITT or craniotomy may be 
considered for local therapy of the study lesion because only these two treatment modalities can 
result in tissue biopsy at time of therapy.  
Two to seven days after local therapy is complete, depending on the extent of the surgical 
procedure and patient recovery, therapy with MK-3475 10mg/kg IV every 2 weeks will begin. 
Patients with NSCLC who will not undergo local therapy will proceed directly to therapy with MK-
3475.  If, at any time while on study, the patient develops symptoms related to any cerebral 
metastases the patient may have brain imaging prior to the pre-defined imaging time points and 
proceed to local therapy of the lesion(s) if indicated.  
     
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At the time of local therapy, tissue from the study lesion will be obtained for correlative endpoint 
studies.  1 cm x 2 mm tissue cores will be obtained at time of biopsy.  Standard operating 
procedures for SNAP freezing of tumors in the operating room will be used.  After frozen section 
confirmation of tumor pathology, tissue will be allocated for study as described in Section 9.  
4.3 MK-3475 Formulation
Clinical Supplies will be provided by Merck & Co., Inc., as summarized in table 1 below.
Table 1. Product Description
Product Name & Potency
Dosage Form
MK-3475 50 mg
Lyophilized Powder for Injection
MK-3475 100 mg/ 4 mL
Solution for Injection
4.4 MK-3475 Storage
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
4.5 MK-3475 Dosage and Administration
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
MK-3475 
10 mg/kg
Q2W
IV infusion
Day 1 of each cycle
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 2. 
 Table 2. Dose Modification Guidelines for Drug-Related Adverse Events
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).

Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion.
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable
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Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.  

Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) 
per standard of 
care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by 
taper.

Monitor changes of renal 
function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on 
severity of AE 
administer 
corticosteroids

Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
Intolerable/ 
persistent Grade 2
Withhold
All other 
immune-related 
AEs
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 

Based on type 
and severity of 
AE administer 
corticosteroids 

Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
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require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM).  
Dose modification and toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 3. 
Table 3  Pembrolizumab Infusion Reaction Dose modification and 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 therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the 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 (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
4.6 Dosing Delays 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. 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. See Tables 2 and 4 for details. 
Table 4. Treatment Delays and Resumption of Therapy.
5
Treatment held on the days of any local 
therapy to brain lesions
One week later
6
Suspicion of pregnancy
Resume if pregnancy ruled out
7
Treatment 
held 
during 
any 
hospitalization for illness 
Resume after discharge from hospital
8
Treatment held on day of any general 
surgery
Resume 1 week later (if outpatient surgery) or 
after discharge from hospital (if hospitalization is 
required for recovery or complications)
4.7 Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 2 
years or until one of the following criteria applies:
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1
Disease progression (see Section 4.8)
2
Symptomatic deterioration of health status without objective evidence of disease 
progression.  Every effort should be made to document objective progression of 
disease in such cases.
3
Imminent risk in the case of progressing lesion or new/worsening edema seen on brain 
MRI
4
Unmanageable toxicity most probably attributed to MK-3475 (see Table 2)
5
Development of intercurrent illness limiting the ability to comply with study or the 
development of uncontrolled concurrent illness that prevents further administration 
of treatment or confound the ability to interpret data
6
General or specific changes in the patient’s condition rendering the patient 
unacceptable for further treatment in the judgment of the investigator
7
Patient request for discontinuation, patient withdrawal from study, or patient lost to 
follow up
8
Development of neurologic or systemic complications following local therapy to any 
lesion
9
Death
10
Study termination by sponsor
4.8  Treatment Beyond Disease Progression
If radiologic imaging shows PD, tumor assessment should be repeated >4 weeks later in order to 
confirm PD with the option of continuing treatment while awaiting radiologic confirmation of 
progression. If repeat imaging shows a reduction in tumor burden compared to the initial scan 
demonstrating PD, treatment may be continued as per treatment calendar.  If repeat imaging 
confirms progressive disease, subject will be discontinued from study therapy.  Patients may 
continue treatment with MK-3475 beyond PD by RECIST 1.1  (in the body) or mRECIST in the 
brain, if they are determined by the investigator to be deriving clinical benefit from treatment 
and they continue to meet all other criteria for treatment.  Patients who have rapid progression 
of disease or clinical deterioration will be removed from study.  The decision to continue 
treatment beyond initial progression should be discussed with the medical monitor.
Additionally, in cases where the majority of the disease is stable or responding, and progressing 
lesions can be controlled with local therapy (ie resection or radiotherapy), the patient may be 
continued on trial following local therapy.
4.9  Duration of Follow Up
Patients who discontinue early or who complete the study treatment period in full will be 
followed for survival after removal from study until death.  
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5
GENERAL CONCOMITANT THERAPY AND SUPPORTIVE CARE GUIDELINES
5.1 Concomitant Medication
Additional anti-tumor therapies are prohibited during study treatment.  Additionally, the use of 
corticosteroids or other immunosuppressive medications will not be allowed during study 
therapy (unless used to treat a drug-related adverse event).  Low-dose steroid use (≤10 mg of 
prednisone or equivalent) as corticosteroid replacement therapy is allowed.  
5.2     Local Therapy
Local therapy for brain metastases:
Local surgical therapy in the form of craniotomy or LITT will be performed on the surgical lesion(s) 
prior to initiating systemic therapy.  At any time point throughout the study, local therapy 
(surgery, gamma knife or LITT) will be administered to a lesion that becomes clinically concerning 
if deemed necessary by the investigators. This can be followed by continuation on MK-3475, 
provided that the patient is otherwise benefiting from therapy and has stable disease or disease 
shrinkage in other lesions by RECIST criteria. Approval from the study PI or co-PIs is required to 
continue treating the patient on MK-3475.  A brain metastasis that has been treated locally will 
not be considered evaluable for response and will not be included when calculating the sum of 
largest dimensions. If the treated lesion constitutes > 25% of the target lesions (for example, if 
one of three target lesions is treated locally), this will be considered progressive disease. If >75% 
of the baseline lesions are not treated with local therapy and evaluable by imaging, the patient 
will be considered evaluable, and response for the primary endpoint analysis will be assessed 
based on the remaining lesions. Additional response evaluation will be performed which will 
consider those patients who require local therapy while on study as having PD at the time of local 
therapy.
Local therapy for extra-cerebral metastases:
Local surgery or radiation therapy (if indicated for palliative measures only after discussion with 
the study PI or co-PIs) may be permitted and the patient can continue to receive MK-3475 
provided there is otherwise evidence of clinical benefit from treatment (i.e. stable disease or 
response in measurable lesions). The criteria applied for assessing brain metastasis response will 
be applied to extra-cerebral metastases as well.
5.3 Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in Table 
2.  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, 
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which might require additional supportive care.  The treatment guidelines are intended to be 
applied when the Investigator determines the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to Table 2 for guidelines 
regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
Management of Infusion Reactions:  Acute infusion reactions (which can include cytokine release 
syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive reactions, 
although some of the manifestations are common to both AEs.  Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity 
(including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea 
(shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; 
Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to 
treatment); Urticaria (hives, welts, wheals); Vomiting.
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475.
Table 4.  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 therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs
Stop Infusion 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.
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
MK-3475 with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic).
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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for 
the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication 
should be permanently discontinued 
from further trial treatment 
administration.
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion and Monitor Symptoms.
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.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov
5.3.1 Supportive Care Guidelines for Events of Clinical Interest (ECIs) and Immune-related 
Adverse Events (irAEs)
Events of clinical interest of a potential immunologic etiology (irAEs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the MK-3475 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
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of potential irAEs.  An irAE can occur shortly after the first dose or several months after the last 
dose of treatment.  
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAEs.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Immune-Related 
Adverse Event Guidance Document.  Subjects who develop a Grade 2 or higher irAEs should be 
discussed immediately with the Merck Clinical Monitor.  
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 
5.
Table 5  General Approach to Handling irAEs
irAEs
Withhold/Discontinue MK-
3475?
Supportive Care
Grade 1
No action
Provide symptomatic treatment
Grade 2
May withhold MK-3475
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment
Grade 3 and Grade 4
Withhold MK-3475
Discontinue if unable to 
reduce corticosteroid dose 
to < 10 mg per day 
prednisone 
equivalent 
within 12 weeks of toxicity
Systemic corticosteroids are indicated in 
addition 
to 
appropriate 
symptomatic 
treatment.  May utilize 1 to 2 mg/kg prednisone 
or equivalent per day.
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks.
5.3.2 Supportive Care Guidelines for Pneumonitis
Subjects with grade 2 pneumonitis (symptomatic pneumonitis requiring medical intervention) 
should immediately stop receiving MK-3475 and have an evaluation.  The evaluation may 
include bronchoscopy and pulmonary function tests to rule out other causes such as infection.  
If the subject is determined to have study drug associated pneumonitis, the suggested 
treatment plan is detailed in Table 6 and follow-up will be as routine for AEs associated with 
study drug including monitoring until full resolution of the AEs/pneumonitis.  
Table 6.  Recommended Approach to Handling Pneumonitis
Study drug associated 
pneumonitis
Withhold/Discontinue MK-
3475?
Supportive Care
Grade 1 (asymptomatic)
No action
Intervention not indicated
Grade 2
Withhold MK-3475, may 
return to treatment if 
Systemic corticosteroids are indicated.  Taper 
as indicated.
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improves to Grade 1 or 
resolves within 12 weeks
Grade 3 and Grade 4
Discontinue MK-3475
Systemic corticosteroids are indicated.
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply:

