Clinical trial NCT01876511
Conditions: MSI Positive Colorectal Cancer MSI Negative Colorectal Cancer MSI Positive Non-Colorectal Cancers
Keywords: microsatellite unstable (MSI) microsatellite stable (MSS) MLH 1 MSH 2 MSH 6 PMS2
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2013-09-01; Completion date: 2019-08-01
Enrollment: 113 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be looking at whether MK-3475 (an antibody that blocks negative signals to T cells) is effective (anti-tumor activity) and safe in three different patient populations. These include: 1. patients with MSI positive colon cancer, 2. patients with MSI negative colon cancer and 3. patients with other MSI positive cancers.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: MK-3475
Intervention descriptions: intervention 1: MK-3475 10 mg/kg every 14 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Phase 2 Study of MK-3475 in 
Patients with Microsatellite 
Unstable (MSI) Tumors 
 
 
 
 
 
NCT01876511 
 
 
 
 
 
 
December 1, 2017 
 
 
 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
Amendment 11/ Version 12/ December 1, 2017  
2 
  
TITLE: Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
  
  
Johns Hopkins Protocol #:   
J1365, NA_00085756  
  
Merck Protocol #:  
MK-3475-016  
  
Coordinating Center:    
  
Sidney Kimmel Comprehensive Cancer Center,   
  
  
  
  
  
  
  
  
  
Johns Hopkins University  
  
Key Principal Investigator: 
 
Dung 
Le, M.D. (Protocol Chair)  
(Johns Hopkins)   
  
 
Principal Investigators:  
Todd Crocenzi, M.D., Providence Medical Center  
(Other Sites)   
 
George Fischer, M.D., Ph.D., Stanford University  
 
  
  
 
Tim Greten, M.D., National Cancer Institute  
 
John Hays, M.D., The Ohio State University  
 
  
  
 
James Lee, M.D., Ph.D., University of Pittsburgh  
Kim Reiss Binder, M.D., University of Pennsylvania  
Luis A. Diaz, M.D., Memorial Sloan Kettering Cancer Center  
 
Statistician:   
 
 
  
Lead Study Coordinator:  
 
Hao Wang, PhD  
Laveet Aulakh  
 
  
Lead Research Nurse:  
  
Regulatory Specialist:    
  
Holly Kemberling, RN  
Jennifer Durham, PhD  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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Merck Supplied Agent:  
MK-3475  
  
IND:   
  
  
  
     
  
IND 118566  
  
IND Sponsor:  
Dung Le, M.D.  
  
 
  
Protocol Type / Version # / Version Date: Original/ Version 1/ May 1, 2013  
Original/ Version 1.1/ May 30, 2013  
Amendment 1/ Version 2/ July 18, 2013  
Amendment 2/ Version 3/ September 19, 2013  
Amendment 3/ Version 4/ January 13, 2014  
Amendment 4/ Version 5/ March 18, 2014  
Amendment 5/ Version 6/ May 5, 2014  
Amendment 6/ Version 7/ November 19, 2014  
Amendment 7/ Version 8/ May 1, 2015  
Amendment 8/ Version 9/ November 20, 2015  
Amendment 9/ Version 10/ January 3, 2017  
Amendment 10/ Version 11/ February 9, 2017  
Amendment 11/ Version 12/ December 1, 2017  
  
  
  
  
  
  
  
  
 
 
 
 
 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
Amendment 11/ Version 12/ December 1, 2017  
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SCHEMA  
  
  
  
 
TABLE OF CONTENTS  
SCHEMA 
.........................................................................................................................................3  
1. 
OBJECTIVES 
......................................................................................................................7  
1.1 
Primary 
Objectives 
...................................................................................................7  
1.2 
Secondary 
Objectives 
...............................................................................................7 1.3  
Exploratory 
Objectives ............................................................................................7  
 
1.4   
Study Design ............................................................................................................8  
2. 
BACKGROUND 
...............................................................................................................11  
2.1 
Study 
Disease 
.........................................................................................................11  
2.2 
MK-3475 
................................................................................................................11  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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2.3 
Preclinical and Clinical Trial Data .........................................................................13  
2.4 
Rationale ................................................................................................................13  
3. 
PATIENT 
SELECTION 
....................................................................................................14  
3.1 
Eligibility Criteria ..................................................................................................14  
3.2 
Exclusion Criteria ..................................................................................................16 
3.3  
Inclusion 
of 
Women 
and 
Minorities 
......................................................................18  
3.4 
MSI Testing ...........................................................................................................18  
3.5 
Testing for high mutational burden........................................................................19  
4. 
REGISTRATION 
PROCEDURES 
...................................................................................19  
4.1 
General 
Guidelines 
.................................................................................................19  
4.2 
Registration 
Process 
...............................................................................................19  
5. 
TREATMENT 
PLAN 
........................................................................................................20  
5.1 
Agent 
Administration 
.............................................................................................20  
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................21  
5.3 
Dosing 
Criteria 
.......................................................................................................23  
5.4 
Definition of an Overdose for this Protocol ...........................................................23  
5.5 
Contraception, Use in Pregnancy, Use in Nursing ................................................24  
5.6 
Duration of Therapy ...............................................................................................25 
5.7  
Off 
Treatment 
Evaluation 
and 
Retreatment 
Criteria 
..............................................26  
5.8 
Off Study/Safety Follow-up Visit ..........................................................................27  
5.9 
Duration of Follow Up ...........................................................................................27  
5.10 
Criteria for Removal from Study ...........................................................................28  
6. 
DOSING 
DELAYS/DOSE 
MODIFICATIONS................................................................30  
6.1 
Dose Modifications ................................................................................................30  
6.2 
Dosing Delays ........................................................................................................30  
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................34  
7.1 
Definitions..............................................................................................................34 
7.2  
Relationship 
...........................................................................................................36  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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7.3 
Expectedness 
..........................................................................................................36  
7.4 
Handling of Expedited Safety Reports ..................................................................36  
7.5 
Reporting................................................................................................................37  
8. 
PHARMACEUTICALINFORMATION 
(MK-3475) 
.......................................................39  
8.1 
Agent Accountability .............................................................................................39  
8.2 
Mode of Action ......................................................................................................39  
8.3 
Description 
.............................................................................................................39  
8.4 
Packaging and Labeling Information .....................................................................39  
8.5 
Preparation .............................................................................................................39  
8.6 
Storage ...................................................................................................................39  
8.7 
Stability 
..................................................................................................................40  
8.8 
Route of Administration ........................................................................................40  
8.9 
Patient Care Implications .......................................................................................40 
8.10  
Agent 
Ordering 
......................................................................................................40  
 
8.11   Returns and Reconciliation ....................................................................................41  
9. 
CORRELATIVE/SPECIAL 
STUDIES 
.............................................................................41  
9.1 
Tumor Tissue Studies ............................................................................................41  
9.2 
Peripheral Blood Lymphocytes (PBLs) .................................................................42  
9.3 
Serum and Plasma Marker Studies ........................................................................42 
9.4   
Normal 
tissue 
based 
studies 
...................................................................................43 9.5  Diagnostic 
Tissue 
Samples ....................................................................................43  
 
9.6   
Microbiome Studies ...............................................................................................43  
10. 
STUDY 
CALENDAR 
.......................................................................................................44  
10.1 
Cohorts A-C ...........................................................................................................44  
10.2 
Cohort D.................................................................................................................47  
11. 
MEASUREMENT 
OF 
EFFECT........................................................................................50  
11.1 
Antitumor Effect – Solid Tumors ..........................................................................50  
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ..........................................52  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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12.1 
Data Management ..................................................................................................52 
12.2  
Safety 
Meetings 
.....................................................................................................53  
 
