Clinical trial NCT02407171
Conditions: Melanoma Lung Cancer
Sponsor: Yale University
Start date: 2015-04-01; Completion date: 2019-02-19
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 until they exhibit progression of disease. At this point (when patients have demonstrated progression of disease) a single target lesion will be selected and treated with SBRT, and then MK-3475 will be restarted and continued until there is further progression of disease. The first phase of the study is a radiation dose escalation with a constant dose of MK-3475. The second part of the study includes expansion cohorts of NSCLC and melanoma patients.

Detailed description:
The phase 1b portion of the trial is a radiation dose escalation study to determine the maximum tolerated dose (MTD) of SBRT when given to patients previously and subsequently exposed to MK-3475. Because the class of PD-1 inhibitory antibodies conveys a risk of pneumonitis, there will be two parallel dose escalation arms- Arm A will include SBRT targets in the lung parenchyma, and Arm B will be limited to targets outside the lung parenchyma. Each arm will be separately escalated, and two MTDs will be determined. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued.

The phase 2a portion of the study includes 2 expansion cohorts, for melanoma and NSCLC, with SBRT delivered at the MTD. The primary endpoint of this phase of the study is the overall response rate to post-SBRT MK-3475. Secondary endpoints include determining the time to progression, overall survival, and exploratory biomarkers.

IND exempt per FDA.

Inclusion/Exclusion Criteria Updated 4/7/2016

Arms: arm 1: Dose escalation cohort for patients with Non Small Cell Lung Cancer (NSCLC). The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. arm 2: Dose escalation cohort for non lung cancer patients. The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and SBRT to that site will be discontinued. arm 3: Phase 2a expansion cohort for patients with melanoma. Patients will be treated at the maximum tolerated dose discovered in phase I. arm 4: Phase 2a expansion cohort for patients with NSCLC. Patients will be treated at the maximum tolerated dose discovered in phase I.
Interventions: intervention 1: MK-3475 intervention 2: Stereotactic Body Radiation Therapy (SBRT)
Intervention descriptions: intervention 1: 200 mg every 2 weeks by IV infusion intervention 2: The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort (3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single fraction).

Protocol documents:
Prot_SAP_000.pdf: 
Title: Evaluating the Combination of MK-3475 and Sterotactic 
Body Radiotherapy in Patients With Metastatic Melanoma or 
NSCLC 
Date: 11/12/2020 
ClinicalTrials.gov ID: NCT02407171 
Document: Protocol and SAP 