First episode of pneumonitis
o
May increase dosing interval by one week in subsequent cycles

Second episode of pneumonitis – permanently discontinue MK-3475 if upon rechallenge 
subject develops pneumonitis  Grade 2

Please consult the Events of Clinical Interest and Immune-Related Adverse Events 
Guidance Document for a more in-depth discussion of pneumonitis. 
6
STUDY ASSESSMENTS AND PROCEDURES
Systemic treatment with MK-3475 is divided into 2-week cycles, with treatment occurring on Day 
1.  A window of +/- 3 days can be applied to scheduled visits if necessary for holidays, vacations, 
inclement weather, etc.
6.1 Screening Visit 
Prior to initiation of therapy, the patient will require a screening visit.  Scans must be done within 
28 days prior to the start of systemic therapy; all other evaluations must be completed within 7 
days prior to starting MK-3475.  At the screening visit, the following will be addressed:
1) Informed consent
2) History and physical examination
3) Measurement of height, weight and vital signs (including blood pressure, 
heart rate, respiratory rate, oxygen saturation, and temperature).
4) Performance status evaluation
5) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, 
glucose, calcium), magnesium, phosphate, liver function tests (albumin, total 
protein, alkaline phosphatase, total and direct bilirubin, ALT, AST), LDH, TSH, 
free T3, free T4
6) Plasma  and pre-treatment tumor tissue for correlative studies. Melanoma 
patients are required to have cerebral and extracerebral tissue, unless it is 
not feasible to obtain the extra-cerebral tissue. Lung cancer patients are 
required to have extracerebral tissue, unless it is not feasible to obtain the 
extra-cerebral tissue. If lung cancer patients undergo a surgical resection or 
biopsy of a brain lesion, they are required to provide a portion of the tissue 
for research.  Plasma can be obtained at screening or any time prior to Cycle 
1 Day 1 dosing.
7) Pregnancy test (serum or urine) for women of childbearing potential. 
Sexually active women of childbearing potential must use an effective 
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method of birth control during the course of the study, in a manner such that 
risk of failure is minimized.
8) Systemic tumor assessment with CT scan of the chest/abdomen/pelvis
9) CNS tumor assessment with Brain MRI.  MRIs should be done with perfusion, 
if possible.  For patients who will undergo local therapy on trial, investigators 
must identify “surgical lesion(s)” and “clinically evaluable lesion(s)”.  Brain 
MRI must be done within 28 days of intervention and should be repeated if 
more than 28 days will have lapsed by the start of systemic therapy. For 
patients who previously underwent local therapy to a brain lesion and have 
tumor tissue available for analysis, or those with NSCLC who are not eligible 
for surgical intervention, only identification of “clinically evaluable lesion(s)” 
is necessary.
10) NSCLC patients will be required to provide a specimen for determination of         
PD-L1 expression using the assay developed by Merck for entry into Cohort 1.
                        11) NSCLC patients will be required to have baseline pulmonary function tests.
6.2 On-Study Visits
Day 1 of each cycle (every 2 weeks):
1) History and physical examination
2) Measurement of height, weight and vital signs (including blood pressure, 
heart rate, respiratory rate, oxygen saturation, and temperature).
3) Performance status evaluation
4) Review concomitant medications; initiation of medications for seizure 
prophylaxis in patients not on anti-convulsants. 
5) Adverse events assessment
6) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, 
glucose, calcium), magnesium, phosphate, liver function tests (albumin, total 
protein, alkaline phosphatase, total and direct bilirubin, ALT, AST), LDH
7) Administration of MK-3475 10mg/kg IV
Day 1 of cycle 3 (after 4 weeks of therapy +/- 5 days)
1) Brain MRI to assess patient safety (i.e., to confirm there is no imminent risk 
in the case of progressing lesion or new/worsening edema).  MRIs should be 
done with perfusion, if possible.
Day 1 every 8 weeks +/- 5 days
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1) TSH with reflex free T4 and free T3 
2) Tumor response assessment with:
a. CT scan of the chest/abdomen/pelvis
b. Brain MRI; MRIs should be done with perfusion, if possible.
3) Plasma for correlative studies
6.3 Follow-up Visits
All patients who discontinue the study treatment will have a follow up visit at Day 28 ±7 days 
from the last study treatment.
1) History and physical examination
2) Measurement of height, weight and vital signs (including blood pressure, 
heart rate, respiratory rate, oxygen saturation, and temperature).
3) Performance status evaluation
4) Review concomitant medications
5) Adverse events assessment 
6) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, 
glucose, calcium), magnesium, phosphate, liver function tests (albumin, total 
protein, alkaline phosphatase, total and direct bilirubin, ALT, AST), LDH
7) Tumor assessment with CT scan of the chest/abdomen/pelvis and brain MRI 
with perfusion, if possible, should continue every 8 weeks (+/- 5 days) until 
progression, withdrawal of consent, death, lost to follow-up, or start of a 
subsequent anti-cancer therapy
All patients who discontinue early or who complete the study treatment period will be followed 
for survival. Survival follow-up information will be collected via telephone calls, patient medical 
records, and/ or clinic visits every 3 months +/- 14 days until death, loss to follow-up or study 
termination. All patients will be followed for survival unless the patient requests to be withdrawn 
from follow-up. If the patient withdraws from study treatment but not from follow-up, the study 
staff may use a public information source to obtain information about survival status.
6.4 STUDY CALENDAR (Table 7).
Screening evaluations are to be conducted within 7 days prior to start of systemic therapy. Scans must be done 28 
days prior to the start of systemic therapy. In the event that the participant’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.
All assessments must be performed prior to administration of any study medication. All study assessments and 
medications should be administered within ± 3 days of the protocol-specified date, unless otherwise noted.
Screening 
Visit
On-Study Visits
Follow-up 
Visit
Long Term 
Follow-up
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Day -28 
to -1
Day 1 of 
each Cycle
Day 1 Cycle 
3 (after 4 
weeks +/- 5 
days of 
therapy)
Day 1 Cycle 
5, and every  
8 weeks, 
thereafter
Day 28 +/- 7 
days from 
last study 
treatment
Every 3 
months +/- 
14 days after 
the follow-up 
visit
Informed Consent
X
History/Physical Exam
X
X
x
Height/Weight/Vital 
SignsA
X
X
x
Performance Status
X
X
x
CBC, serum chemistry, 
liver function tests, 
LDHB
X
X
x
PT/INR (for patients 
on warfarin)
X
X
X
Carbamazepine 
or 
Phenytoin level (for 
patients on drug)
X
X
x
TSH, free T3, free T4
X
x
NSCLC patients: 
Determination of PD-
L1 expression in 
tumor (Cohort 1 only)
X
Plasma for correlative 
studies
XI
x
Obtain extracerebral 
tumor specimen for 
correlative studies 
(Refer to Section 6.1 
and 9.2)
X
Pregnancy TestC
x
CT 
chest/abdomen/pelvis
x
XD
x E
Brain MRI
x F
X G
X H
x E
Selection of “surgical 
lesion(s)” and 
“clinically evaluable 
lesion(s)”
x
Pulmonary Function 
Tests – NSCLC 
patients only
X