12.3   Monitoring .............................................................................................................53  
13. 
STATISTICAL 
CONSIDERATIONS...............................................................................54  
13.1 
Study Design/Endpoints.........................................................................................54 
13.2 
Sample 
Size/Accrual 
Rate 
......................................................................................54 13.3 Stratification Factors 
..............................................................................................56 13.4 Analysis of 
Primary Endpoints ..............................................................................56  
13.5 
Analysis of Secondary Endpoints ..........................................................................57  
13.6 
Safety Analysis ......................................................................................................58  
13.7 
Biomarker Analysis ...............................................................................................58  
REFERENCES ..............................................................................................................................60  
APPENDIX A: Performance Status Criteria .................................................................................65 
APPENDIX B: Foundation One Tumor Mutational Burden (TMB) Testing................................66  
APPENDIX C: Adverse Event of Clinical Interest (ECI) Reporting Form ...................................67  
APPENDIX D: SAE Reporting Form ...........................................................................................70  
APPENDIX E: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for  
Evaluating Response in Solid Tumors ...............................................................................73  
APPENDIX F: Immune Related Response Criteria ......................................................................76  
APPENDIX G: Data Safety Monitoring Plan (DSMP) .................................................................78  
 
 
  
  
  
  
  
  
  
  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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1. OBJECTIVES  
  
1.1  Primary Objectives  
  
1.1.1 Cohorts A and B: To determine the immune-related progression free survival 
(irPFS) rate at 20 weeks and objective response rate (irORR) in patients with 
MSI positive and negative colorectal adenocarcinoma treated with MK-3475 
using immune related response criteria (irRC) during stages 1 and 2.   
  
1.1.2 Cohort C: To determine the immune-related progression free survival (irPFS) rate 
in patients with MSI positive non-colorectal solid tumor malignancies treated 
with MK-3475 using immune related response criteria (irRC) at 20 weeks 
during stages 1 and 2.   
  
1.1.3 Cohorts A and C: To determine the progression free survival (PFS) rate at 20 
weeks and the objective response rate (ORR) in patients with MSI positive solid 
tumor malignancies treated with MK-3475 using RECIST 1.1 criteria during the 
second expansion.  
  
1.1.4 Cohort D: To estimate objective response rate in patients with MSI-negative solid 
tumor malignancies with a mutator phenotype (i.e. high mutational burden) 
treated with MK-3475 using RECIST 1.1 criteria.  
  
 
1.2  
Secondary Objectives  
  
1.2.1 To determine the overall survival of patients with MSI positive and negative 
tumors treated with MK-3475.  
  
1.2.2 To estimate irPFS and PFS in patients with MSI positive and negative tumors 
treated with MK-3475 at 28 weeks using irRC and RECIST 1.1.  
  
1.2.3 To estimate best overall response rate and disease control rate in patients with 
MSI positive and negative tumors treated with MK-3475.  
  
1.2.4 To assess safety and characterize toxicities of MK-3475 in patients with MSI 
positive and negative tumors.  
  
1.2.5 To evaluate MSI as a marker to predict treatment response.  
  
 
1.3  
Exploratory Objectives  
  
1.3.1 To explore the association of MSI positive, PD-L1 positivity, and tumor 
infiltrating lymphocyte characteristics with clinical responses. Archived tumor 
tissue (when available) and tumor tissue obtained at baseline and during 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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treatment will be compared. In addition, we will compare differences in PD-L1 
expression between the primary and secondary sites of cancer.  
  
1.3.2 To assess tumor tissue for molecular determinants of response, progression and 
disease stability using next generation sequencing technology.    
  
1.3.3 To assess tumor burden dynamics using both standard protein biomarkers such as 
CEA, CA19-9, and other exploratory circulating biomarkers in serial collections 
of sera and plasma at baseline and throughout treatment.    
  
1.3.4 To assess the baseline characteristic of the subjects enrolled and to correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity.  
DNA will be extracted from whole blood and used to evaluate for any germline 
mutations which may correlate with response or toxicity.  
  
1.3.5 To collect peripheral blood lymphocytes to explore the association of MSI 
positive, PD-1 positivity, and lymphocyte activation markers with clinical 
responses.    
  
1.3.6 To determine alternative markers of MSI status. This includes but is not limited 
to MLH 1, MSH 2, MSH 6, PMS2, BRAF pV600E, and TGFBR2.  
  
 
1.4   Study Design  
  
This is a multi-center, open label, two-stage, phase 2 study to evaluate the clinical 
activity of MK-3475 in MSI positive and MSI negative solid tumors.  We will enroll 
four cohorts of patients to receive MK-3475:  patients with MSI positive colorectal 
adenocarcinomas (Cohort A); patients with MSI negative colorectal adenocarcinomas 
(Cohort B); and patients with MSI positive solid tumor malignancies but not colorectal 
adenocarcinoma (Cohort C); and patients with MSI-negative solid tumor malignancies 
that have a mutator phenotype (Cohort D). MK-3475 will be administered at 10 mg/kg 
every 14 days for Cohorts A, B, and C. MK-3475 will be administered at 200 mg every 
21 days for Cohort D. Archived tumor samples or newly obtained biopsies will be used 
for determining MSI, or a mutator phenotype.   
  
MSI positive tumors will be defined using standard clinical criteria and require at least 
two affected loci[1, 2].  Patients in Cohorts A, B, and C will be evaluable if they receive 
one dose of MK-3475 and if MSI results are confirmed using the MSI Analysis System 
from Promega (Section 3.4). With amendment 9, the decision was made to not require 
retesting with Promega if MSI status is confirmed by IHC or other PCR.  
  
Eligibility for Cohort D will be determined using a CLIA certified test measuring 
mutational burden. Patients in Cohort D will be evaluable if they receive one dose of 
MK-3475 and have a MSI-negative solid tumor malignancies with a documented 
mutation burden level measured at > 20 mutations per megabase pairs (MB) using the 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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Foundation Medicine (FoundationOne.com) targeted sequencing panel that reports 
mutation burden.   
  
The primary endpoints for Cohorts A and B are immune-related progression-free  
survival (irPFS) rate at 20 weeks and objective response rate (irORR) assessed using 
immune related response criteria (irRC); irPFS is defined as the proportion of subjects 
alive and free of disease progression at 20 weeks per irRC; and irORR is the proportion 
of subjects whose best overall response is a CR or PR. Each cohort will be assessed 
separately.    
  
The primary endpoint for Cohort C is immune-related progression-free survival (irPFS) 
rate assessed using immune related response criteria (irRC) at 20 weeks, defined as the 
proportion of subjects alive and free of disease progression at 20 weeks per irRC.  
  
The primary endpoint for Cohort D will be response rate, which is defined as the 
proportion of subjects who have response of CR or PR, using RECIST 1.1 criteria.    
  
This design aims to evaluate treatment benefit and evaluate MSI as a predictive 
biomarker for treatment with MK-3475 simultaneously.  
  
For Cohorts A and B, MK-3475 will be considered to be inactive and of no interest for 
further evaluation if the irPFS rate at 20 weeks is 5% (p10) or less or irORR is 5% (p20) 
or less, and considered active if the irPFS rate at 20 weeks is 25% or greater (p11) and 
irORR is 21% or greater (p21). The endpoints will be tested in the hierarchical order 
first with irPFS at 20 weeks. If the null hypothesis of 20-week irPFS being 5% is 
rejected (i.e. the result reaches statistical significance), we will proceed to test for 
irORR. If irPFS is not significant at the 0.05 level (one-sided test), the statistical testing 
for irORR will not occur.   
  
A two-stage Green-Dahlberg design is used for Cohort A and B. An interim analysis 
will be conducted in order to assess futility after irPFS at 20 weeks are available for the 
first 15 evaluable patients. Based on Green-Dahlberg design, if 0 irPFS are observed, 
enrollment in that cohort will be terminated. If at least one patient is free of disease 
progression at 20 weeks per irRC, an additional 10 evaluable subjects will be enrolled 
into that cohort. If 3 or fewer patients are progression free at 20 weeks in the total of 25 
evaluable patients enrolled in that cohort, then the regimen will be considered inactive 
in that cohort. If 4 or more patients are progression free at 20 weeks, we proceed to test 
for the endpoint of irORR in that cohort. If 4 or more responders (CR or PR) are 
observed, we conclude the regimen is promising with that cohort and warrants further 
study for that cohort.  
  