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TITLE:
A Phase I/II trial of Evaluating the Combination of MK-3475 and 
Stereotactic Body Radiotherapy in Patients with Metastatic Melanoma or NSCLC
SPONSOR:
Yale Cancer Center
FUNDING SOURCE: Yale Cancer Center, Merck and Co., Inc. 
DATE:
December 9, 2019
PRINCIPAL INVESTIGATOR:
Roy H. Decker, M.D., PhD 
Department of Therapeutic Radiology 
Yale Cancer Center
PO Box 208040
New Haven, CT 06520 – 8040
Tel: (203) 737-2758
Fax: (203) 785-4622
roy.decker@yale.edu
CO- INVESTIGATORS:
Harriet Kluger, M.D.
Section of Medical Oncology, 
Yale Cancer Center
333 Cedar Street, FMP114 
New Haven, CT 06520 
Tel: (203) 785-6221
Fax: (203) 785 3788
Harriet.Kluger@Yale.edu
Scott Gettinger, M.D.
Section of Medical Oncology, 
Yale Cancer Center
333 Cedar Street, FMP127 
New Haven, CT 06520 
Tel: (203) 785-6221
Fax: (203) 785 3788
Scott.Gettinger@Yale.edu
STATISTICIAN:
Xiaopan Yao, PhD
Section of Medical Oncology 
Yale Cancer Center
60 College Street
New Haven, CT 06510 
(203) 737-4856
SUB-INVESTIGATORS:
Anne Chiang, M.D. 
Sarah Goldberg, M.D. 
Roy Herbst, M.D. 
Zain Husain, M.D.
Rogerio Lilenbaum, M.D. 
Mario Sznol, M.D. 
Michael Hurwitz, M.D.
Henry Park, M.DSarah Weiss, M.D. 
Marianne Davies, A.P.R.N.
Emily Duffield, A.P.R.N. 
Vanna Dest, A.P.R.N. 
Kristen Crowley, A.P.R.N. 
Lauren Cardone, A.P.R.N
PROTOCOL COORDINATOR:
Jennifer Pope, CCRP
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Protocol Revision History:
Amendment Number
Date
Original
17-Jul-2014
Amendment 1
23-Jul-2015
Amendment 2
12-Nov-2015
Amendment 3
12-April-2016
Amendment 4
29-July-2016
Amendment 5
16-Aug-2017
Amendment 6
09-Dec-2019
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY ....................................................................................................5
2.0
TRIAL DESIGN ..........................................................................................................5
2.1
TRIAL DESIGN .........................................................................................................................................5
2.2
TRIAL SCHEMA........................................................................................................................................7
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).....................................................................8
3.1
PRIMARY OBJECTIVES ..........................................................................................................................8
3.2
SECONDARY OBJECTIVES....................................................................................................................8
4.0
BACKGROUND & RATIONALE.............................................................................8
4.1
MELANOMA..............................................................................................................................................8
4.2
NON-SMALL CELL LUNG CANCER (NSCLC)..............................................................9
4.3
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND OF MK-3475 ..........................9
4.4
SBRT........................................................................................................................10
4.5
RADIATION AND THE IMMUNE RESPONSE...................................................................................11
4.6
RATIONALE ............................................................................................................................................12
5.0
METHODOLOGY.....................................................................................................14
5.1
ENTRY CRITERIA..................................................................................................................................14
5.2
TRIAL TREATMENT PLAN..................................................................................................................16
5.2.1
Study Design ........................................................................................................17
5.2.2
MK-3475 Dose and Dose Modification...............................................................18
5.2.3
Stereotactic Body Radiation Therapy (SBRT) .....................................................20
5.3
SBRT DOSE-ESCALATION OR DE-ESCALATION.......................................................................22
5.4
CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) ..............24
5.5
RESCUE MEDICATIONS & SUPPORTIVE CARE ...........................................................................25
5.6
OTHER CONSIDERATIONS .................................................................................................................29
5.7
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA .........................................................30
5.8
SUBJECT REPLACEMENT STRATEGY .............................................................................................30
5.9
CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION..........................................................31
6.0
STUDY CALENDAR ................................................................................................32
7.0
TRIAL PROCEDURES ............................................................................................36
7.1
TRIAL PROCEDURES............................................................................................................................36
7.2
SCREENING VISIT.................................................................................................................................36
7.3
ON-STUDY VISITS................................................................................................................................36
7.4
POST-STUDY VISITS............................................................................................................................37
7.5
TUMOR IMAGING..................................................................................................................................38
7.6
STUDY ASSESSMENTS ........................................................................................................................38
8.0
ADVERSE EVENT REPORTING...........................................................................41
8.1
DEFINITIONS ..........................................................................................................................................41
8.2
ATTRIBUTION ........................................................................................................................................43
8.3
REPORTING TO MERCK ......................................................................................................................44
8.4
REPORTING TO THE FOOD AND DRUG ADMINISTRATION ......................................................45
8.5
REPORTING TO YALE HUMAN INVESTIGATION COMMITTEE ...............................................46
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8.6
YALE SAFETY REPORTING AND MONITORING (DSMP).............................................46
9.0
STATISTICAL ANALYSIS PLAN..........................................................................47
10.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................48
10.1
INVESTIGATIONAL PRODUCT ...........................................................................................................48
10.2
PACKAGING AND LABELING INFORMATION ...............................................................................49
10.3
CLINICAL SUPPLIES DISCLOSURE...................................................................................................49
10.4
STORAGE AND HANDLING REQUIREMENTS................................................................................49
10.5
RETURNS AND RECONCILIATION....................................................................................................49
11.0
LABORATORY CORRELATIVE/SPECIAL STUDIES......................................50
11.1
HANDLING OF TISSUE.........................................................................................................................50
11.2
CORRELATIVE STUDIES .....................................................................................................................50
12.0
MEASUREMENT OF RESPONSE .........................................................................50
12.1
EVALUATION OF BEST OVERALL RESPONSE..............................................................................51
12.2
PROGRESSION-FREE AND OVERALL SURVIVAL ........................................................................51
12.3
LOCAL CONTROL .................................................................................................................................51
13.0
ADMINISTRATIVE AND REGULATORY DETAILS........................................51
14.0
LIST OF REFERENCES ..........................................................................................52
15.0
APPENDICES............................................................................................................56
15.1
ECOG PERFORMANCE STATUS ......................................................................................................56
15.2
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE).............56
15.3
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 CRITERIA FOR
EVALUATING RESPONSE IN SOLID TUMORS ..............................................................................................56
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-3475 and SBRT in Metastatic Melanoma and NSCLC
Trial Phase
Phase 1b / 2a
Clinical Indication
Patients with metastatic melanoma or NSCLC, with at least 2 measurable 
lesions
Trial Type
This is a phase 1b dose escalation of SBRT, given in combination with 
MK-3475 at a constant dose of 200 mg every 3 weeks (+/- 7 days). There 
is then a phase 2a expansion with an NSCLC cohort
Route of administration
MK-3475 is intravenous, every 3 weeks (+/- 7 days)
Treatment Groups
Phase 1b: dose escalation cohorts based on anatomic site of the SBRT 
target (lung and non-lung).
Phase 2a: expansion cohort of patients with NSCLC
Number of trial subjects
Maximum of 60 to complete SBRT
Estimated duration of trial
2 years
Estimated average length of 
treatment per patient
Approximately 1 year
2.0 TRIAL DESIGN
2.1
Trial Design
This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy 
(SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who 
progress on this antibody. Patients with metastatic melanoma and NSCLC will be enrolled 
after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously 
untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 
until they exhibit progression of disease (as defined in section 5.2.1). At this point (when 
patients have demonstrated progression of disease) a single target lesion will be selected and 
treated with SBRT, and then MK-3475 will be restarted and continued until there is further 
progression of disease. The first phase of the study is a radiation dose escalation with a constant 
dose of MK-3475. The second part of the study includes an expansion cohort of NSCLC 
patients.
The phase 1b portion of the trial is a radiation dose escalation study to determine the maximum 
tolerated dose (MTD) of SBRT when given to patients previously and subsequently exposed 
to anti-PD-1 therapy, including MK-3475. Because the class of PD-1 inhibitory antibodies 
conveys a risk of pneumonitis, there will be two parallel dose escalation arms- Arm A will 
include SBRT targets in the lung parenchyma, and Arm B will be limited to targets outside the 
lung parenchyma. Each arm will be separately escalated, and two MTDs will be determined. 
The starting dose will be 3000 cGy in 5 fractions; there will be one dose escalation cohort 
(3000 cGy in 3 fractions), and if necessary one dose de-escalation cohort (1000 cGy in a single 
fraction). If there is dose-limiting toxicity at the lowest cohort, that arm will be closed and 
SBRT to that site will be discontinued.
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The phase 2a portion of the study includes an expansion cohort for NSCLC, with SBRT 
delivered at the MTD. The primary endpoint of this phase of the study is the overall response 
rate to post-SBRT MK-3475. Secondary endpoints include determining the time to 
progression, overall survival, and exploratory biomarkers.
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Progression of Disease
Phase 1b
SBRT to a single lesion
Arm A: dose escalation for lung targets
Arm B: dose escalation for non-lung targets
MK-3475 200 mg every 3 weeks
re-staging per the study calendar until progression
Progression of Disease
OR unacceptable treatment-related toxicity 