Review concomitant 
medications
X
x
Adverse events 
assessment
X
x
Administration of MK-
3475
X
Survival Follow-up
X
AIncludes blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature.  Height at Visit 1 only.
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BIncludes CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, glucose, calcium), magnesium, 
phosphate, liver function tests (albumin, total protein, alkaline phosphatase, total and direct bilirubin, ALT, AST), 
LDH
CPregnancy test (serum or urine) is required for women of childbearing potential only. 
DCT scan of the chest/abdomen/pelvis should be performed every 8 weeks +/- 5 days of therapy.  Response 
evaluation is performed using RECIST 1.1 and ir-RECIST
ECT scan of the chest/abdomen/pelvis and brain MRI should continue every 8 weeks (+/- 5 days) until progression, 
withdrawal of consent, death, lost to follow-up, or start of a subsequent anti-cancer therapy
FFor patients who will undergo local therapy on trial, investigators must identify “surgical lesion(s)” and “clinically 
evaluable lesion(s)”.  Brain MRI must be done within 28 days of intervention and should be repeated if more than 
28 days will have lapsed by the start of systemic therapy. For patients who previously underwent local therapy to a 
brain lesion and have tumor tissue available for analysis, only identification of “clinically evaluable lesion(s)” is 
necessary.
GBrain MRI on Day 1 of Cycle 3 to assess patient safety only; response assessment should not be performed. MRIs 
should be done with perfusion, if possible.
HBrain MRI should continue every 8 weeks (+/- 5 days) along with systemic evaluation.  CNS response evaluation is 
performed using mRECIST and ir-mRECIST criteria. Perfusion will be done, if possible.
I Can be done at screening or any time prior to Cycle 1 Day 1 dosing
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1 Safety Analysis
Safety will be analyzed for patients treated in this study.  All patients who receive any amount 
of study drug will be evaluable for toxicity.
At each visit, a brief focused history will be obtained and any indication of treatment- related 
toxicity will be evaluated by appropriate examination and/or laboratory/radiographic studies.
Safety analyses will include summaries of adverse event rates and changes in laboratory results, 
as well as number of CTCAE (v4.0) toxicity grades for both laboratory and non-laboratory data.
The evaluation period should extend from date of first treatment until 90 days  from 
discontinuation of treatment or until resolution from all acute toxicities associated with the 
drug administration.
7.2 Definition of Adverse Event Terms
Adverse Event: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). [NIH Guidelines, January 
2001]
Serious Adverse Event (SAE): Any adverse drug experience occurring at any dose that results in 
any of the following outcomes: 
1
Death
2
A life-threatening adverse drug experience
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3
In-patient hospitalization or prolongation of existing hospitalization
4
Any persistent or significant disability/incapacity
5
A congenital anomaly/birth defect
6
Is a new cancer (that is not a condition of the study)
7
Is associated with an overdose
8
Is an other important medical event
9
Pregnancy
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
[21CFR312.32(a)].
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
“Serious” Versus “Severe” Adverse Events : There is a distinction between serious and severe 
AEs.  Assessment of seriousness will be made solely by the serious criteria listed above.  
Severity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse 
Events v4.0.  Therefore, serious events will not be automatically considered severe.  For 
example, a stroke that results in only a limited degree of disability may be considered a mild 
(not severe) stroke, but it would still meet serious criteria and thus, be captured as an SAE.  
Similarly, severe events may not always be serious.  An example would be an episode of severe, 
transient nausea which persists for several hours.  This would be classified as a “severe” 
episode of nausea, but if it did not require treatment, intervention, or somehow meet other 
serious criteria, it would not be considered an SAE.
Life-threatening Adverse Drug Experience : Any adverse drug experience that places the 
patient or subject, in the view of the investigator, at immediate risk of death from the reaction 
as it occurred, i.e. it does not include a reaction that, had it occurred in a more severe form, 
might have caused death. [21CFR312.32(a)]
Unexpected Adverse Drug Experience: Any adverse drug experience, the specificity or severity 
of which is not consistent with the current investigator brochure; or, if an investigator brochure 
is not required or available, the specificity or severity of which is not consistent with the risk 
information described in the general investigational plan.  “Unexpected” as used in this 
definition, refers to an adverse drug experience that has not been previously observed (e.g., 
included in the investigator brochure) rather than from the perspective of such experience not 
being anticipated from the pharmacological properties of the pharmaceutical 
product.[21CFR312.32(a)]
Laboratory test abnormalities: Laboratory abnormalities that constitute an Adverse event in 
their own right (are considered clinically significant, induce clinical signs or symptoms, require 
concomitant therapy or require changes in study treatment), should be recorded. Whenever 
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possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. Please note that a dose hold or medication for a lab abnormality may 
be required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for ≥1000 mg of pembrolizumab. No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, study treatment should be discontinued 
and the subject should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine 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 by the investigator 
within 24 hours to the Sponsor either by electronic media or paper.
7.3 Toxicity Grading
Toxicities will be graded according to the current version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0.  The full text of the NCI CTCAE is available 
online at: http://ctep.cancer.gov/forms/CTCAEv4.pdf
If a certain event or symptom is not described in the CTCAE grades, use the following grading 
scale:
Mild
Awareness of event, but easily tolerated
Moderate
Discomfort enough to cause some interference with usual activity
Severe
Inability to carry out usual activity
Very Severe
Debilitating, significantly incapacitates patient despite symptomatic 
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therapy
7.4 Toxicity Attribution
Assessment of attribution is made by consideration of all clinically relevant data prior to, 
during, and after occurrence of the event, including diagnostic tests to assess the cause of the 
event.  Clinically relevant data include, but are not limited to; underlying disease, past and 
present medical history (all concurrent non-malignant disease), concurrent medications, and 
timing between event and drug administration.  The mechanism of action and prior toxicology 
of the study drug should be considered.
An adverse event is associated with the use of the drug when there is a reasonable possibility 
that the experience may have been caused by the drug. [21CFR312.32(a)]