For Cohort C, MK-3475 will be considered to be inactive and of no interest for further 
evaluation if the irPFS rate at 20 weeks is 5% (p0) or less and considered active if the 
irPFS rate at 20 weeks is 25% or greater (p1).   
  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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A two-stage Green-Dahlberg design is used for Cohort C. An interim analysis will be 
conducted in order to assess futility after irPFS at 20 weeks are available for the first 
14 evaluable patients. If 0 irPFS are observed, enrollment in Cohort C will be 
terminated. If at least one patient is free of disease progression at 20 weeks per irRC, 
an additional 7 evaluable subjects will be enrolled into Cohort C. If 3 or fewer patients 
are progression free at 20 weeks in the total of 21 evaluable patients enrolled in Cohort 
C, then the regimen will be considered inactive in that cohort. If 4 or more patients are 
progression free at 20 weeks, we conclude the regimen is promising and warrants 
further study for this patient population.  
  
As of 28Jan2015, four irPFS at 20 weeks and four PRs have been observed in each 
Cohort A and Cohort C. Since the emerging clinical data suggest promising clinical 
activity, up to an additional 50 patients will be enrolled in each of these cohorts under 
a second expansion in Amendment 7. Tumor assessments in the second expansion 
cohort will be evaluated by RECIST 1.1 criteria only, and ORR will be the primary 
endpoint for the expanded Cohort A and Cohort C.  
  
For Cohort D, the regimen would be considered of insufficient activity for further study 
if the response rate is 5% or less, and the minimum required level of efficacy that would 
warrant further study with the proposed regimen is a 21% response rate. A two-stage 
Green-Dahlberg design is planned. A total of 20 subjects will be entered in the first 
stage. If zero response is observed, that cohort will be terminated and we will conclude 
the regimen is ineffective. If >1 subjects respond, then additional 15 subjects will be 
studied for that cohort.  If < 4 subjects respond in stage one and two combined, we 
consider this regimen ineffective. If >5 responses are observed, we conclude the 
regimen is promising and warrant further study. Each cohort could also be terminated 
as soon as 5 responses are observed before the total cohort is enrolled or evaluated in 
that cohort. The maximum sample size will be 35 for each cohort. This design provides 
90% power to detect an absolute difference of 16% of response with a type I error of 
0.05. There is a 36% chance to stop the trial early for futility under 5% response rate.  
  
No intra-subject dose escalation or reduction is allowed.  Patients who do not receive 
at least 1 dose of MK-3475 will be replaced.  
  
Patient immune and clinical responses will be evaluated through the following methods 
at baseline and during treatment: 1. tumor biopsies, 2. peripheral blood lymphocytes, 
3. serum and plasma, and 4. CT/MRI scans will be obtained for assessment of activity 
and correlative studies.   
  
Patients who have a confirmed complete response by two scans ≥ 4 weeks apart and 
who have been on MK-3475 treatment for at least 6 months may discontinue MK3475 
treatment at the discretion of the investigator after receiving at least two doses beyond 
the initial determination of CR. MK-3475 may be resumed upon disease recurrence in 
these patients. Treatment may also be resumed in patients with SD, PR or CR who 
stopped MK-3475 treatment after 24 months of study therapy for reasons other than 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
Amendment 11/ Version 12/ December 1, 2017  
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disease progression or intolerability. Criteria and procedures for retreatment are 
described in Section 5.6 and 10.0.   
  
Patients with tumor progression by RECIST imaging or laboratory parameters prior to 
their 7 month evaluation but without rapid clinical deterioration or significant change 
in performance status who do not require additional immediate therapy, may continue 
to be treated with MK-3475 and clinically observed following the assigned imaging 
schedule to allow detection of a subsequent tumor response (see Section 5.10.1 for 
further details).   
  
All patients will be followed for at least 30 days after their last dose of study drug 
(serious adverse events will be collected for 90 days after the last infusion of MK3475) 
or until initiation of a new anti-cancer treatment, whichever occurs first.  
Patients who are discontinued from the study due to an unacceptable drug-related AE 
will be followed until the resolution of the AE to Grade 0-1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. Information of the 
new cancer therapy will be collected.  
Patients who discontinued study therapy without documented disease progression 
should continue to be monitored for disease status by radiologic imaging.  Disease 
monitoring should continue to be assessed every approximately every 12 weeks for 3 
years (approximately every 6 months after 3 years) until, 1) start of a new antineoplastic 
therapy (information of the new cancer therapy will be collected),  2) documented 
disease progression, 3) study closure, or 4) until death, whichever occurs first.  
  
Patients who discontinue from treatment should be contacted every three months to 
monitor overall survival.  Information of other cancer therapies after discontinuation 
from the study treatment will be collected.  
  
2. BACKGROUND  
  
 
2.1  
Study Disease  
  
Microsatellite instability (MSI) is the accumulation of sequencing errors in 
microsatellites.  This occurs in tumors with deficiency in DNA mismatch repair.  MSI 
is present in Lynch Syndrome which is an inherited cancer syndrome that predisposes 
patients to colon, endometrial, gastric cancer, ovarian, small intestine, liver, 
hepatobiliary, upper urinary tract, brain, and prostate cancer.  MSI is also present in 10-
20% of sporadic colorectal [3], gastric [4], prostate [5], lung [6, 7], ampullary [8], and 
endometrial cancers [9].   Between 0.3% and 13% of pancreatic cancers are reported to 
be MSI as well [10]. The study is designed to test an immunotherapy in MSI colorectal 
adenocarcinomas with an additional exploratory cohort in other MSI disease types.   
  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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2.2  
MK-3475  
  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [11].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies [12-47].  In particular, the presence of 
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems 
to correlate with improved prognosis and long-term survival in solid malignancies such 
as ovarian, colorectal and pancreatic cancer, hepatocellular carcinoma, malignant MEL 
and RCC.  TILs can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as melanoma [48; 49].  
  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control [11].   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. The ligands for PD1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in various tumors [12-15].  
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 [50].  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found 
to correlate with poor prognosis and survival in various cancer types, including renal 
cell carcinoma (RCC) [16], pancreatic carcinoma [17], hepatocellular carcinoma [18], 
ovarian carcinoma [19] and non-small cell lung cancer (NSCLC) [28].  Furthermore, 
PD-1 has been suggested to regulate tumor-specific Tcell expansion in patients with 
malignant MEL [20]. The observed correlation of clinical prognosis with PD-L1 
expression in multiple cancers suggests that the PD1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention.  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
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2.3  
Preclinical and Clinical Trial Data  
  
Refer to the Investigator’s Brochure [IB] for Preclinical and Clinical Data  
  
 
2.4  
Rationale  
  
Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA4) 
and programmed death-1 (PD-1) is showing promise in patients with cancer.  CTLA-4 
and PD-1 are upregulated on activated T cells and provide inhibitory signals to T cells 
undergoing activation. Inhibitory antibodies directed at these receptors have been 
shown to break immune tolerance and promote anti-tumor immunity.  MK-3475 is a 
humanized monoclonal IgG4 antibody against PD-1 and is showing activity in multiple 
tumor types including melanoma and non-small cell lung cancer (NSCLC).  Previously, 
activity of a different PD-1 blocking antibody, BMS-936558, a fully humanized 
monoclonal  IgG4 antibody, also showed activity in melanoma, NSCLC, and a 
complete response in a single patient with colorectal cancer [28, 51].    
  