OR 1 year
Arm A:
Patients with NSCLC, no prior PD-1 therapy
Arm B:
Patients with Melanoma, 
or NSCLC, Previously 
treated, with irPD
Phase 2a
Progression of Disease
SBRT to a single lesion (at MTD)
MK-3475 200 mg every 3 weeks
re-staging per the study calendar until progression
Progression of Disease
OR unacceptable treatment-related toxicity 
OR 1 year
2.2
Trial Schema
Off study, post-treatment assessment
MK-3475 200 mg every 3 weeks
re-staging per the study calendar until progression
Off study, post-treatment assessment
,
Patients with Melanoma, or
NSCLC, Previously treated, 
with irPD
MK-3475 200 mg every 3 weeks 
re-staging every 6 weeks
until progression
Patients with NSCLC, no prior PD-1 therapy
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3.0 OBJECTIVE(S) & HYPOTHESIS(-ES)
The hypothesis is that SBRT might induce a systemic response to MK-3475 in patients who 
have previously progressed, by enhancing the host immune response. The overall objective of 
the phase 1b component is to determine a safe dose of SBRT in the lung and other organs, 
when given with MK-3475. In the phase 2a component, it is to determine whether SBRT can 
induce a response to MK-3475 in patients who have previously progressed on the antibody.
3.1
Primary Objectives
The primary objective of the phase 1b portion of the trial is to determine the MTD of SBRT 
to lung (Arm A) and non-lung (Arm B) targets in patients receiving MK-3475.
The primary objective of the phase 2a portion is to determine the overall response rate to 
post-radiation MK-3475, in patients whose disease had previously progressed on MK-3475 
or another anti-PD-1 therapy.
3.2
Secondary Objectives
(1) To determine the local control of SBRT, when SBRT is given with MK-3475
(2) To determine the time to progression in patients receiving post-radiation MK-3475, in 
patients whose disease had previously progressed on MK-3475 or another anti-PD-1 
therapy.
(3) To determine the progression-free and overall survival in patients receiving MK-3475, 
who receive SBRT
(4) To determine the safety and toxicity of the combination of SBRT and MK-3475
(5) To examine potential predictive biomarkers in tumor samples and peripheral blood in 
patients treated with MK-3475 and SBRT.
4.0 BACKGROUND & RATIONALE
4.1
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 metastasizes[3], 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
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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. 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 observed[9]. 
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 dacarbazine[10]. Based on these studies, vemurafenib was recently 
FDA approved for metastatic melanoma.
The FDA granted accelerated approval to MK-3475 on September 4, 2014 for treatment of 
patients with advanced or unresectable melanoma. It is intended for use following treatment 
with Ipilimumab, and after Ipilimumab and a BRAF inhibitor in patients with BRAF V600E 
mutation.
4.2
Non-Small Cell Lung Cancer (NSCLC)
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 year[1]. 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, 
respectively[11]. 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%.
4.3
Pharmaceutical and Therapeutic Background of MK-3475
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades[12]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies[13-17]. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors.
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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)[18, 19]. The 
structure of murine PD-1 has been resolved[20]. 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[18, 21-23]. 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[24, 25]. 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[26, 27]. Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells[28]. 
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[24, 29- 
31]. 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[24]. 
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated 
to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor- 
specific T-cell expansion in subjects with melanoma (MEL)[32]. This suggests that the PD- 
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as 
an attractive target for therapeutic intervention.
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.
For further preclinical and clinical trial data, refer to the investigator’s brochure.
4.4
SBRT
Stereotactic body radiation therapy (SBRT) is a technique that has become increasingly used 
over the past decade. In contrast to conventionally fractionated radiation therapy, which uses 
daily fractions of 1.8 to 2 Gy per day over the course of 30 or more fractions, an SBRT
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treatment plan typically delivers 30 to 60 Gy over 3 to 8 fractions. This results in a much higher 
biologically effective dose than is possible with conventionally fractionated radiation, and 
requires a high degree of precision to avoid delivering the increased dose to the surrounding 
tissue. This necessitates the use of advanced simulation techniques that capture the internal 
motion of tumors, reliable patient immobilization, and modern radiation treatment devices with 
on-board imaging capability. SBRT conveys a markedly higher rate of local control and 
survival, and markedly lower toxicity, when compared to conventional radiotherapy. The 
majority of the prospective experience using this technology has been for the curative treatment 
of early-stage NSCLC in patients who are at high surgical risk. In this cohort, trials demonstrate 
that local control after SBRT is in excess of 90%, in comparison to external beam radiation 
where the expectation is 40 to 50%[33].
The use of SBRT in patients with metastatic disease has been evaluated in several prospective 
a retrospective studies, primarily directed at oligometastatic lesions in the lung and liver but 
also including targets in bone and soft tissue. A prospective study of SBRT in 38 patients with 
1 to 3 pulmonary metastases reported 96% local control of the radiated metastases at 2 years, 
with low toxicity (8% grade 3, and no grade 4 or 5) using doses of 48 to 60 Gy in 3 
fractions[34]. The risk of grade 3 pneumonitis in this study was 2.6%, particularly low 
considering the relatively high dose, and the use of SBRT to treat multiple targets 
simultaneously. This is consistent with a large body of retrospective data; a review compiling 
the data from more than 250 patients in more than a dozen series suggests that grade 3 or 
greater toxicity is between 0 and 14%, and grade 3 or greater pneumonitis is between 0 and 
6% when patients are treated with SBRT to lung lesions, at doses in the range of 40 to 60 
Gy[35].
The risk of radiation pneumonitis following SBRT is not only low but also predictable using 
accepted dose and volume metrics during treatment planning. In a group of 143 patients treated 
with SBRT to a median dose was 60 Gy in 3 fractions, the volume of lung receiving 20 Gy or 
greater (V20) was established to significantly predict the risk of pneumonitis. Radiation 
pneumonitis (Grade 2-4) occurred in 9.4% of all cases, but only 4.3% of patients with a V20 ≤ 
4%. In our own institutional experience of 350 patients treated to 50 to 60 Gy, with more than 
one year of follow-up, the overall rate of acute Grade 3 or greater pneumonitis was 4.8%; V20 
was predictive. The proposed doses in the present study are significantly lower, and based on 
standard regimens and following more conservative dose constraints.
4.5
Radiation and the Immune Response
For many years, there have been case reports of patients with metastatic disease who receive 
radiation to a target site, and subsequently have a partial or complete response of unirradiated 
metastatic sites. This so-called “abscopal effect” has been clinically observe in multiple tumor 
types, in patients who did not receive any systemic therapy[36, 37] and may be due to the 
activation of the activation of the host immune response to the tumor. This is supported by the 
observation that radiation induces a local inflammatory response, and that after radiation anti- 
tumor antibodies are observed in patient peripheral blood[38]. The abscopal effect has also 
been observed in patient receiving anti-CTLA4 antibody, in both NSCLC and melanoma[39, 
40]. Beyond case reports, this interaction has not been documented in a prospective study, and 
the details of the mechanism are unclear.
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4.6
Rationale
Rationale for the Trial and Selected Subject Population
Immunotherapy is an area of active interest in both melanoma and NSCLC. Although clinical 
trials are ongoing in both diseases with MK-3475 and demonstrate promisingly long survival, 
the response is not uniform within the populations. In patients unselected for PD-L1 
expression, approximately 40% of patients with melanoma and 20% of patients with NSCLC 
will respond to therapy. While PD-L1 expression appears to predict response in both 
populations, some PD-L1 positive patients will not respond and some PD-L1 negative patients 
will respond. A number of studies have shown that PD-L1 may be induced after drug treatment, 
and that expression is correlated to lymphocytic infiltrate in melanoma patients. The latter has 
been observed to increase after radiation therapy, suggesting a mechanism by which radiation 
might make some patients more responsive to PD-1 antibodies. We propose to treat patients 
with metastatic NSCLC or melanoma without regard to PD-L1 expression, to determine 
whether the use of radiation may sensitize otherwise non-responsive patients to therapy, and 
to determine whether these patients subsequently express PD-L1 on specimens obtained after 
radiation.
Rationale for Dose Selection/Regimen/Modification
Prospective and retrospective studies suggest that the use of SBRT for patients with 
oligometastatic disease is associated with a low risk of significant toxicities, at doses as high 
as 60 Gy in 3 fractions (A biologically effective dose (BED) of 180 Gy). Lower doses appear 
to result in similar local control in this population, with equivalent overall survival. Because 
the risk of significant radiation-related toxicity to organs at risk is relatively predictable using 
accepted radiation dose and volume limits, the use of a lower SBRT dose will minimize the 
expected risk of treatment while simultaneously allowing the inclusion of moderately larger 
tumors, as well as those in closer proximity to critical normal organs.
The proposed starting SBRT dose of 30 Gy in 5 fractions (BED = 48) is a widely used regimen 
in patients with melanoma first reported by this institution in 1976[41], and adopted in several 
prospective trials since then[42]. Our institutional experience is that this is associated with 
excellent local control and low toxicity when used in small to moderate sized melanoma 
metastases, in patients receiving concurrent anti-CTLA4 antibodies – in 12 melanoma patients 
treated with a BED of 48 Gy with concurrent ipilumimab, none had progression of disease at 
the treated site. The dose de-escalation cohort of 10 Gy in 1 fraction (BED = 20) is one of 
several standard palliative doses, associated with negligible toxicity when used as single agent 
in a wide variety of body sites, in patients with metastatic disease who have been heavily pre- 
treated[43]. This schedule was chosen because a single large fraction has been demonstrated 
to have the largest ablative and immunologic potential. The dose escalation cohort of 30 Gy in 
3 fractions (BED = 60) is a common, conservative SBRT dose used in liver, lung, and spine 
treatment, and associated with a low risk of toxicity.
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Rationale for Biomarker Research
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 not 
entirely clear[44]. In NSCLC there appears to be an association between PD-L1 expression 
and response, although the numbers are small and the correlation is not perfect. 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 patients[45, 46]. 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 vemurafenib[47]. The expression of 
PD-L1 has also been correlated with the extent of tumor lymphocytic infiltrate. The latter has 
been observed to be increased after radiation therapy, suggesting one possible mechanism for 
an improved systemic response after SBRT. We propose here to treat NSCLC and melanoma 
patients without regard to PD-L1 expression on biopsies done just prior to initiating protocol 
treatment. When feasible, tissue specimens will be obtained after MK-3475 treatment, and 
again after SBRT, and local and systemic response will be correlated to expression.