Attribution Standards per NCI – CTEP:
Unrelated
The Adverse Event is clearly not related to the investigational agent (s)
Unlikely
The Adverse Event is doubtfully related to the investigational agent(s)
Possible
The Adverse Event may be related to the investigational agent(s)
Probable
The Adverse Event is likely related to the investigational agent(s)
Definite
The Adverse Event is clearly related to the investigational agent(s)
7.5 Yale Principal Investigator Safety Reporting Requirements 
7.5.1 Expedited Reporting of Unexpected SAEs
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely attributed 
to drug administration, or SAEs whose frequency exceeds expectations, require expeditious 
handling and reporting.
The PIs will promptly investigate all safety information related to an adverse experience.  If the 
results of the PIs’ investigation show an adverse drug experience not initially determined to be 
reportable (based on whether the event is serious, unexpected, and associated with drug 
administration) is so reportable, the PIs will report such experience.  Follow-up information to a 
safety report shall be submitted as soon as the relevant information is available.
7.5.2 Reporting to the Yale Human Investigation Committee
All SAEs, whether originating at Yale or a collaborating center, meeting the criteria for 
expedited reporting will be reported to the Yale University Human Investigation Committee 
(HIC) using HIC Form 710 FR 4: Unanticipated Problem Involving Risks to Subjects or Others 
(UPIRSOs), including Adverse Events (AEs) Reporting Form as per IRB Policy 710.  
A copy of the IRB Policy 710 Reporting Unanticipated Problems Involving Risks to Subjects or 
Others, including Adverse Events is available at: 
http://www.yale.edu/hrpp/policies/documents/NewIRBPolicy710_UPIRSOSAE_4.3.2014_withfl
owchart_vF.PDF  
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7.5.3 Reporting to the Food and Drug Administration
This study will be conducted under an IND (Investigational New Drug application) that will be 
held by Yale University. The Principal Investigator will report in an expedited manner all SAEs 
meeting the criteria of “serious”, “unexpected” and “related to study treatment”.  Written 
safety reports will use a MedWatch Form 3500A.  A “fillable pdf” version with instructions is 
available at: http://www.fda.gov/medwatch/safety/FDA-3500A_Fillable_08-16-2006.pdf 
There are two types of expedited safety reports to the FDA:
1. 7-Calendar-Day FDA Telephone or Fax Report:  The sponsor-investigator will directly 
notify the FDA, within 7 calendar days after his initial receipt of the information, of any 
adverse event that is ALL of the following:
Death or immediately life-threatening
Unexpected
Associated with the use of MK-3475
Notification to the FDA will be made directly to the new drug review division in the Center for 
Drug Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever was responsible for the review of the IND. 
[21CFR312.32(c)] A written report of the event is to follow within 15 calendar days.
2. 15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly notify the 
FDA within 15 calendar days of any adverse event that is ALL of the following:
Serious(due to non-fatal and non-life threatening criteria
Unexpected
Associated with the use of MK-3475
Note:  Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report.
7.5.4 Reporting to Merck
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 (Investigator-Sponsor) and within two (2) working days to Merck 
Global Safety (GS). 
Non-serious Events of Interest will be forwarded to Merck GS 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 
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any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Investigator-Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck GS 
facsimile number:  +1-215-993-1220.
Additionally, investigators will report any pregnancy occurring in association with use of a 
Merck Product to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 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.
7.5.5 Duration of Reporting of SAEs
From the administration of first treatment until 90 days (unless otherwise specified) 
subsequent to last treatment or withdrawal of subject, new onset adverse events will be 
captured.  Follow-up and reporting of these events will follow the same procedure as for AEs 
observed during the study period.  In addition, any unexpected Serious Adverse Event that 
occurs more than 90 days after drug administration but is possibly, probably or definitely 
attributed to drug administration will be recorded and reported.  
7.6 Yale Safety Reporting and Monitoring (DSMP) 
The PIs and IND holders will monitor the clinical trial for safety.  The PIs will assess all expedited 
adverse events and will periodically review all adverse events observed on the trial.  Yale 
Cancer Center standard operating procedures (SOPs) for assessment and reporting of adverse 
events are followed which are in compliance with 21 CFR 312.32 and 312.22.
The clinical trial data consisting of all required observations, AEs, and laboratory data are 
entered into a computerized database in a timely manner.  The accuracy and completeness of 
the database, timely submission of SAEs and compliance with the protocol, is assured by 
periodic auditing conducted by the Yale Cancer Center Office of Protocol Review and 
Monitoring, which reports to the Yale Data and Safety Monitoring Committee (DSMC) 
Committee.  Safety data will be submitted to the DSMC at least once yearly or more often as 
required by the DSMP.  On a regular interval basis, status reports of all laboratory parameters, 
AEs and SAEs are reviewed by the PI to view composite data across subjects.  Regular meetings 
are held to discuss ongoing patient treatment and adverse events.  
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Expedited SAE reports submitted by the Investigator to FDA are also copied to the HIC and 
other relevant institutional safety committees within the timeframes required by Yale.  These 
are also copied to Merck.   The Principal Investigator will distribute manufacturer-provided 
safety reports and updated Toxicity Lists to the institution’s HIC and all relevant personnel 
involved in the conduct of the study.  The Toxicity List, in addition to the Investigator’s 
Brochure, will be used as a reference for reporting any new SAE.
Possible actions taken by the PIs or the Yale DSMC if a new unexpected toxicity is identified 
from the above safety review, or if the periodic review of all adverse events and laboratory data 
indicates a pattern of incidence or severity of toxicity that raises a safety concern, can be to:
1. Revise consent form
2. Amend the protocol
3. Suspend the protocol
All AEs found to be expected or non-serious, will be included in the Annual Report.
7.7   Pregnancies
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.  
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 Yale IRB, and within two (2) business days to 
Merck GS.  (Attn: Worldwide Product Safety; FAX 215 993-1220)
7.8 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days following 
cessation of treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, either by electronic media or paper.  
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Electronic reporting procedures can be found in the EDC data entry guidelines.  Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:

an overdose of Merck product, as defined in Section 7.2.1 – Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  

an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. 
7.9 Warnings and Precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated in 
the form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
8. PHARMACEUTICAL INFORMATION
Please see Investigators Brochure for details regarding the study drug.
8.1 MK-3475 Availability
MK-3475 is an investigational agent supplied to investigators by Merck.
8.2 Agent Accountability
Agent Inventory Records: The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from Merck. 
9. LABORATORY CORRELATIVE/SPECIAL STUDIES
9.1 Handling of Tissue
9.1.1
Collection and Shipment of Specimen(s):
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Before initiation of systemic therapy, local surgical therapy may be performed on the surgical 
lesion, and samples of brain tumor will be obtained. After tissue is obtained, it will be formalin 
fixed and embedded in paraffin. If sufficient tissue is available, a portion will be subjected to flash 
freezing in liquid nitrogen and SNAP frozen tissue will be stored for further studies.  If a patient 
has previously undergone local therapy to a brain lesion and tissue is available for analysis, 
paraffin-embedded tissue will be obtained from the sample.  A portion of the biopsy specimen 
will be used to conduct the studies mentioned in section 9.2.  For patients with NSCLC who do 
not have tissue from a brain lesion available, tissue from a systemic lesion will be used to perform 
the planned studies.  This tissue may include a FFPE specimen or SNAP frozen tissue.  Please see 
the Procedures Manual for tissue requirements and handling of tissue.
9.1.2 Site(s) Performing Correlative Study:
The stored tissue specimens will be analyzed at Yale University.  Please see Section 11 on 
Statistical Analysis for information on how results will be analyzed.  FFPE specimens will be 
analyzed for PD-L1 expression by a Merck assay for eligibility in the lung cohort.  
9.2
Correlative Studies
Correlative studies will be conducted on the pre-treatment tissue specimen.  PD-L1 positivity for 
study eligibility for the NSCLC cohort will be determined by Merck in a CLIA-certified laboratory 
on FFPE tissue.  A number of additional biomarkers will be studied for their potential predictive 
value in pre-treatment CNS specimens taken at the time of surgery or LITT and/or on tumor tissue 
from a systemic site. These exploratory studies include (but are not limited to):
1) Markers to be studied on tumor cells: B7H1, PDL2, B7H4, Galactin-9. 
 