As with all targeted therapies, we expect a subset of patients will respond to 
immunotherapy and there may be genetic determinants that define an ‘immune 
responsive’ phenotype.  A cancer genomics perspective may provide insight as to why 
patients with melanoma and NSCLC, and perhaps other tumor types, respond to these 
therapies. The average number of somatic mutations in human cancer varies widely 
(Table 1) [52]. Three factors are known to be associated with high somatic mutation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
Amendment 11/ Version 12/ December 1, 2017  
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burdens:  exposure to environmental carcinogens (e.g. UV radiation and tobacco) [53, 
54]; repair defects (e.g., mismatch repair gene inactivation) [55]; or exposures to 
mutagenic therapies (e.g., alkylating agents) [56].  Melanomas and NSCLC are known 
to have high burdens of somatic mutations. We therefore hypothesize that there will be 
a correlation between the number of somatic mutations in individual tumors and the 
response to immune checkpoint inhibitors since each protein‐coding mutation has the 
potential to serve as a novel antigen for an immune response. If this hypothesis is 
correct, it would suggest that immune checkpoint inhibitors might work best in tumors 
with exceptionally high mutation burdens (>500 somatic mutations per exome).  
Furthermore, tumors deficient in mismatch repair, as well as other genetic alterations 
consistent with a mutator phenotype such as POLD1, and POLE mutations, may be 
particularly susceptible to immunotherapy as this phenotype results in ongoing 
accumulation of mutations at a high frequency.    
  
  
  
MSI tumors are deficient in DNA mismatch repair which leads to a high rate of 
spontaneous mutations and the potential for the expression of neo-antigens.  
Furthermore, similar to melanoma, MSI positive colon cancers, there is often prominent 
lymphocyte infiltration [3, 4].  This is another clue that this subset of tumors may have 
baseline tumor infiltrating lymphocytes that can be harnessed with immune checkpoint 
blockade.  Interestingly, the colorectal patient with the complete response is known to 
have an MSI positive tumor [57].  This study aims to evaluate MSI as a predictor of 
response to anti-PD-1 blockade with MK-3475.  
  
Recent prospective studies looking at mutational burden (i.e. MSI) and PD-L1 staining 
have shown a positive correlation between these biomarkers and clinical response.  
Retrospectively, several candidate biomarkers appear promising including mutational 
burden in non-MSI tumors. Mechanistically, we believe that a tumor with high degree 
of ‘foreignness’ will trigger a potent anti-tumor immune response.  A tumor will look 
foreign to the host immune system if they have a very high mutational burden or 
hypothetically (yet to be proven) if they harbor a virus or express an embryonic protein.  
The functional consequence of a highly foreign tumor is a lymphocytic infiltrate and 


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16 
high IFN-γ levels.  As a mechanism of immune evasion a number of immune 
checkpoints (i.e.PD-1) are upregulated. Since the functional consequence of tumor 
foreignness is lymphocytic infiltration of the tumor, we propose that this may be a 
highly sensitive predictive marker of response to checkpoint blockade.  
  
3. PATIENT SELECTION  
  
 
3.1  
Eligibility Criteria  
  
3.1.1 Cohort A:  Patients with histologically proven metastatic or locally advanced MSI 
colorectal adenocarcinoma.    
  
3.1.2 Cohort B:  Patients with histologically proven metastatic or locally advanced 
microsatellite stable (MSS) colorectal adenocarcinoma.  
  
3.1.3  Cohort C: Patients with histologically proven metastatic or locally advanced non-
colorectal MSI solid tumor malignancies.  
  
3.1.4 Cohort D: Patients with histologically proven metastatic or locally advanced solid 
tumor malignancies that are microsatellite stable with a documented mutation 
burden level measured at > 20 mutations per megabase pairs (MB).   
  
3.1.5  Patients with the presence of at least one lesion with measurable disease as 
defined by 10mm in longest diameter for a soft tissue lesions or 15mm in short 
axis for a lymph node by RECIST 1.1 and irRC criteria for response 
assessment.  
  
3.1.6 Patients must agree to have a biopsy at baseline and on treatment if the lesion can 
be biopsied with acceptable clinical risk (as judged by the investigator).  
  
3.1.7 Patients with colon cancer (Cohort A and B) must have received at least 2 prior 
cancer therapy regimens.  Patients with other cancer types (Cohort C) must have 
received at least 1 prior cancer therapy regimen. Patients in Cohort D must have 
received at least 1 prior cancer therapy regimen. Patients must have progressive 
disease on study entry.  
  
 
3.1.8  Age >18 years.    
  
 
3.1.9  ECOG performance status 0-1 (Appendix A).  
  
3.1.10 Life expectancy of greater than 3 months.  
  
3.1.11 Patients must have normal organ and marrow function as defined below:  
  
 Absolute neutrophil count   
>1,000/mcL  


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 Platelets   
  
  
  
  
  
3 
>90 x 10 /uL  
 Hemoglobin   
  
  
  
  
>9.0 g/dL  
 Total bilirubin   
  
  
  
<1.5x 
ULN 
(patients 
with 
diagnosed 
Gilbert’s Syndrome will not be excluded if 
their direct bilirubin is within normal 
institutional limits)  
 AST(SGOT)/ALT(SGPT)   
<3x ULN   
 Creatinine    
  
  
  
  
1.5 x ULN  
  
3.1.12 Female patient of childbearing potential has a negative urine or serum pregnancy 
test.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  The serum pregnancy test must be negative for 
the patient to be eligible.  
  
3.1.13 Female patients enrolled in the study, who are not free from menses for >2 years, 
post hysterectomy / oophorectomy, or surgically sterilized, must be  
willing to use either 2 adequate barrier methods or a barrier method plus a 
hormonal method of contraception to prevent pregnancy or to abstain from 
heterosexual activity throughout the study, starting with Visit 1 through 120 
days after the last dose of study therapy.  Approved contraceptive methods 
include for example; intra uterine device, diaphragm with spermicide, cervical 
cap with spermicide, male condoms, female condoms with spermicide, or oral 
contraceptives.  Spermicides alone are not an acceptable method of 
contraception.  
Male patients must agree to use an adequate method of contraception starting 
with the first dose of study drug through 120 days after the last dose of study 
therapy.  
  
3.1.14 Ability to understand and the willingness to sign a written informed consent 
document.  
  
 
3.2  
Exclusion Criteria  
  
3.2.1 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 1 week prior to trial treatment.  
This is not applicable to patients with primary brain tumors.  
  


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3.2.2  Patient who has had chemotherapy, or biological cancer therapy within 2 weeks 
prior to the first dose of study drug. Patient who has had radiation within 2 
weeks prior to the first dose of study drug.    
  
3.2.3 Patient is currently participating or has participated in a study of an investigational 
agent or using an investigational device within 4 weeks of the first dose of study 
drug.  
  
3.2.4   Patient is expected to require any other form of systemic or localized 
antineoplastic therapy while on study.  
  
3.2.5 Patients who have had surgery within 4 weeks of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc), celiac plexus block, 
and biliary stent placement.  
  
3.2.6  Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-
PDL2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies.  
  
3.2.7 Patients who have received any of the following concomitant therapy: IL-2, 
interferon or other non-study immunotherapy regimens; immunosuppressive 
agents; other investigational therapies; or chronic use of systemic 
corticosteroids (used in the management of cancer or non-cancer-related 
illnesses) within 1 week prior to first dose. Note: Systemic steroid therapy 
allowed for subjects with primary brain tumors as long as ≤ dexamethasone 4 
mg or its steroid equivalent.  
  
3.2.8 Patients who have received a live vaccine within 4 weeks prior to or after any 
dose of MK-3475.   
  
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines, and are not allowed.  
  
3.2.9 Patients receiving growth factors including, but not limited to, granulocytecolony 
stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor 
(GM-CSF), erythropoietin, etc. within 2 weeks of study drug administration. 
Use of such agents while on study is also prohibited. Prior use of growth factors 
should be documented in the patient’s medical history.  
  