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. [48] 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 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 [49, 50]. Galectin-9 (the ligand to TIM- 
3), has been proposed as a mediator of PD-1 related T-cell exhaustion [51].
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 [51]. 
LAG-3 (lymphocyte-activation gene 3) synergizes with PD-1 to inhibit T cell activation. [52] 
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. [53] The T-cell stimulatory role of 
PD-1H (PD-1 Homologue) on T cells was recently described by Dr. Chen’s laboratory; its 
association with anti-tumor response in the setting of PD-1 blockade has yet to be determined. 
[54]
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An additional potential biomarker of tumor response is cell-free tumor-derived circulating 
DNA (ctDNA). The laboratory of Abhi Patel has developed an ultrasensitive assay for 
measuring small amounts of cell-free mutant DNA released into the blood from dying tumor 
cells. The assay covers a broad panel of mutations and uses novel error suppression techniques 
applied to next-generation sequencing data to enable identification of rare mutant DNA down 
to a fractional abundance of ~0.02%. Because such ctDNA is highly tumor-specific and is 
rapidly cleared from the bloodstream, it is showing excellent promise as a quantitative cancer 
biomarker. Indeed, we (and others) have observed decreases in ctDNA levels following 
treatment with surgery, radiation therapy, and systemic therapy (sometimes with an initial 
spike from tumor kill). Thus, we hypothesize that quantitative changes in ctDNA may provide 
information that is complementary to radiologic studies for tracking the efficacy of treatment 
with the PD-1 inhibitor MK3475 in patients with metastatic melanoma or non-small cell lung 
cancer.
5.0 METHODOLOGY
5.1
Entry Criteria 
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be  18 years of age on day of signing informed consent.
3. Have metastatic melanoma or NSCLC, or locally advanced NSCLC not suitable for 
curative-intent local therapy.
4. For melanoma patients and NSCLC patients treated with prior anti-PD-1 therapy, 
patients must have received prior PD-1 therapy and have progressed (irPD) by irRC.
5. Have 2 or more measurable sites of disease as defined by either RECIST 1.1, or 
cutaneous lesions at least 1 cm in greatest dimension
6. Have at least one site of disease that is considered potentially suitable for treatment 
with SBRT
7. Have provided tissue from an archival or newly obtained tissue sample of a tumor 
lesion, sufficient for analysis of PD-L1 and other biomarkers. Patients who have had 
PD-L1 analysis previously performed at Merck can substitute earlier analysis results 
and are not required to submit additional tissue for PD-L1 testing. Expression of PD- 
L1 is NOT required for study entry.
8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 28 days of protocol treatment.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL
Renal
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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
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
aCreatinine clearance should be calculated per institutional standard.
10. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.
11. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in section 5.6 – Contraception, for the course of the study 
through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
12. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in section 5.6 – Contraception, starting with the first dose of 
study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has had radiation therapy within 2 weeks of the first protocol treatment.
2. Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 2 weeks of the first protocol treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 2 weeks of the first protocol 
treatment. The use of low-dose steroids for management of chronic conditions is 
allowed.
4. Non-small cell lung cancer patients enrolling to MK-3475 as first protocol therapy (no 
prior anti-PD-1 therapy): Has had a prior monoclonal antibody within 4 weeks prior to 
first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to agents administered more than 4 weeks earlier.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks of the first protocol treatment or who has not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to a previously administered agent.
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-
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study.
-
Note: Patients who have had prior treatments with Tyrosine Kinase Inhibitors 
(e.g. Tarceva) require only a 72-hour washout period prior to starting protocol 
treatment.
6. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.
7. Has known active and untreated brain (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate.
8. Has an active autoimmune 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 example of an exception to 
this rule. Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study. Those with a history of 
hypothyroidism who are now stable on hormone replacement will not be excluded. 
Those with Sjorgen’s syndrome will not be excluded from the study.
9. Has a history of (non-infectious) pneumonitis that required steroids, current 
pneumonitis or evidence of interstitial lung disease.
10. Has an active infection requiring systemic therapy.
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
15. Has received a live vaccine within 30 days prior to the first protocol treatment.
5.2
Trial Treatment Plan
The treatment to be used in this trial is outlined below in Table 2 
Table 2 Trial Treatment
Treatment
Dose
Frequency
Route
Use
MK-3475
200 mg*
Every 3 weeks
(+/- 7 days)
IV
infusion
Experimental
SBRT
30Gy **
One time over 1 
to 5 fractions
Standard
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*MK-3475 may be modified as described in Section 5.2.1
**SBRT dose escalated/de-escalated as described in Section 5.2.2
5.2.1
Study Design
This is a two-part study, including both phase 1b and 2a portions.
The phase 1b is an SBRT dose escalation study, in which patients with both NSCLC and 
melanoma will be enrolled. NSCLC patients will be enrolled and treated with MK-3475 until 
they have progression of disease (irPD). Patients who have progression within 12 months of 
study entry will be evaluated for SBRT and re-initiation of MK-3475. Patients who do not have 
progression of disease within that timeframe may continue to receive MK-3475 for up to 18 
months per protocol. These patients will not be evaluable for the study endpoints, although their 
response rates and overall survival will be reported.
Melanoma and selected NSCLC patients will be enrolled after having progression of disease 
on prior PD-1 therapy (irPD). They will be immediately treated with SBRT, followed by re- 
initiation of MK-3475.
After progression of disease on an initial course of anti-PD-1 therapy (either prior to 
enrollment, or during trial therapy), a target for SBRT will be selected and patients will be 
assigned to one of two arms on the basis of the anatomic location of the target (Arm A: lung, 
Arm B: non-lung). The SBRT target will be chosen and ideally SBRT will be delivered as 
quickly as feasible after the last infusion of MK-3475. NSCLC patients who do not have a 
suitable SBRT target (as defined in section 5.2.3) on the imaging study that shows progression 
of disease may undergo interval re-imaging without further therapy, but if no suitable target 
has been identified for SBRT within 12 weeks of the last infusion of MK-3475, that patient 
will be removed from treatment and moved to survival follow up.
Patients may continue to receive MK-3475 post disease progression while radiation therapy 
with SBRT is scheduled. Patients who require continuing corticosteroid treatment, or who have 
adverse events (grade 3 or greater non-hematologic, or grade 2 pneumonitis) due to MK-3475 
that do not resolve within 12 weeks of AE start date will not receive SBRT and will also be 
removed from study. Patients who develop grade 3 pneumonitis will be removed from the 
study, regardless of whether it resolves. SBRT will delivered in dose cohorts as described 
below in section 5.3.
Following SBRT, all patients will restart MK-3475 as soon as feasible. They will continue 
until they have further progression of disease, defined as irPD, or at the discretion of the 
treating physician if they are felt to receiving clinical benefit.
If MK-3475 is held at any point during a subject’s participation in the trial for any reason, the 
subject will be followed as per standard of care until treatment with MK-3475 is resumed. 
When treatment with MK-3475 is resumed, the subject will continue with Day 1 procedures 
for the next planned cycle.
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The phase 2a portion is an expansion cohort with enrollment closing when 20 NSCLC patients 
have been enrolled (including those enrolled on phase I). Similar to the phase Ib portion, 
NSCLC patients who initiated trial therapy on MK-3475 will receive MK-3475 until there is 
progression of disease (irPD). Patients who do not have progression of disease within that 
timeframe may continue to receive MK-3475 for up to 18 months per protocol. These patients 
will not be evaluable for the study endpoints, although their response rates and overall survival 
will be reported. NSCLC patients will be enrolled after they have irPD on anti-PD-1 therapy 
received prior to study entry. After progression, an SBRT target will be selected and patients 
will be treated at the SBRT MTD as determined in the Phase Ib portion of the study, for lung 
and non-lung targets. The SBRT target will be chosen and ideally SBRT will be delivered as 
quickly as feasible after the last infusion of MK-3475. In the event of drug-related toxicity or 
other delay, SBRT may start up to 12 weeks after the last infusion as detailed below in section 
5.2.3. Following SBRT, all patients will receive MK-3475 until they develop progression of 
disease (as defined by irPD), or until they are no longer receiving clinical benefit.
For each phase of the study, the first course of MK-3475 will start on day 1, and will be given 
every 3 weeks (+/- 7 days) (one cycle). Patients will undergo re-imaging CT of the chest, 
abdomen, and pelvis at the end of cycle 2, cycle 4, and every 4 cycles thereafter (i.e., at cycles 
8, 12, etc.). After the SBRT, when MK-3475 is re-initiated, imaging will be done at the end of 
cycles 2, 4, and then every 4 cycles. Exceptions to the timing of re-imaging can be made by 
the treating investigator as necessary to determine course of treatment.
Following SBRT, MK-3475 will be re-started and administered in 3-week cycles as quickly as 
feasible. Dose modifications or delays may be made per section 5.2.2, based on prior toxicity 
from the first course of drug treatment. Treatment will continue until progression of disease, 
which will be defined for this purpose as progression in comparison to the tumor imaging 
obtained immediately before or after SBRT (whichever is more recent). At the discretion 
of the principal investigator, patients may continue to receive treatment if they are receiving 
clinical benefit. For the purpose of measuring response, the irradiated lesion will no longer 
qualify as measurable disease.
Progression of Disease (irPD) for this study will be defined using the Immune-Related 
Response Criteria (irRC), with the following qualification:
Radiographic progression of disease by RECIST criteria (but not by irRC) where, in 
the opinion of the investigator, the patient would no longer benefit from continuing 
drug therapy, will be considered progression of disease.
During the pre-SBRT MK-3475, radiation to isolated sites of metastatic disease is not 
permitted.
During the post-SBRT MK-3475, local surgery and/or radiation therapy to isolated sites of 
metastatic disease is permitted and the patient can continue the MK-3475 provided there is 
evidence of continuing benefit from systemic treatment (i.e., stable disease or response in at 
least one other measurable lesion, or clinical improvement).
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5.2.2
MK-3475 Dose and Dose Modification 
Drug Dose & Storage
Clinical Supplies will be provided by Merck & Co., Inc., as summarized in table 3 below.
Table 3. Product Description
Product Name & Potency
Dosage Form
MK-3475 100 mg/ 4 mL
Solution for Injection
MK-3475 will be administered at 200 mg, by IV infusion, every 3 weeks (+/- 7 days) on day 
1 of each cycle.
Dose Modification (Escalation/Titration/Other)