2) Percent of tumor sample that constitutes CD4 and CD8 cells
3) Markers on T cells: LAG-3 on CD4 cells, PD1-H (PD-1 homologue) on T cells, CTLA4 on T cells
TIM3 on T cells
 
4) SALM 5 on neuronal cells will also be studied.
 
Patients who undergo surgical procedures (either of the CNS or peripheral) while on systemic 
treatment will also be asked to provide a research specimen to determine changes in the above 
markers in the context of response or resistance to therapy. 
Levels of all of the above markers will be measured by a method of Automated Quantitative 
Analysis (AQUA) of in situ protein levels in Dr. Kluger’s laboratory at Yale University. This method 
has been validated for epithelial cancers and melanoma, and has shown to be more precise than 
pathologist-based scoring of 3,3′-diaminobenzidine stain. AQUA is highly reproducible and 
quantitative, as reviewed 77.  Tumors will be stained with a number of fluorophores: A tumor 
mask for melanoma will be made using a cocktail of anti-S100 and anti-Melan-A, and for NSCLC 
the mask will be generated by anti-cytokeratin antibodies. The methods for masking tumor have 
been described in the literature78-80.  The mask will by conjugated to Cy-2, and will be 
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differentiated from the target antigen, which will be conjugated to Cy-5. Lymphocytes will be 
identified by the appropriate antigen conjugated to Cy-7.  After fluorescent staining is completed, 
images are taken at the different wavelengths, and the images will be analyzed using algorithms 
that have been extensively described 58. A monochromatic, high-resolution images of each 
histospot will be obtained using the 10× objective of an Olympus AX-51 epifluorescence 
microscope (Olympus) with automated microscope stage and digital image acquisition driven by 
a custom program and macrobased interfaces with IPLabs software (Scanalytics, Inc.). Tumor will 
be distinguished from stromal elements by the tumor mask signal.  The signal intensity of the 
target biomarker will be scored on a scale of 0-255 (the AQUA score). This will provide 
quantitative results. 
Biomarker analysis will be conducted using standard methods. Associations between continuous 
AQUA scores and binarized outcome variables (such as response) will be done by ANOVA. Cox 
univariate analysis will be used to study the associations between the survival endpoints and 
biomarker expression; Kaplan Meier curves will be generated to depict the association between 
binarized biomarker levels and survival endpoints. Multivariable models will be generated to 
predict response.
Immune monitoring will be performed as a part of this study.  Peripheral blood lymphocytes 
(PBLs) and plasma (approximately 40cc) will be collected before treatment, every 8 weeks on 
treatment, and when patients come off of study. Peripheral blood mononuclear cells will be 
separated and cryopreserved for T and B cell studies. Samples will be stored for future 
immunophenotyping studies and serological profiling to be conducted by Dr. Dhodapkar’s 
laboratory, as well as cytokine profiling at the Yale Immune Monitoring Core Facility.  
10. MEASUREMENT OF RESPONSE
Response will be evaluated after 8 weeks of systemic therapy and then every 8 weeks thereafter.  
The purpose of the 4 week scans is to determine safety. If symptoms develop or clinical 
deterioration occurs, patients may be imaged prior to the pre-specified time points for imaging. 
All responses must be confirmed by repeat imaging at least 4 weeks following initial 
documentation of objective response.
10.1
Brain Metastases Response Assessment 
RECIST criteria v1.1 will be modified to account for differences in measuring the response of 
clinically evaluable brain lesions as opposed to systemic lesions (modified RECIST, or mRECIST).  
Size is considered the tumor’s largest diameter.  Measurements from multiple lesions are 
summed to calculate the sum of the diameters (SD). The SD calculated on a baseline scan 
performed within 28 days of study drug initiation will be used as a reference to determine the 
objective response of the clinically evaluable lesions.  All responses must be confirmed at 4 weeks 
with an equivalent or better response.  Please refer to the original RECIST criteria if further 
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reference is necessary. Please see section 5.2 for response assessment in patients requiring local 
therapy while on study.
Measurable disease 
Specification of a minimal lesion diameter for measurable lesions reduces the potential for 
variation in the measurement of smaller lesions due to slice selection and volume averaging. The 
minimal lesion diameter should be greater than or equal to 2 times the section thickness and a 
minimum of 5mm. A previously irradiated lesion will not be measured as a target lesion unless it 
is documented to have progressed since treatment.
Nonmeasurable disease
Nonmeasurable lesions at baseline are important in clinical trials because tumor progression may 
occur at these sites. Nonmeasurable lesions include enhancing lesions that are less than the 
specified smallest measurable diameter (5mm when slice thickness is 2.5mm or twice the slice 
thickness), hemorrhagic or predominantly cystic or necrotic lesions that are difficult to accurately 
measure and track, and lesions that are indeterminate for metastatic disease. Intrinsic T1-
hyperintensity is noted within hemorrhagic lesions that may be misinterpreted as enhancing 
tumor, and for this reason, the precontrast T1-weighted image must be examined at baseline to 
prevent this error. Nonmeasurable lesions should be briefly described on the imaging case report 
form for each study.81
RECIST 1.1 limits the number of lesions measured to 5 in total, with 2 per organ.  For our 
purposes, even if there are multiple measurable lesions in the brain, the sum of diameters of up 
to a maximum of 5 of the largest lesions will be considered for response assessment.            
Modified response criteria for brain metastases
Complete Response (CR): Disappearance of all target lesions.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum recorded since the treatment started or the appearance of one or 
more new lesions  (new lesions must be greater than slice thickness). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters since the treatment started.
Please refer to RECIST v1.1 for additional details regarding response criteria.
                                          