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.  
  


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3.2.11 Has an active autoimmune disease that has required systemic treatment in past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
  
3.2.12 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment.  
  
3.2.13 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Patients with a history of 
allogeneic hematopoeitic stem cell transplant will be excluded.  
  
3.2.14  Patients with a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies).  
  
3.2.15 Patients with a known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected).  
  
3.2.16 Patients with evidence of interstitial lung disease.  
  
3.2.17 Patients with a pulse oximetry of <92% on room air.  
  
3.2.18 Patients on supplemental home oxygen.  
  
3.2.19 Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or had a recent history (within the last 
year) of substance abuse (including alcohol).  
  
3.2.20 Women who are pregnant or breastfeeding.  
  
3.2.21 Women with a positive pregnancy test on enrollment or prior to investigational 
product administration.  
  
3.2.22 Sexually active fertile men not using effective birth control if their partners are 
WOCBP.  
  
 
3.3  
Inclusion of Women and Minorities  
  
Both men and women of all races and ethnic groups are eligible for this trial.    
  
 
3.4   MSI Testing  
  


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MSI testing is already standardized and performed in CLIA-certified laboratories 
without need for assay development. Archived tumor samples or newly obtained 
biopsies will be used for determining MSI. For patients who do not have sufficient 
normal tissue for MSI testing purposes, a buccal swab or purple top blood tube will be 
obtained. MSI testing in colorectal cancer is already clinically indicated. For other non-
colorectal cancers where MSI testing is not currently clinically indicated, a 
prescreening consent will be obtained to collect tissue for MSI testing. The 
prescreening consent can be obtained over the phone.  A copy of the consent will be 
faxed to the site and the original will be mailed.  MSI status will be performed locally 
by CLIA certified immunohistochemistry (IHC) or PCR based tests for eligibility.   
  
Evaluable patients will be confirmed using the MSI Analysis System from Promega. 
This test will determine MSI status through the insertion or deletion of repeating units 
in the five nearly monomorphic mononucleotide repeat markers (BAT-25, BAT-26, 
MON0-27, NR-21 and NR-24). At least 2 MSI loci are required to be evaluable in 
Cohorts A and C. Patients may be assigned to a new cohort and/or replaced based on 
the Promega test results. With amendment 9, the decision was made to not require 
retesting with Promega if MSI status is confirmed by IHC or other PCR.  
  
The MSI Analysis System (Promega), Version 1.2, is a fluorescent multiplex PCRbased 
method used to detect microsatellite instability (MSI), a form of genomic instability. 
This instability is due to insertion or deletion of repeating units during DNA replication 
and failure of the mismatch repair system (MMR) to correct these errors. MSI analysis 
typically involves comparing allelic profiles of microsatellite markers generated by 
amplification from matching pairs of test samples, which may be MMR-deficient, and 
normal tissue samples. New alleles in the abnormal sample not found in the 
corresponding normal sample indicate the presence of MSI.   
  
The MSI Analysis System, Version 1.2, includes fluorescently labeled primers (marker 
panel) for co-amplification of seven markers for analysis of the MSI-high (MSI-H) 
phenotype, including five nearly monomorphic mononucleotide repeat markers (BAT-
25, BAT-26, MON0-27, NR-21 and NR-24) and two highly polymorphic 
pentanucleotide repeat markers (Penta C and Penta D). Amplified fragments are 
detected using an ABI PRISM® 310, 3100, 3100-Avant, 3130 or 3130xl Genetic 
Analyzer after spectral calibration. GeneMapper® 4.0 software will be used for data 
analysis and assignment of genotype.  
  
For cohort D, any testing performed in a CLIA-certified laboratory for mismatch repair 
deficiency (MRD) or MSI using IHC, PCR or next generation sequencing (NGS) 
approach can be used to exclude the presence of MRD or MSI.  
  
 
3.5   Testing for high mutational burden  
  
We postulate that tumors that harbor a high number of somatic mutations will have a 
favorable response to checkpoint blockade. The best way to determine mutational 


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Amendment 11/ Version 12/ December 1, 2017  
21 
burden is through whole genome or exome sequencing.  A surrogate to exome or whole 
genome sequencing is targeted sequencing of a large fraction of the exome to determine 
total mutational burden.  Mutations can occur as silent mutations (synonymous) or 
missense mutations (non-synonymous).  We would like to treat tumors that harbor > 20 
mutations per megabase pairs.  
  
For the purposes of this study, measuring mutational burden will be performed locally 
by a CLIA certified test for eligibility. Evaluable patients will be confirmed using 
Foundation Medicine (http://foundationone.com/) targeted sequencing panel that 
reports mutation burden.  Please see Appendix B for information regarding this test.  
  
4. REGISTRATION PROCEDURES  
  
 
4.1   General Guidelines  
  
Eligible patients will be entered on study centrally at the Sidney Kimmel 
Comprehensive Cancer Center at the Johns Hopkins University by the Lead Study 
Coordinator.  All sites should contact the Protocol Chair at 
to verify 
ongoing study enrollment.  The fax cover sheet, Registration Form, and Eligibility 
Worksheet will be supplied to each participating site.  
  
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified 
of cancellations as soon as possible.  
  
 
4.2  
Registration Process  
  
To register a patient, the following documents should be completed and sent to the  
Lead Study Coordinator at the Coordinating Center at 
  
• 
Fax cover sheet  
• 
Registration Form  
• 
Signed patient consent form  
• 
HIPAA authorization form  
• 
Eligibility Screening Checklist  
• 
Copy of required screening tests and scans  
  
The Research Nurse or Study Coordinator at the participating site will then call or email 
the Lead Study Coordinator at the  Coordinating Center to verify eligibility.  To 
complete the registration process, the Coordinating Center Lead Study Coordinator 
will:  
• 
Assign a patient study number  
• 
Register the patient on the study  
• 
Fax or e-mail the patient study number to the participating site  


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Amendment 11/ Version 12/ December 1, 2017  
22 
• 
Call or e-mail the research nurse or data manager at the participating site and 
verbally confirm registration.  
  
  
5. TREATMENT PLAN  
  
 
5.1  
Agent Administration  
  
Treatment will be administered on an outpatient basis.  Appropriate dose modifications 
are described in Section 6.  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
malignancy.  
  
 
REGIMEN DESCRIPTION  
 
 
Agent  
Premedications; Precautions  
Dose  
Route  
Schedule  
Cycle 
Length  
MK-3475  
No prophylactic pre-
medication will be given 
unless indicated by previous 
experience in an individual 
patient per section 5.2.1.  
10 mg/kg  
(Cohorts  
A, B, and  
C)  
  
200 mg  
(Cohort  
D)  
IV over 30 
minutes  
Day 1  
14 days  
(Cohort 
s A, B,  
and C)  
  
21 days  
(Cohort  
D)  
  
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).  
The pharmacists will prepare the MK-3475 medication for administration.  The  
Procedures Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.  This document is 
available for reference by the pharmacist and study personnel.  
  
 
5.2  
General Concomitant Medication and Supportive Care Guidelines  
  
MK-3475 is a humanized monoclonal Ab. Subjects should be closely monitored for 
potential adverse reactions during antibody infusion and potential adverse events 
throughout the study. Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined in Section 6.2.  
  
5.2.1 Infusion Reactions  


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23 
MK-3475 infusion reactions may consist of fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, 
dizziness or hypertension.  Severe reactions may include acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock.  
Patients should be closely monitored for such reactions.  Guidelines for patients who 
experience an infusion related or allergic reaction during or after infusion with MK-
3475 are shown below.  
  
Guidance on Infusion and Hypersensitivity Reactions:  
  
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 further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:  
  
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).  
  
Acetaminophen 500-1000 mg po  
(or equivalent dose of antipyretic).  
NCI CTCAE Grade  
Treatment  
Premedication at subsequent 
dosing  
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  


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Amendment 11/ Version 12/ December 1, 2017  
24 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.  
  