MK-3475 will be withheld for drug-related Grade 4 hematologic or laboratory toxicities, non- 
hematological toxicity ≥ Grade 3, or severe or life-threatening AEs as per Table 4 below. If 
MK-3475 is held at any point during a subject’s participation in the trial for any reason, the 
subject will be followed as per standard of care until treatment with MK-3475 is resumed. 
When treatment with MK-3475 is resumed, the subject will continue with Day 1 procedures 
for the next planned cycle.
Table 4: Dose modification guidelines for drug-related adverse events.
Toxicity
Hold 
Treatmen 
t For 
Grade
Timing for Restarting Treatment
Treatment Discontinuation
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
Diarrhea/Colitis
4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose
AST, ALT, or
Increased 
Bilirubin
3-4
Permanently discontinue 
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure
Resume pembrolizumab when patients are clinically and 
metabolically stable
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
Hyperthyroidism
4
Permanently discontinue
Permanently discontinue
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Toxicity
Hold 
Treatmen 
t For 
Grade
Timing for Restarting Treatment
Treatment Discontinuation
Hypothyroidism
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted
2b
Toxicity resolves to Grade 0-1
Permanently discontinue if toxicity develops despite adequate 
premedication
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks
All Other Drug- 
Related Toxicityc
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then patients should be discontinued.
b 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; Refer 
to Error! Reference source not found. – Infusion Treatment Guidelines for further management details.
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug 
for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose.
In case toxicity does not resolve to Grade 0-1 within 12 weeks of AE start date, trial treatment 
should be discontinued after consultation with the sponsor. With sponsor and principal 
investigator agreement, subjects with a laboratory adverse events still at Grade 2 after 12 weeks 
may continue treatment in the trial only if asymptomatic and controlled. For information on 
the management of adverse events, see Section 5.5.
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment.
Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0). Trial treatment may be 
administered up to 7 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.
MK-3475 will be administered as a 30 minute IV infusion. Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/ +10 min).
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5.2.3
Stereotactic Body Radiation Therapy (SBRT) 
Target Selection
Target selection for SBRT will occur after the patient develops progression of disease on the 
pre-SBRT treatment with MK-3475. For the Phase Ib portion, patients will be allocated to Arm 
A (Lung target) if the SBRT target overlaps the lung parenchyma, otherwise patients will be 
allocated to Arm B (Non-Lung target). Targets suitable for SBRT for all phases of the study 
must meet all of the following requirements. Melanoma and NSCLC patients with prior 
treatment on anti-PD1 therapy will only be enrolled if there is a suitable target. In NSCLC 
patients initiating MK-3475 as first protocol treatment, if there are no suitable targets for SBRT 
after the pre-SBRT MK-3475, the patient may be observed and interval re-imaging may be 
obtained at the discretion of the investigators. Patients who cannot be treated with SBRT within 
12 weeks of the most recent infusion of MK-3475 will be taken off treatment and moved to 
survival follow up. Exceptions to the 12 week window may be allowed for individual patients 
at the discretion of the Principal Investigator. MK-3475 may be administered after progression 
has been determined while SBRT is planned. Additionally, target lesions:
1. Must not be located in the liver, small or large bowel
2. Treatment must be accomplished without exceeding any normal tissue dose limit, as 
defined in the report of the American Association of Physicists in Medicine, Task 
Group 101 report[55].
SBRT Planning
Patients will undergo CT simulation and treatment planning per standard practice. Patient 
immobilization should be sufficient to ensure minimal intra- and inter-fraction set-up error, 
and is otherwise left to the discretion of the treating radiation oncologist. For lung targets, a 
technique for motion management is required, which may include tumor tracking, respiratory 
gating, or 4D-CT simulation. The treating physician will define a planning target volume 
(PTV) to which the dose will be described, and which will be used to define local control or 
local failure. At least 90% of the PTV should receive 90% or more the prescription dose. All 
organs at risk within 5 cm of the PTV will be contoured, and dose-volume histograms 
produced. For all organs at risk contoured, dose limits will be followed without exception[55].
SBRT Treatment Administration
The first fraction of SBRT should be delivered as soon as feasible after progression of disease. 
For the following events, SBRT should be delayed until they resolve (for toxicities, to grade 0 
or 1), up to 12 weeks after the last infusion of MK-3475. If the listed events do not resolve 
within 12 weeks of the last infusion of MK-3475, the patient will be removed from the study 
and replaced.
1. Grade 2 or greater pneumonitis
2. Corticosteroid use within 2 weeks of SBRT, except in individual cases allowed by 
the Principal Investigator
3. Grade 3 or greater non-hematologic toxicity related to study therapy
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Patients who develop grade 3 or greater pneumonitis during the pre-SBRT MK-3475 will be 
taken off of the study, and will not be eligible for SBRT, or re-initiation of MK-3475.
Patients will be treated on non-consecutive days whenever possible, with all fractions to be 
scheduled within 15 calendar days from first to last. Localization of the tumor target before 
each fraction is required, by either cone-beam CT scan, kilovoltage on –board imaging, or an 
internal fiducial.
SBRT Dose Modification and Supportive Care
SBRT will be discontinued if any grade 3 or greater adverse event occurs during radiation 
treatment that is probably or definitely attributable to radiation. This will be counted as a DLT 
if it occurs during the phase Ib portion of the study. These patients will be allowed to continue 
with trial therapy (the second course of MK-3475, but not the remainder of their SBRT) if the 
toxicity resolves to grade 0 or 1 with supportive measures within 12 weeks of AE start date.
SBRT will also be discontinued if the completion of all fractions is prolonged beyond 30 days 
for reasons unrelated to toxicity (i.e., intercurrent illness, or patient refusal). This will not be 
counted as a DLT, and these patients will be allowed to continue with trial therapy (the second 
course of MK-3475, but not the remainder of their SBRT) as long as the investigator believes 
that they will be compliant with the remainder of the trial therapy. In the phase Ib portion of 
the study, these patients will not be counted towards the minimum number of patient treated at 
that dose level as long as they have not experienced a DLT before treatment is abort, but instead 
will be replaced. If they have experienced a DLT during that period, then they will be counted 
toward that dose cohort.
No other SBRT dose modification for individual patients is permitted during the phase Ib 
portion of the study. During the phase 2a portion, at the discretion of the treating radiation 
oncologist and with the agreement of the principal investigator, the prescription dose for SBRT 
may be reduced in an effort to reduce the risk of toxicity. In this case, one of the 3 dose levels 
specified in the dose escalation section 5.3 will be used.
Adverse events that occur during or after SBRT should be managed per section 5.5, or with 
best supportive care.
5.3
SBRT Dose-Escalation or De-Escalation
In the Phase 1b (SBRT dose escalation/de-escalation) portion, patients will be allocated to Arm 
A (Lung) or Arm B (non-Lung) based on the anatomic site of the target chosen for SBRT. 
Dose escalation or de-escalation will be done separately for each arm, and the MTD determined 
separately for each arm. Once an MTD has been determined for lung and non-lung targets, 
future patients with those SBRT targets will be allocated to the Phase IIa portion of the trial.
In the Phase 2a (expansion) portion, patients will be treated at the SBRT MTD for lung or non-
lung lesions, as appropriate.
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Dose-Escalation or De-Escalation
In the Phase Ib portion of the trial, the SBRT dose will be escalated or de-escalated in 
successive cohorts. The starting dose will be 3000 cGy in 5 fractions. A single de-escalation 
cohort (1000 cGy in a single fraction), and a single escalation cohort (3000 cGy in 3 fractions) 
will be allowed.
Because SBRT target selection and treatment will occur in a rolling fashion after a patient 
progresses on the pre-SBRT MK-3475, availability for enrollment on the dose escalation 
cohorts will be somewhat unpredictable. In an effort to maximize the number of available 
treatment slots, enrollment in the dose escalation arms will be done using a “Rolling Six” 
design, following the guidelines in Table 5, below[56]. A minimum of two patients will be 
enrolled at each dose level. After 2 patients have been enrolled, the treatment cohort will be 
determined by the number of patients enrolled, the number who have experienced a DLT, the 
number who have not, and the number who have not yet completed the DLT follow-up period. 
The rolling enrollment design allows more than three patients to be enrolled within a dose 
cohort before safety has been demonstrated, and reflects the fact that both MK-3475 and SBRT 
have demonstrated safety at higher doses than prescribed in this protocol, as single agents.
If the lowest dose cohort of 1000 cGy in a single fraction is not completed with acceptable 
toxicity, those targets (i.e., lung or non-lung) will be excluded from the remainder of the study. 
If neither arm is able to be completed at the lowest SBRT dose level, the study will be 
terminated. If the highest dose level of 3000 cGy is reached and successfully completed, that 
will be the MTD for the phase IIA portion of the study. A minimum of 6 patients will be treated 
at the MTD in the phase Ib portion of the study.
Table 5.
Enrolled       DLT      No  DLT   In follow-up
Cohort to enroll
2
0, 1
Any
Any
Enroll at same dose level
2
2
Any
Any
Enroll at lower dose level
3
0
0, 1, 2
3, 2, 1
Enroll at same dose level
3
0
3
0
Enroll at higher dose level*
3
1
0, 1, 2
2, 1, 0
Enroll at same dose level
3
>= 2
Any
Any
Enroll at lower dose level
4
0
0, 1, 2, 3
4, 3, 2, 1
Enroll at same dose level
4
0
4
0
Enroll at higher dose level*
4
1
0, 1, 2, 3
3, 2, 1, 0
Enroll at same dose level
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4
>= 2
Any
Any
Enroll at lower dose level
5
0
0,1,2,3,4
5,4,3,2,1
Enroll at same dose level
5
0
5
0
Enroll at higher dose level*
5
1
0,1,2,3,4
4,3,2,1,0
Enroll at same dose level
5
>= 2
Any
Any
Enroll at lower dose level
6
0
0,1,2,3,4
6,5,4,3,2
SUSPEND enrollment
6
0
5, 6
1, 0
Enroll at higher dose level**
6
1
0,1,2,3,4
5,4,3,2,1
Suspend enrollment
6
1
5
0
Enroll at higher dose level**
6
>= 2
Any
Any
Enroll at lower dose level
*At the maximum dose level, continue current dose cohort
**At the maximum dose level, STOP, this is the MTD
Definition of Dose Limiting Toxicity
For the purpose of determining the MTD of SBRT, a DLT will be considered to be any of the 
following adverse events which are probably or definitely attributable to study treatment, and 
which occur between the first fraction of SBRT and within 60 days of the last fraction of SBRT.
1. Any non-hematologic, non-laboratory toxicity which is grade 3 or greater and does not 
resolve to grade 2 or lower with supportive care within 14 days.
2. Any non-hematologic, non-laboratory toxicity which is grade 4 or greater
3. For patients in Arm A (lung targets), the development of grade 3 or greater pneumonitis 
that is probably or definitely attributable to either SBRT or MK-3475 within the follow- 
up period will be considered a DLT, regardless of whether it resolves.
5.4
Concomitant Medications/Vaccinations (allowed & prohibited) 
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
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All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs as 
defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Anti-cancer systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than MK-3475