10.2 Systemic Disease Response Assessment 
Response of all systemic, non-cerebral metastases will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
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Committee v1.1.  Version 1.1 stipulates that the number of lesions required to assess tumor 
burden for response determination has been reduced to a maximum of five total lesions (two 
lesions maximum per organ).  
Briefly, measurable lesions must have a minimum size of 10 mm by CT scan (CT scan slice 
thickness no greater than 5 mm) in at least one dimension. Lesions with a longest diameter of 
<10 mm are considered non measurable lesions and will be tracked as non-target disease. Tumor 
lesions in a previously irradiated area, or in an area subject to other loco-regional therapy, are 
not considered measurable unless there has been demonstrated progression in the lesion. For 
complete definitions of measurable and non-measurable disease, please refer to the RECIST v1.1 
criteria.
10.3 Evaluation of Best Overall Response 
The Best Overall Response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.  The best 
response will take into consideration both the clinically evaluable brain metastases and 
systemic metastases, and therefore will include measurements from both mRECIST criteria (in 
the brain) and RECIST criteria (in the body) as follows:  
Complete Response (CR): Disappearance of all target lesions in the brain and systemic disease.
Partial Response (PR): Partial response in both the brain and the systemic disease, or if there is 
PR at one site and SD at the other, the sum of diameters from the brain and systemic disease 
will be added and the best overall response will be considered PR if there is at least a 30% 
decrease, taking as reference the baseline sum diameters.
Progressive Disease (PD): Progressive disease in either the brain or the systemic disease will 
qualify as PD as the best overall response. 
Stable Disease (SD): Stable disease in both the brain and systemic disease, or if the sum of 
diameters from the brain and systemic disease does not qualify for PR or PD (at least a 20% 
increase in the sum of diameters of target lesions), taking as reference the smallest sum 
diameters since the treatment started.
10.4 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time that 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. Please note that objective 
documentation implies confirmation of response by imaging. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
10.5
Progression-Free Survival (PFS)
PFS is defined as the time from initiation of study drug until the first documented, confirmed 
progression of clinically evaluable brain metastases based on mRECIST criteria, systemic disease 
based on RECIST criteria, or death.  If there is progression of disease that is then confirmed on a 
follow up scan at least 4 weeks later, the initial date of documented progression should be used 
in the PFS analysis.
10.6
Response Review
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion. Simultaneous review of the patients’ files and radiological images is the best 
approach. 
11. STATISTICAL CONSIDERATIONS
11.1 Study Design/Sample Size Justification
This two-arm, phase II study will enroll patients with melanoma or NSCLC who have untreated 
brain metastases.  Subjects with melanoma must have at least 1 brain lesion that requires 
immediate local therapy that is amenable to surgical resection or LITT, and at least 1 brain lesion 
that does not require immediate local therapy and can be assessed for response. In certain 
situations, one lesion can be biopsied and then assessed for response.  Subjects with NSCLC are 
only required to have at least 1 brain lesion that does not require immediate local therapy and 
can be assessed for response.  Subjects will undergo local therapy to 1 or more brain metastases 
(required for subjects with melanoma, optional for those with NSCLC), followed by treatment 
with MK-3475.  
The primary goal of this study is to determine the efficacy of MK-3475 in patients with untreated 
brain metastases from melanoma or NSCLC.  The primary endpoint is the brain metastasis 
response rate (BMRR).  A drug with minimal activity would be expected to have a BMRR of 10%. 
Alternatively, MK-3475 will be considered worthy of further study in patients with untreated 
brain metastases if its true BMRR is similar to the systemic response rate with MK-3475 which is 
38% for melanoma and 25% for NSCLC. 48 and internal data.
  
Power and Sample Size
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Melanoma Arm
The melanoma arm will enroll a minimum of 8 subjects.  If at least one of the first 8 has a brain 
metastasis response, a sequential monitoring procedure will be used to evaluate efficacy and 
futility simultaneously, based on the number of subjects with a confirmed or unconfirmed 
response according to the rules outlined in Figure 1, Table 8 and Table 9.   Only patients who 
remain on treatment for at least 12 weeks will be considered evaluable for the futility analysis.  
Accrual will not be suspended during the interim evaluation. Subsequent decisions for pursuing 
future interim evaluations will be based on the boundaries identified by the sequential 
monitoring procedure.  We will enroll an approximate maximum of 20 subjects in this arm.  
With an approximate maximum of 20 subjects enrolled, we will have 86% power to demonstrate 
that the best brain metastasis response rate exceeds 10% at an overall one-sided 10% alpha-
level, if the true best brain metastasis response rate is 38%.  The calculation is based on the 
binomialSPRT function in the gsDesign package. 
For the final analysis, the response assessment will be based on confirmed best brain metastasis 
response rate.  The adjusted p-value and repeated confidence interval will be computed using 
sequential methods outlined by Jennison and Turnbull (2000).   The minimum criterion for 
success is that the lower bound of the repeated CI > 10%. Given the null hypothesis underlying 
the true rate, this may occur when at least 6/20 subjects develop a confirmed brain metastasis 
response.  
If the efficacy boundary is crossed at any time during the trial, enrollment may still continue to 
20 subjects and subsequent trial planning may be initiated.
Operating characteristics are shown in Table 10.
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Figure 1. Sequential Monitoring Rules for Efficacy and Futility in Melanoma Arm
Table 8.  Decision Rules based on Efficacy Bounds for Melanoma Arm
Monitoring Point (# subjects)
Minimum # Responders to 
Determine Efficacy
 