  
5.2.2 Immune-Related Adverse Events (IRAEs)   
  
Blocking PD-1 function may permit the emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/pruritis, diarrhea/colitis, pneumonitis, hepatitis, 
and hypothyroidism were drug-related, presumptive autoimmune events, now termed 
IRAEs, noted in previous BMS 936558 studies.   
  
For the purposes of this study, an IRAE is defined as an AE of unknown etiology, 
associated with drug exposure and is consistent with an immune phenomenon. Efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an AE an IRAE. Serological, immunological, and histological 
(biopsy) data should be used to support the diagnosis of an immune-mediated toxicity. 
Suspected IRAEs must be documented on an AE or SAE CRF. Identification and 
treatment of IRAEs can be found in Section 6.2.  
  
Patients who experience a Grade 3 or higher irAE should be discussed with Dr. Le 
immediately. In addition, AEs listed in Section 7.1.3 must be reported as an Event of 
Clinical Interest (ECI) within 24 hours to the IND Sponsor and Merck Global Safety 
even if no Serious Adverse Event Criteria are met.  
  
5.2.3 Prohibited Medications  
  
The following therapies are not permitted during the treatment period (if administered, 
the subject may be removed from the study):  
  
• Any non-study anticancer chemotherapy or immunotherapy (approved or 
investigational)  
• Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF)  
• Live vaccines (examples of live vaccines include, but are not limited to: 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 IND Sponsor.  
  
Note: Inhaled steroids for management of asthma are permitted.  
  
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV 
contract dye) is permitted.  


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25 
  
Note: Physiologic doses of corticosteroids for adrenal insufficiency are permitted.  
  
 
5.3   Dosing Criteria  
  
Dosing will be delayed for the following laboratory criteria:   
  
• 
AST, ALT > 3 x ULN    
• 
Total bilirubin >1.5 x ULN  (patients with diagnosed Gilbert’s Syndrome, direct 
bilirubin should be within normal institutional limits)  
• 
Hemoglobin < 8 g/dL  
• 
ANC < 1000/uL   
• 
Platelets < 80 x 103/uL  
  
 
5.4  
Definition of an Overdose for this Protocol  
  
Overdose is defined as:  
The patient has taken (accidentally or intentionally) a dose exceeding the dose 
prescribed in the protocol by 20%. 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 experience(s) is associated with (“results from”) the overdose of test drug 
or vaccine, the adverse experience(s) is reported as a serious adverse experience, even 
if no other criteria for serious are met.  
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose 
is reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.”  
All reports of overdose with and without an adverse experience must be reported within 
24 hours to the Sponsor and Merck Global Safety.  Merck Global Safety (GS) contact 
information can be found in Section 7.5.1.  
 
5.5  
Contraception, Use in Pregnancy, Use in Nursing  
  
5.5.1 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.  Nonpregnant, 
non-breast-feeding women may be enrolled if they are considered highly unlikely to 
conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater 
than 2 years will be considered postmenopausal), or 3) amenorrheaic for <2 years 


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without a hysterectomy and oophorectomy and with a documented FSH value in the 
postmenopausal range, or 4) not heterosexually active for the duration of the study, or 
5) heterosexually active and willing to use 2 methods of birth control (which is also 
required for the female partners of male patients). The 2 birth control methods can be 
2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy, 
used throughout the study starting with Visit 1through 120 days after the last dose of 
study medication.  Male patients enrolled in this study must also agree to use an 
adequate method of contraception starting with Visit 1 through 120 days after the last 
dose of study drug.  
  
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide.  
Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including 
oral, subcutaneous, intrauterine, or intramuscular agents).  
  
Patients should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  In order 
to participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study.  If there is any question that a patient will not 
reliably comply with the requirements for contraception, that patient should not be 
entered into the study.  
  
5.5.2 Use in Pregnancy  
  
MK-3475 may have adverse effects on a fetus; therefore, women with a positive 
pregnancy test at screening will not be eligible for enrollment.  If a patient inadvertently 
becomes pregnant while on treatment with MK-3475, the patient will immediately be 
removed from the study.  The site will contact the patient at least monthly and document 
the patient’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck Global Safety without 
delay.  The outcome must be reported to the Sponsor within 24 hours and to Merck 
Global Safety if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or lifethreatening complication to the mother or 
newborn).  If a male patient’s partner becomes pregnant on study the pregnancy must 
be reported to the Sponsor and to Merck Global Safety as described in Section 7.5.1.  
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 and to Merck Global Safety.  
  
5.5.3 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, patients who are breast-feeding are not eligible for enrollment.  


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5.6  
Duration of Therapy  
  
A subject must be discontinued from the trial for the following reason:  
  
• The subject or legal representative (such as a parent or legal guardian) 
withdraws consent.  
A subject must be taken off study (but may continue to be monitored in the 
posttreatment follow-up portion of the trial per Section 5.9) for any of the following 
reasons:  
  
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent for treatment  
• 
Disease progression after 7 months of therapy.  Approval for continuation 
from the IND sponsor may be obtained if the patient is thought to be 
clinically benefiting.   
  
• 
Intercurrent illness that prevents further administration of treatment,  
  
• 
Unacceptable adverse event(s) (see section 5.10.2),  
  
• 
Need for >2 dose delays due to the same toxicity as per the dose delay 
guidelines (see Section 6.2)  
  
• 
Patient withdraws consent,  
  
• 
If in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the patient.  The 
IND Sponsor and Merck should be included in this decision,  
  
• 
Noncompliance with trial treatment or procedure requirements,  
  
• 
Patient is lost to follow-up, or  
  
• 
Patient becomes pregnant.  
  
  
A subject must be taken off treatment (but continue to be monitored in the post-treatment 
follow-up portion of the trial per Section 5.7.1) for the following reason:  
  
 
  Completed 24 months of treatment with MK-3475 (see Section 5.7)  
  
Note: 24 months of study medication is calculated from the date of first dose.   


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28 
    
 
5.7  
Off Treatment Evaluation and Retreatment Criteria  
  
5.7.1 Off Treatment Evaluation  
  
If a patient is discontinued from MK-3475 after completion of 24 months of treatment 
(or the patient has discontinued MK-3475 after an investigator determined confirmed 
CR), a mandatory Off Treatment Evaluation should be performed 30 days (+/- 7 days) 
after the last infusion of MK-3475 as described in Section 10. The assessment of AEs 
and medications can be made either as part of a clinical visit or over the phone. Patients 
should continue to be monitored for disease status by radiologic imaging and tumor 
marker(s) every 12 weeks (+/- 2 weeks) for 1 year (and then every 24 weeks +/- 2 weeks 
after 1 year) while off treatment. These evaluations can be done locally if approved by 
the IND Sponsor. In addition, we will also continue to collect clinical labs, as well as 
peripheral blood, serum, and plasma research samples every 12 weeks (+/- 2 weeks) for 
1 year starting from the last research blood draw as described in Section 10. After 1 
year, clinical labs and research bloods should be collected every 24 weeks (+/- 2 
weeks). Patients will also continue to be monitored for new drugrelated AEs and the 
resolution of ongoing drug-related AEs to ≤ Grade 1. SAEs that occur within 90 days 
of the last infusion of MK-3475 or before initiation of a new antineoplastic treatment, 
whichever occurs first, should also be followed and recorded.  
  