Radiation therapy except for that specified by protocol

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects 
may receive other medications that the investigator deems to be medically necessary.
There are no prohibited therapies during the Post-Treatment Survival Follow-up Phase.
5.5
Rescue Medications & Supportive Care 
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 adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might
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require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.

Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/ Colitis: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
o
For Grade 2 diarrhea/ colitis, administer oral corticosteroids.
o
For Grade 3 or 4 diarrhea/ colitis, treat with intravenous steroids followed by 
high dose oral steroids. All subjects who experience diarrhea/ colitis should be 
advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake 
is not feasible, fluid and electrolytes should be substituted via IV infusion. For 
grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm 
or rule out colitis.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For T1DM or Grade 3-4 Hyperglycemia
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
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly).

Treat with IV or oral corticosteroids
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o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Table 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of MK-3475.
Table 6 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (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.
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
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
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.
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
5.6
Other Considerations 
Contraception
MK-3475 may have adverse effects on a fetus in utero.
Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.
For this study, male subjects will be considered of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to any underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either:
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
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OR
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:
(1) practice abstinence† from heterosexual activity; 
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner

contraceptive rod implanted into the skin 
Combination method (requires use of two of the following):

Diaphragm
with spermicide (cannot
be
used
in
conjunction
with
cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous women only)

Contraceptive sponge (nulliparous women only)

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen / progestin pill or progrestin- 
only pill), contraceptive skin patch, vaginal contraceptive ring or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region
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Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study drug initiation (or 14 days prior to the initiation of 
study drug of oral contraception) throughout the study period up to 120 days after the last dose 
of study drug. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject will 
immediately be removed from the study. The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor and to Merck and followed as described above and 
in Section 8.
Use in Nursing Women
It is unknown whether MK-3475 is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment.
5.7
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.
A subject must be discontinued from treatment, or removed from the study for any of the 
following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Progression of disease during the second course of MK-3475 (as defined in section 
5.2.1)

Unacceptable adverse experiences as described in Section 5.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test
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
Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 12 months of treatment with post-SBRT MK-3475
Note: 12 months of study medication is calculated from the date of first dose of the 
second course. Subjects who stop MK-3475 after 12 months will be eligible for up to 
one year of additional study treatment if they progress after stopping study treatment

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Sections 6 and 7. After the 
end of treatment, each subject will be followed for 30 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment as described in 
Section 8). Subjects who discontinue treatment will be followed for survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first. Survival follow up may 
be a phone call only.
5.8
Subject Replacement Strategy
In both phases of the study, patients will be replaced if
1. They do not complete at least one fraction of SBRT.
2. They do not complete their entire course of SBRT as prescribed due to reasons other 
than toxicity (e.g., patient refusal, or intercurrent illness).
5.9
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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6.0 STUDY CALENDAR – NSCLC PATIENTS WITHOUT PRIOR ANTI-PD-1 THERAPY
Trial Period:
Treatment
End of Treatment
Follow Up
Treatment Cycle/Title:
Screening
1
2
3+
4+
At 
Progression10
SBRT
1
2
3+
4+
At Progression, 
Discontinuation
Safety 
Follow- 
Up Visit
Survival 
Follow-up
Scheduling Window (Days):
-28 to -1
± 7
± 7
± 7
± 7
+ 7
± 7
± 7
± 7
± 7
+ 7
30 Days 
post
End of 
Treatment
(+ 7)
Every 12 
weeks
(+ 7)
Informed Consent
X
Medical History
X
Full Physical Exam, VS & weight
X
Height
X
Medication Review
X
X
X
X
X
X
X
X
X
X
X
CT chest/abdomen/pelvis1
X
X
X
X
X
Directed Physical Exam, VS & weight
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
X3
X
X
X
X
X
X14
Pregnancy Test – Urine or Serum -HCG
X11
Archival or Fresh Tumor Collection4
X2
CBC with Differential
X
X
X
X
X
X
X
X
X
CMP, LDH
X
X
X
X
X
X
X
X
X
TSH & Free T4 15
X
X
X
X
X
Selection of SBRT target7
X
Blood for correlative studies
X5, 12
X5, 12
X5
X5
X5
X5
X5, 12
X5, 12
X5
X5
X5
X5
Survival follow-up
X
Administer study drug, MK-34759
X11
X
X
X6, 13
X8
X
X
X16
1 During week 3 every 2 cycles (during the last week of cycles 2 and 4), and then every 4 cycles (at the end of cycles 8, 12, etc.). See Section 8.5 for exceptions.


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2 Includes PD-L1 testing
3 Study visit the last day of SBRT
4 When feasible, if a biopsy is done for clinical purposes as per standard of care at any point during a subject’s participation on trial, tissue may be collected at the time of the 
biopsy
5 Blood for correlative studies will be drawn at cycles 2 through 4 for both pre- and post-SBRT, then every even-numbered cycle thereafter (e.g. 6, 8, 10, etc.). If MK-3475 is held 
for any reason when blood for correlative samples is to be drawn, the blood may be drawn at the discretion of the Principal Investigator. When MK-3475 is resumed, blood for 
correlative samples will be taken as per the calendar above.
6 May be administered for up to 18 months if no disease progression. If no disease progression and > 12 months on study drug, patient cannot receive SBRT on trial
7 Must be determined within 12 weeks of last dose of MK-3475 or patient will be removed from study and replaced. Exceptions to timing may be made by the Principal 
Investigator
8 Will be restarted following SBRT as soon as possible
9 Given every 3 weeks on Day 1 of each cycle (+/- 7 days) until progression
10 Patients who have progression within 12 months of study entry will be evaluable for SBRT and re-initiation of MK-3475. First SBRT fraction should be administered as soon as 
feasible after disease progression, following resolution of toxicities listed in section 5.2.3, and at least 1 week post last MK-3475 infusion
11 Pregnancy test within 72 hours of first dose of study medication for WOCBP
12 First pre-treatment correlative lab draw for lung patients can be drawn either during screening and/or prior to first MK-3475 administration and post-SBRT and/or prior to cycle 
1 dose of MK-3475 following SBRT. Both are not required, but can be collected.
13 Following disease progression, MK-3475 may continue to be administered while subjects wait for radiation therapy with SBRT to begin at the discretion of the treating 
investigator.
14 Required 30 days (+/- 7 days) from the End of Treatment visit, unless there were no toxicities > Grade 1 probably, or definitely related to protocol treatment at the End of 
Treatment visit. In this case, the End of Treatment visit will suffice as the safety follow up visit.
15 After the screening period, TSH and Free T4 to be done every other cycle starting with week 2
16 Drug may be administered for up to 12 months from the first dose of the second course. Subjects who stop drug after 12 months will be eligible for up to 1 year of additional 
treatment if they progress after study drug is stopped.
STUDY CALENDAR – MELANOMA PATIENTS AND NSCLC PATIENTS WITH PRIOR ANTI-PD-1 THERAPY
Treatment
End of Treatment
Follow-Up
Treatment Cycle/Title:
Screening
SBRT
1
2
3+
4+
At Progression, 
Discontinuation
Safety Follow-Up 
Visit
Survival Follow-Up