8
3
 
9-12
4
13-17
5
18-20
6
Table 9. Decision Rules based on Futility Bounds for Melanoma Arm
Monitoring Point (# subjects)
Maximum # subjects w/ response to 
declare Futility
8
0
9-13
1
14-17
2
18-20
3
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Table 10. Operating Characteristics of Sequential Monitoring Approach for Melanoma Arm
True RR
Probability of 
Declaring 
Futility
Probability of 
Go at end of 
Study
Average 
Sample Size
10%
0.93
0.05
10.3
15%
0.79
0.16
12.3
20%
0.61
0.32
14.3
25%
0.43
0.50
16.1
30%
0.27
0.66
17.4
35%
0.16
0.80
18.4
40%
0.09
0.89
19.1
45%
0.05
0.94
19.5
50%
0.02
0.97
19.7
Non-Small Cell Lung Cancer Arm
Cohort 1:
The non-small cell lung cancer arm will enroll a minimum of 18 patients into Cohort 1.  Following 
the time that the first 18 subjects have had at least 2 brain metastasis responders, a sequential 
monitoring procedure will be used to evaluate for efficacy and futility simultaneously, based on 
the number of subjects with a confirmed or unconfirmed brain metastasis response according to 
the rules outlined in Figure 2, Table 10, and Table 11. Only patients who remain on treatment for 
at least 12 weeks will be considered evaluable for the futility analysis.  Accrual will not be 
suspended during the interim evaluation. Subsequent decisions for pausing enrollment and 
pursuing future evaluations will be based on the boundaries identified by the sequential 
monitoring procedure.  A maximum of 44 subjects will be enrolled in this arm.  
With a maximum of 44 patients enrolled in Cohort 1, we will have approximately 80% power to 
demonstrate that the best brain metastasis response rate exceeds 10% at an overall one-sided 
10% alpha-level, if the true best brain metastasis response rate is 25%.  The calculation is based 
on the binomialSPRT function in the gsDesign package. 
For the final analysis, the response assessment will be based on confirmed best brain metastasis 
response rate.  The adjusted p-value and repeated confidence interval will be computed using 
sequential methods outlined by Jennison and Turnbull (2000).   The minimum criterion for 
success is that the lower bound of the repeated CI > 10%. Given the null hypothesis underlying 
the true rate, this may occur when at least 10/44 subjects develop a confirmed response. 
If the efficacy boundary is crossed at any time during the trial, enrollment may still continue to 
44 subjects and subsequent trial planning may be initiated.
Operating characteristics are shown in Table 13.
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Cohort 2:
A maximum of 10 patients with NSCLC will be enrolled in Cohort 2.  These patients will meet the 
same eligibility requirements as other NSCLC patients, except for the following: they will be 
required to have had at least 1 prior platinum-based systemic therapy, and they must either be 
negative or unevaluable for PD-L1 expression.  The response rate with MK-3475 in PD-L1 negative 
patients in a previous trial is 9%, however the efficacy in brain metastases is unknown.  Therefore 
this cohort will be exploratory in nature.
Figure 2. Sequential Monitoring Rules for Efficacy and Futility in NSCLC Arm
Table 11.  Decision Rules based on Efficacy Bounds for NSCLC Arm
Monitoring Point (# subjects)
Minimum # Responders to 
Determine Efficacy
 
10-12
4
13-18
5
 
19-24
6
25-30
7
31-36
8
37-42
9
43-44
10
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Table 12. Decision Rules based on Futility Bounds for NSCLC Arm
Monitoring Point (# subjects)
Maximum # subjects w/ response to 
declare Futility
                       10-14
0
15-20
1
21-26
2
27-32
3
33-38
4
39-44
5
Table 13. Operating Characteristics of Sequential Monitoring Approach for NSCLC Arm
True RR
Probability of 
Declaring Futility
Probability of Go 
at end of Study
Average 
Sample Size
10%
0.87
0.05
24.9
15%
0.58
0.25
32.2
20%
0.29
0.55
38.1
25%
0.12
0.80
41.5
30%
0.04
0.93
43.1
35%
0.01
0.98
43.7
11.2 Analytic Plan for Primary Objectives:  
We will use mRECIST criteria to determine brain metastasis response rate (BMRR). The 
proportion of patients with a brain metastasis response in the clinically evaluable lesion(s) will 
be calculated along with a 95% confidence interval.  
11.3 Analytic Plan for Secondary Objectives:
(1) Best overall response rate (ORR) is defined as the percentage of patients who experience 
a CR or PR in any metastases (clinically evaluable cerebral or systemic) as determined by 
mRECIST criteria in the brain or RECIST criteria in the body. The proportion of patients 
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with an ORR will be calculated with a 95% confidence interval.  A similar analysis will be 
performed using ir-mRECIST and ir-RECIST.
(2) B7-H1 (PD-L1) expression and other potential biomarkers will be correlated to clinical 
endpoints.  Exploratory, hypothesis-generating analyses will be performed.
(3) Progression-free survival will be calculated as the time from start of MK-3475 to 
progression (using mRECIST criteria for brain lesions and RECIST criteria for systemic 
disease) or death.  Overall survival will be calculated as the time from start of MK-3475 to 
death.  Patients who do not meet the endpoint will be censored at the date of last follow-
up.  PFS and OS will be determined separate for each arm and median survival will be 
estimated by using Kaplan-Meier methodology 
(4) Safety and toxicity will be assessed using CTC v4.0 criteria.  All participants who receive 
any amount of study drug will be evaluable for toxicity.
11.4
 Reporting and Exclusions
11.4.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with MK-3475.
11.4.2 Evaluation of response.  All patients included in the study must be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are ineligible.  Each 
patient will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Treatment response includes categories 1 and 2 (complete and partial response). Patients in 
response categories 4-9 should be considered to have a treatment failure (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
Conclusions will be based on all eligible patients.  Sub analyses may then be performed on the 
basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these sub analyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals will also be provided. 
11.5
Accrual Rate and Study Duration
The plan is to enroll 74 patients total: 20 with melanoma, 44 with NSCLC in Cohort 1, and 10 with 
NSCLC in Cohort 2.   The first interim analysis will be after 8 patients on the melanoma arm, 18 
with NSCLC on the NSCLC arm. Our estimated rate of accrual based on current volume and 
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referral patterns is approximately 4 melanoma patients, 8 NSCLC patients with brain metastases 
at our institution monthly. Assuming a conservative 50% eligibility rate (based on the relatively 
high likelihood of screen failures) for the melanoma arm, the overall anticipated time of accrual 
is approximately 18 months. The eligibility rate for the NSCLC arm will be approximately 20%; 
accrual will take approximately 36 months.
APPENDIX A
Performance Status Criteria
ECOG Performance Status Scale
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Grade
Descriptions
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
5
Dead.
                                                                       
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