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APPROVED BY THE YALE UNIVERSITY IRB 6/6/2019
Scheduling Window (Days):
-28 to -1
± 7
± 7
± 7
± 7
+ 7
30 Days post 
End of Treatment 
(+ 7)
Every 12 weeks
(+ 7 days)
Informed Consent
X
Medical History
X
Full Physical Exam, VS & weight
X
Height
X
Medication Review
X
X
X
X
X
X
CT chest/abdomen/pelvis1
X
X
X
Directed Physical Exam, VS & weight
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Event Assessment
X
X3
X
X
X
X
X
X9
Pregnancy Test – Urine or Serum -HCG
X7
Archival or Fresh Tumor Collection4
X2
CBC with Differential
X
X
X
X
X
CMP, LDH
X
X
X
X
X
TSH & Free T4 10
X
X
X
Selection of SBRT target
Blood for correlative studies
X 8
X 8
X8
X5
X5
X5
X
Survival Follow-up
X
Administer study drug, MK-3475 6
X7
X
X
X
1 During week 3 every 2 cycles (during the last week of cycles 2 and 4), and then every 4 cycles (at the end of cycles 8, 12, etc.)
2 Includes PD-L1 testing
3 Study visit the last day of SBRT
4 When feasible, if a biopsy is done for clinical purposes as per standard of care at any point during a subject’s participation on trial, tissue may be collected at the time of the 
biopsy
5 Blood for correlative studies will be drawn at cycles 2 through 4 for both pre- and post-SBRT, then every even-numbered cycle thereafter (e.g. 6, 8, 10, etc.). If MK-3475 is held 
for any reason when blood for correlative samples is to be drawn, the blood may be drawn at the discretion of the Principal Investigator. When MK-3475 is resumed, blood for 
correlative samples will be taken as per the calendar above.
6 Will be started following SBRT as soon as possible every 3 weeks on Day 1 of each cycle (+/- 7 days) until progression. Drug may be administered for up to 12 months from the 
first dose of the second course. Subjects who stop drug after 12 months will be eligible for up to 1 year of additional treatment if they progress after study drug is stopped.
7 Pregnancy test within 72 hours of first dose of study medication for WOCBP
8 Correlative lab draw can be taken either post-SBRT and/ or prior to cycle 1 dose of MK-3475 following SBRT. Both are not required, but can be collected.


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9Required 30 days (+/- 7 days) from the End of Treatment visit, unless there were no toxicities > Grade 1 probably, or definitely related to protocol treatment at the End 
of Treatment visit. In this case, the End of Treatment visit will suffice as the safety follow up visit.
10 After the screening period, TSH and Free T4 to be done every other cycle starting with week 2
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart summarizes the trial procedures to be performed at each visit. Individual 
trial procedures are described in detail below. It may be necessary to perform these procedures 
at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigators for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
7.2
Screening Period
Prior to initiation of study therapy, the patient will require a screening visit(s). Scans, 
evaluations, and laboratory studies should be done as close to the initiation of therapy as 
feasible, and no more than 28 days prior. The following should be addressed during the 
screening period:
1.
Informed Consent
2.
Medical History
3.
Complete physical examination, vital signs, and measurement of height and weight 
(pre-recorded height may be used from medical record)
4.
Review of prior and concomitant medications
5.
CT scan of chest, abdomen and pelvis (a PET/CT scan will be deemed sufficient)
6.
Performance status evaluation
7.
Determination of baseline adverse event status
8.
Pregnancy test for women of childbearing potential, and counseling that sexually active 
women of childbearing potential must use an effective form of birth control during the 
entire study period
9.
Determination of sufficient tumor specimen for evaluation of PD-L1 status
10.
Laboratory studies: CBC with differential, serum chemistries, liver function tests, 
LDH, TSH and Free T4
11.
Submission of blood for correlative studies (see footnote 5 above in the non-small cell 
lung cancer calendar and footnote 9 above in the melanoma calendar)
7.3
On-Study Visits
On-study visits will occur on day 1 of each cycle of MK-3475, and will include the following 
at every visit for melanoma and non-small cell lung cancer patients:
1.
Directed physical examination, vital signs, and measurement of weight
2.
Review of concomitant medications
3.
Performance status evaluation
4.
Determination adverse events
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5.
Laboratory studies: CBC with differential, CMP, LDH
6.
TSH and Free T4 will be done every other cycle starting with Cycle 2
7.
CT scans of chest, abdomen and pelvis (a PET/CT scan will be deemed sufficient) will 
be done during week 3 every 2 cycles (at the end of cycles 2 and 4) and then every 4 
cycles thereafter (at the end of cycle 8, 12, etc.)
A study visit will occur after clinically evident progression of disease on the first course of 
MK-3475 for non-small cell lung cancer patients, prior to SBRT treatment, and the following 
will be done prior to the initiation of SBRT:
1.
Directed physical examination, vital signs, and measurement of weight
2.
Review of concomitant medications
3.
Performance status evaluation
4.
Determination adverse events
5.
Selection of SBRT target, and determination of lung versus non-lung arm
After clinically evident progression on the second course of MK-3475, the patient will be seen 
for a study visit, at which the following will be addressed:
1.
Directed physical examination, vital signs, and measurement of weight
2.
Review of concomitant medications
3.
Performance status evaluation
4.
Determination adverse events
During selected on-study visits, blood for correlative studies will be submitted per the study 
flow chart. Fresh tumor specimens will be obtained if feasible during therapy if the patient 
undergoes resection or biopsy for a standard-of-care clinical purpose per the study flow chart 
footnotes.
7.4
Post-Study Visits 
Safety Follow-Up Visit
A follow-up will be conducted approximately 30 days (+/- 7 days) after the End of Treatment 
visit, or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs 
should be recorded. Subjects with an AE of Grade > 1 probably or definitely related to protocol 
treatment will be followed until the resolution of the AE to Grade 0-1 or until the beginning of 
a new anti-neoplastic therapy, whichever occurs first. However, if at the End of Treatment visit 
there are no toxicities Grade > 1 probably or definitely related to protocol treatment, the End 
of Treatment visit may be used as the safety follow up visit. SAEs that occur within 90 days 
of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded.
Survival Follow-up
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Once a subject withdraws from study treatment, or discontinues trial therapy, the subject moves 
into a survival follow-up phase. They should be assessed for survival every 12 weeks, which 
may include being contacted by telephone. This should continue until patient death, until the 
patient withdraws consent for further follow-up, or until the study closes.
7.5
Tumor Imaging
CT scan of the chest, abdomen, and pelvis will be obtained at baseline. Then for each course 
of MK-3475 it will be obtained during the 3rd week of cycles 2 and 4, and then every 4 cycles 
thereafter (e.g., cycles 8, 12, etc). Additional re-imaging may be obtained at the discretion of 
the investigator. A PET/CT may be substituted for CT of the chest, abdomen, and pelvis if 
clinically appropriate. In the event the patient’s insurance denies part of the scan (e.g only CT 
of the chest is approved), the Principal Investigator or patient’s treating physician may waive 
part of the imaging requirement, or adjust the timing of imaging as medically necessary.
7.6
Study Assessments 
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Medical History
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A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.
Prior and Concomitant Medications Review 
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening,
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure. Height will be measured at screening only, or taken from the 
subject’s medical record.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart. After Cycle 8 assessment of ECOG status will be 
performed every other cycle in conjunction with the directed or full physical exam.
Tumor Tissue Collection and Correlative Studies Blood Sampling
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Before and during trial therapy, if an irradiated or unirradiated lesion is biopsied or resected 
for clinical purposes, a sample will be retained for protocol-related correlative studies. After 
tissue is obtained, it will be subjected to flash freezing in liquid nitrogen and SNAP frozen 
tissue will be stored for further studies. If a patient has had a previous biopsy, the pre-treatment 
sample may be taken from paraffin-embedded tissue.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of the 
trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures Manual.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre- 
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Procedures Manual.
Study-Related Biopsies and Tissue Collection
Tissue from fresh or archival tissue (see below) is required at study entry. When a biopsy is 
being done for standard-of-care clinical purposes, tissue will be obtained from this procedure, 
if available.
Tumor tissue will be obtained prior to initiation of study therapy from any primary or 
metastatic site and processed according to the specifications of the lab manual. At the 
discretion of the principal investigator, archival tissue may be used in place of a fresh biopsy.
8.0 ADVERSE EVENT REPORTING 
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
8.1
Definitions
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
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specified procedure, whether or not considered related to the medicinal product or protocol- 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the trial therapy, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. All adverse 
events that after the consent form is signed but before treatment allocation must be reported by 
the investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol- 
specified procedure or intervention. If the subject requires a fresh tumor biopsy, the subject is 
first required to provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.
Serious Adverse Events
A serious adverse event is any of the following:

Death

Any adverse event which is life threatening;

Any adverse event leading to persistent or significant disability/incapacity;

Any adverse event which results in or prolongs an existing inpatient hospitalization;

A congenital anomaly/birth defect as a result of trial therapy;

Any other important medical event

Pregnancy
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
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)]. Hospitalization related to convenience (e.g., transportation issues, etc.) will 
not be considered a SAE.
Progression of the cancer under study is not considered an adverse event.
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“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.
Duration of Reporting of SAEs: From the administration of first treatment until 30 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.
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)]
Events of Clinical Interest:
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor-Investigator and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).
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-Investigator and within 2 working days to Merck 
Global Safety 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 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new
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anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor-Investigator and within 24 
hours to Merck Global Safety.
Events of clinical interest for this trial include:

an overdose of Merck product. For the purposes of this trial, an overdose will be defined 
as any dose exceeding the prescribed dose for MK-3475 by 20% over the prescribed dose.

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.
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 
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.
Definition of an Overdose for This Protocol and Reporting of Overdose
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose.
8.2
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.
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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)
8.3
Reporting to Merck
The Principal Investigator will report to Merck in an expedited manner all SAEs meeting the 
criteria of “serious”, “unexpected” and “related to study treatment”.
For the time period beginning when the consent form is signed until treatment allocation/ 
randomization, 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 must be reported within 24 hours to the Sponsor-Investigator and within two (2) 
working days to Merck Global Safety (GS) 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 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anti-cancer therapy, whichever is earlier, 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 whether or not related to Merck product, must be reported within 24 hours to the 
Sponsor-Investigator and within 2 working days to Merck GS.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Investigator-Sponsor and to Merck GS.
All subjects with serious adverse events must be followed up for outcome.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
GS facsimile number: +1-215-993-1220.
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Reporting of Overdose
No specific information is available on the treatment of overdose of MK-3475. In the event of 
overdose, MK-3475 should be discontinued and the subject should be observed closely for 
signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220)
Reporting of Pregnancy and Lactation
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure/
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
to the investigator. All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
8.4
Reporting to the Food and Drug Administration
At the discretion of the Principal Investigator, SAEs may be reported to the FDA. Written 
safety reports will use a MedWatch Form 3500 for voluntary reporting of adverse 
events, product problems and product use errors. 8.5 Reporting to Yale Human 
Investigation Committee
Expedited Reporting of Unexpected SAEs
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All SAEs meeting the criteria for expedited reporting will be reported to the Yale University 
Human Investigation Committee (HIC) using HIC Form 6A within 48 hours of discovery.
The Yale University Human Investigation Committee expedited reporting criteria are either:
a. Serious AND unanticipated AND possibly, probably or definitely related events;
b. Anticipated Adverse Events occurring with a greater frequency than expected.
8.6
Yale Safety Reporting and Monitoring (DSMP)
The PIs 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 Data and Safety Monitoring Committee 
(YCC DSMC). Safety data will be submitted at least once yearly or more often as required by 
the YCC DSMC. 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.
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 YCC 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
9.0 STATISTICAL ANALYSIS PLAN
In the phase 1b portion of the trial, patients will be enrolled in parallel dose escalation cohorts 
using the “Rolling Six” method, as described in Section 5.
The primary endpoint of the phase 2a portion of the study is the response rate to post-SBRT 
MK-3475, separately determined for a NSCLC cohort. A total of 12 patients will be treated at 
the MTD in the first phase of the study (6 each of lung and non-lung SBRT
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targets), and we project that this will include an approximately equal number of NSCLC and 
melanoma patients. In the second phase of the study, an expansion cohort will be enrolled until 
a total of 20 NSCLC patients eligible to undergo SBRT is reached (including NSCLC patients 
treated in the phase I and II portions of the study). We project that approximately 30% of 
patients (unselected for PD-L1 expression) will respond to the initial MK-3475 for 12 months 
or more and be replaced. Of those who go on to progress and being SBRT, we estimate that 
30% will drop out, or otherwise be ineligible for assessment of response to post-SBRT MK-
3475. 
There is no published data to suggest a historical control for response to re-treatment with MK- 
3475, in patients who have been previously treated with MK-3475 and have prior documented 
progression of disease. In melanoma patients treated with anti-CTLA4 antibody, there is a 
documented response rate for re-treatment of patients who previously responded and 
subsequently progressed. In a series of 31 patients who initially had a partial or complete 
response, and then had progression of disease, re-induction with antibody resulted in a response 
in 13% of patients. It should be noted, however, that treatment beyond standard RECIST 
criteria was not permitted in the initial treatment course for these patients, so some may have 
had pseudoprogression. It is therefore presumed that the expected ORR without SBRT in this 
population, allowing for treatment beyond RECIST in their initial therapy with MK-3475 is 
less than 5%. If 4 of 20 patients (20%) in in the NSCLC expansion cohort develop a partial or 
complete response to post-SBRT MK-3475, this strategy will be deemed worth of further 
investigation. The 95% confidence interval will be (0.05, 0.49) by using one-sample proportion 
test with continuity correction.
The primary endpoint of this trial will be response rate and the secondary endpoint will be 
progression-free survival. We will use descriptive statistics to calculate frequency and 
proportion for the response rate to post-SBRT MK-3475. 95% confidence interval will also be 
provided. Exact binomial test will be used to compare the observed response rate versus 
historical control. For the secondary endpoint, we will use Kaplan-Meier estimator to present 
the progression-free survival.
10.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
10.1 Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by Merck as summarized in Table 9.
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Table 9. Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 100 mg/ 4mL
Solution for Injection
10.2 Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
10.3 Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
10.4 Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
10.5 Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
11.0
LABORATORY CORRELATIVE/SPECIAL STUDIES
11.1 Handling of Tissue
Before initiation of systemic therapy, local surgical therapy may be performed to obtain fresh 
tumor tissue. After tissue is obtained, it will be subjected to flash freezing in liquid nitrogen
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and SNAP frozen tissue will be stored for further studies. If a patient has a previously obtained 
paraffin-embedded tissue that is available, a portion may be used to conduct the studies 
mentioned below.
The SNAP frozen tissue specimens will be analyzed at Yale University. FFPE specimens will 
be analyzed for PD-L1.
11.2 Correlative Studies
Correlative studies will be conducted tissue specimens obtained before and during trial therapy. 
PD-L1 positivity will be determined on FFPE tissue. A number of additional biomarkers will 
be studied for their potential predictive value. 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) Antigen-specific markers on T cells
Patients who undergo surgical procedures 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.
Immune monitoring will be performed as a part of this study. Peripheral blood lymphocytes 
(PBLs) and plasma will be collected before and during 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, as well as cytokine profiling at the Yale Immune Monitoring Core Facility.
12.0 MEASUREMENT OF RESPONSE
Response will be evaluated by imaging studies as described in the study calendar. If symptoms 
develop or clinical deterioration occurs, patients may be imaged prior to the pre-specified time 
points for imaging.
Response of all systemic metastases will be evaluated in this study using two methods: the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee v1.1, and the Immune-Related Response Criteria (irRC). The irRC will be used to 
make protocol-related decisions regarding treatment response. Response by RECIST will be 
recorded for later analysis. RECIST 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. Following SBRT, response will be measured in comparison to the most immediate pre-
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SBRT imaging study, or imaging immediately following SBRT, whichever is most recent. For 
this purpose, the metastatic target chosen for SBRT will not qualify as a measurable lesion. 
For complete definitions of measurable and non-measurable disease, please refer to the 
RECIST v1.1 criteria.
12.1 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). For purpose of the primary endpoint of 
the study, the overall response will be measured during the post-SBRT MK-3475, in 
comparison to the most immediate pre-SBRT imaging.
12.2 Progression-Free and Overall Survival
For the purpose of the secondary endpoints of this study, PFS is defined as the time from 
initiation of study drug post-SBRT, until the first documented, confirmed progression of 
disease as described in Section 5. PFS will also be measured and report from the initiation of 
study drug, pre-SBRT. OS will be measure from the initiation of study therapy.
12.3 Local Control
The target lesion selected for SBRT will be followed for local control. For the purpose of the 
study, local control will be defined as a complete response, partial response, or stable disease 
within the planning target volume. The duration of local control will be measured from the 
final SBRT treatment fraction.
13.0 ADMINISTRATIVE AND REGULATORY DETAILS
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.
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15.0 APPENDICES
15.1 ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.
15.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)
15.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan,
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
In addition, volumetric analysis will be explored by central review for response assessment.
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