5.7.2 Retreatment with MK-3475  
  
Patients who stop MK-3475 with SD or better may be eligible for up to one year of 
additional MK-3475 therapy if they progress after stopping MK-3745 and they meet 
the following criteria:   
  
EITHER  
  
o Stopped initial treatment with MK-3475 after attaining an investigator 
determined confirmed CR according to RECIST 1.1  
 Was treated for at least 24 weeks with MK-3475 before discontinuing 
therapy  
 Received at least two treatments with MK-3475 beyond the date when the 
initial CR was declared  
  
OR  
  
o Subject had SD, PR or CR and stopped MK-3475 treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability  
  
AND  
  


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• 
Experienced 
an 
investigator-determined 
confirmed 
radiographic 
disease 
progression after stopping their initial treatment with MK-3475  
• 
Did not receive any anti-cancer treatment since the last dose of MK-3475  
• 
Have a performance status of 0 or 1 on the ECOG Performance Scale  
• 
Demonstrate adequate organ function as detailed in Section 5.3  
• 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  
• 
Female subjects of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication (Section 
5.5.1).   
• 
Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.  
• 
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.  
Subjects who restart treatment should resume at the same dose and cycle interval which 
they were receiving prior to discontinuation. Study visit requirements are outlined in 
the Study Calendar (Section 10.0).  
  
 
5.8  
Off Study/Safety Follow-up Visit  
  
After a patient is discontinued from MK-3475, a mandatory Off Study/Safety FollowUp 
Visit should be performed approximately 30 days after the last infusion of study 
medication (or within 7 days prior to initiation of a new anti-cancer treatment, 
whichever comes first). Procedures and assessments performed at this visit and beyond 
should follow the respective guidelines described in Section 10.0 as appropriate.  The 
patient will be monitored for adverse events up to the mandatory Off Study/Safety 
Follow-Up Visit or to resolution of toxicity to Grade 0-1, whichever occurs later.  SAEs 
that occur within 90 days of the last infusion of MK-3475 or before initiation of a new 
antineoplastic treatment should also be followed and recorded.  
  
 
5.9  
Duration of Follow Up  
  
Patients who are discontinued from the study due to an unacceptable drug-related AE 
should continue to be followed for resolution of the AE to Grade 0-1 or stabilization or 
until initiation of a new therapy for their cancer, whichever occurs first.  
Patients, who discontinued study therapy without documented disease progression, 
should continue to be monitored for disease status by radiologic imaging.  Disease 
monitoring should continue to be assessed approximately every 12 weeks for 3 years 
(approximately every 6 months after 3 years) until, 1) start of a new antineoplastic 
therapy (information of the new cancer therapy will be collected),  2) documented 
disease progression, 3) study closure, or 4) until death, whichever occurs first.  
  


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Patients that have come off study to receive the FDA approved dose of pembrolizumab 
for microsatellite instability-high cancer should continue to be monitored for disease 
status by radiologic imaging.  Disease monitoring should continue to be assessed 
approximately every 12 weeks for 3 years (approximately every 6 months after 3 years) 
until, 1) start of a new antineoplastic therapy (information of the new cancer therapy 
will be collected),  2) documented disease progression, 3) study closure, or 4) until 
death, whichever occurs first.  
  
Patients who discontinue from treatment should be contacted every three months to 
monitor overall survival.  Information of other cancer therapies after discontinuation 
from the study treatment will be collected.  
  
SAEs that occur within 90 days of the last infusion of MK-3475 or before initiation of 
a new antineoplastic treatment should also be followed and recorded.  
  
5.10 Criteria for Removal from Study  
  
Patients will be removed from study when any of the criteria listed in Section 5.6 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form.  
  
5.10.1 Disease Progression  
  
MK-3475 is expected to trigger immune-mediated responses, which require activation 
of the immune system prior to the observation of clinical responses.  Such immune 
activation may take weeks to months to be evident.  Some patients may have objective 
volume increase of tumor lesions or other disease parameters within weeks following 
the start of MK-3475 dosing.  Such patients may not have had sufficient time to develop 
the required immune activation or, in some patients, tumor volume or other disease 
parameter increases may represent infiltration of lymphocytes into the original tumor.  
In conventional studies, such tumor volume or relevant laboratory parameter increases 
during the first 2-4 months of the study would constitute PD and lead to discontinuation 
of imaging to detect response, thus disregarding the potential for subsequent immune-
mediated clinical response.   
  
Therefore, patients with tumor progression by RECIST imaging or laboratory 
parameters  prior to their 7 month evaluation but without rapid clinical deterioration or 
change in PS who do not require additional immediate therapy, may continue to be 
treated with MK-3475 and clinically observed following the assigned imaging schedule 
to allow detection of a subsequent tumor response.  Tumor assessments will be made 
using RECIST 1.1 and immune-related RECIST criteria (irRC). Subjects that meet the 
above criteria and continue on study therapy must discontinue MK-3475 if there are no 
signs of disease stabilization by 7 months using irRC (or by the radiologist if irRC is 
still pending). Tumor assessments in the second expansion cohort and Cohort D will be 


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evaluated by RECIST 1.1 criteria only.  Approval for continuation from the IND 
sponsor may be obtained if the patient is thought to be clinically benefiting.   
  
5.10.2 IRAEs  
  
Permanent discontinuation of MK-3475 should be considered for any of the following:  
1. Severe or life-threatening related adverse reactions, including, but not limited to, 
any of the following (IND Sponsor and Merck must be notified in the event of these 
AEs, and final decision regarding treatment will be made after a discussion):  
 Grade 3-4 toxicity (non-hematologic or hematologic).  Grade 3 toxicities may 
be able to be re-dosed on a case by case basis after approval of the IND Sponsor 
and Merck.  
 Diarrhea with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more over baseline), stool incontinence, need for intravenous 
hydration for more than 24 hours, gastrointestinal hemorrhage, and 
gastrointestinal perforation  
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times 
upper limit of normal  
 Total serum bilirubin >3 times upper limit of normal  
 Steven-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by 
full thickness dermal ulceration or necrotic, bullous or hemorrhagic 
manifestations  
 Severe (i.e., CTCAE Grade 3 or 4) motor or sensory neuropathy  
 Any grade Guillain-Barré syndrome, or myasthenia gravis or other neurologic 
symptoms that impact activity of daily living  
 Severe immune-mediated reactions involving any other organs (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis)  
 Immune-mediated 
ocular 
disease 
that 
is 
unresponsive 
to 
topical 
immunosuppressive therapy  
 Grade 3 or 4 infusion reaction  
2. Inability to reduce corticosteroid dose for immune-related adverse reactions to ≤10 
mg prednisone or equivalent per day  
If any of the above events occur, the investigator should discuss with the IND 
Sponsor and Merck to make a decision on discontinuation of MK-3475 study 
treatment.    


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In case toxicity does not resolve or improve to ≤ Grade 1 within 12 weeks after last 
administration of MK-3475 study drug, study therapy discontinuation should be 
considered after discussion with the IND Sponsor and Merck.  With IND Sponsor and 
Merck agreement, patients still at Grade 2 may continue in the study only if 
asymptomatic and controlled.  Two dosing delays due to the same toxicity will be 
permitted.  In the event of a third occurrence of the same toxicity which would require 
dosing delay, study therapy will be discontinued permanently.  
  
6. DOSING DELAYS/DOSE MODIFICATIONS  
  
 
6.1   Dose Modifications  
  
     
Dose reduction or dose increase of MK-3475 will not be permitted in individual 
patients.  
  
 
6.2   Dosing Delays  
  
MK-3475 will be withheld for the following drug-related toxicities and severe or 
lifethreatening AEs as per the table below:  
  
  


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


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34 
AST / ALT  
elevation or 
Increased 
bilirubin  
Grade 2  
Withhold  
 Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper  
  Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable  
Grade 3 or 4   
Permanently 
discontinue   
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper  
Type 1 diabetes  
mellitus (T1DM) 
or  
Hyperglycemia  
  
Newly onset 
T1DM or   
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure  
Withhold  
• Initiate insulin replacement therapy 
for participants with  
T1DM   
• Administer anti-hyperglycemic in 
participants with hyperglycemia   
  
  Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.  
Hypophysitis  
Grade 2  
Withhold  
 Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.    
  
  Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)   
Grade 3 or 4   
Withhold or 
permanently 
discontinue1   
Hyperthyroidism   Grade 2  
Continue   
 Treat with non-selective 
betablockers (eg, propranolol) or 
thionamides as appropriate   
  Monitor for signs and symptoms of thyroid 
disorders.   
 
Grade 3 or 4   
Withhold or  
permanently 
discontinue1  
Hypothyroidism  
Grade 2-4  
Continue   
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care  
  
  
Monitor for signs and symptoms of thyroid 
disorders.   
Nephritis and 
Renal dysfunction  
Grade 2  
Withhold   
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.  
  
  
Monitor changes of renal function  
Grade 3 or 4   
Permanently 
discontinue  


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35 
Myocarditis  
Grade 1 or 2  
Withhold  
 Based on severity of AE administer 
corticosteroids  
  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes  
 
Grade 3 or 4  
Permanently 
discontinue  
All other 
immune-related  
AEs2  
  
Intolerable/ 
persistent Grade 2  
Withhold  
 Based on type and severity of AE 
administer corticosteroids   
  
  
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes  
All other immune-
related  
AEs2  
Grade 3  
Withhold 
or 
discontinue 
based 
on the type of event.  
Events that require 
discontinuation 
include 
and 
not 
limited to:  Gullain-
Barre 
Syndrome, 
encephalitis  
Grade 4 or recurrent 
Grade 3   
Permanently 
discontinue  
NOTES:     
1 
 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. For participants with Grade 3 
or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and 
is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
2 
 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks 
of the last dose.  
  
  
  


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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the IND Sponsor.  With IND Sponsor and Merck 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue 
treatment in the trial only if asymptomatic and controlled.  
  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the IND Sponsor. The reason for 
interruption should be documented in the patient's study record.  
  
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
  
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for adverse 
event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected, recorded, and followed as appropriate.   
  
All adverse events experienced by subjects will be collected and reported from the first dose of 
the investigational agent, throughout the study, and will only be followed for 30 days unless 
related to the investigational agent.  All Serious adverse events will be collected for 90 days 
after the last infusion of MK-3475.  
  
Subjects who have an ongoing adverse event related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff until 
the event is resolved or determined to be irreversible by the investigator.  
  
Patients who experience a Grade 2 or higher irAE should be discussed with Dr. Le. In addition, 
AEs listed in Section 7.1.3 must be reported as an Event of Clinical Interest (ECI) within 24 
hours to the IND Sponsor and to Merck Global Safety even if no Serious Adverse Event Criteria 
are met.  
  
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all grade 
3 and 4 clinical laboratory results that represent an increase in severity from baseline will be 
reported as adverse events. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an adverse event only if it is considered clinically significant by the investigator.  
  
 
7.1  
Definitions  
  
7.1.1 Adverse Event (AE)  


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Adverse event is defined as any undesirable sign, symptom or medical condition 
occurring after starting the study drug (or therapy) even if the event is not 
considered to be related to the study. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). 
Medical conditions/diseases present before starting the study treatment are only 
considered adverse events if they worsen after starting the study treatment (any 
procedures specified in the protocol). Adverse events occurring before starting the 
study treatment but after signing the informed consent form will not be recorded. 
Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy.  
  
7.1.2 Serious Adverse Event (SAE)  
  
A serious adverse event is an undesirable sign, symptom or medical condition 
which:   
• Results in death   
• Is life threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe)   
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions)   
• Results in persistent or significant disability/incapacity   
• Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Supplemental Form)   
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.). Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
• Is a new cancer (that is not a condition of the study)  
• Is associated with an overdose  
  
Events not considered to be serious adverse events are hospitalizations for the:   
• Admissions as per protocol for a planned medical/surgical procedure or to 
facilitate a procedure  
• Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)   
• Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required 
in these cases   


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• Admission encountered for another life circumstance that carries no bearing on  
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative).  
  
7.1.3 Adverse Events of Clinical Interest (ECI) for MK-3475  
  
These selected non-serious related adverse experiences are also known as Events 
of Clinical Interest (ECI) and must be recorded as such on the Adverse Event of 
Clinical Interest Case Report Form found in Appendix C.  
Events of clinical interest for this trial include:  
• 
an overdose of Merck's product, as defined in Section 5.4, that is not 
associated with clinical symptoms or abnormal laboratory results.   
• 
an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
*Note:  These criteria are based upon available regulatory guidance documents.  
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.    
 
7.2  
Relationship  
  
Definite – The AE is clearly related to the study treatment.  
Probable – The AE is likely related to the study treatment.  
Possible – The AE may be related to the study treatment.  
 
  
Unlikely – The AE is doubtfully related to the study treatment.  
 
  
  
Unrelated – The AE is clearly NOT related to the study treatment.  
  
 
7.3  
Expectedness  
  
Unexpected adverse event: An adverse event, which varies in nature, intensity or 
frequency from information on the investigational drug/agent provided in the 
Investigator’s Brochure, package insert or safety reports. Any adverse event that is not 
included in the informed consent is considered “unexpected”.   
  
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is 
included in the informed consent document as a risk.  
  


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7.4  
Handling of Expedited Safety Reports  
  
In accordance with local regulations, the IND Sponsor (Dr. Le) will notify investigators 
of all SAEs that are unexpected (i.e., not previously described in the Investigator 
Brochure), and definitely, probably, or possibly related to MK-3475. This notification 
will be in the form of an expedited safety report (ESR) that is to be faxed to the 
investigators and the study coordinators. Upon receiving such notices, the investigator 
must review and retain the notice with the Investigator’s Brochure and where required 
by local regulations, the investigator will submit the ESR to the appropriate IRB. The 
investigator and IRB will determine if the informed consent requires revision. The 
investigator should also comply with the IRB procedures for reporting any other safety 
information.   
  
 
7.5   Reporting  
  
7.5.1  General  
  
All adverse events (both expected and unexpected) will be captured on the 
appropriate study-specific case report forms (CRFs).   
  
In addition, all serious adverse events, regardless of causality to study drug and/or 
administration device, will be reported promptly to Dr. Dung Le (e-mail:  
) within 24 hours of recognition of the adverse event  
using the form found in Appendix D.  If this falls on a weekend or holiday, an email 
notification is acceptable but must be followed by an SAE reporting form on the 
next business day.  
  
All serious adverse events, regardless of causality to study drug and/or 
administration will be forwarded to Merck’s Global Safety (“Merck GS”) group 
within 24 hours of learning of the event.    
  
After the initial SAE report, the investigator is required to proactively follow each 
subject and provide further information to the IND Sponsor and Merck in regards 
to the subject’s condition.  
  
All SAE(s) will be followed until:  
• 
Resolution  
• 
The condition stabilizes  
• 
The event is otherwise explained  
• 
The subject is lost to follow-up  
  
As soon as relevant information is available, a follow-up SAE report will be 
submitted to the IND Sponsor and Merck GS.  
  


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Non-serious Events of Interest will be forwarded to Merck GS and will be handled 
in the same manner as SAEs.   
  
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation 
in a subject (spontaneously reported to them), including the pregnancy of a male 
subject's female partner who has provided written consent to provide information 
regarding pregnancy, that occurs during the trial or within 120 days of completing 
the trial.  All subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported to Merck GS.  
SAE reports and any other relevant safety information are to be forwarded to  
Merck GS facsimile number:  
  
  
7.5.2  Institutional Review Board (IRB)  
  
Participating sites will be responsible for reporting to their IRB. All serious adverse 
events will be reported to the IRB per institutional standards. Upon receipt, follow-
up information will be given to the IRB (as soon as relevant information is 
available) per institutional standards.  
  
7.5.3  Food and Drug Administration (FDA)  
  
All reporting to the FDA will be completed by the IND Sponsor (Dr. Le).  
  
7.5.3.1 Expedited IND Safety Reports:  
  
7 Calendar-Day Telephone or Fax Report:    
The IND Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the investigational agent.  Such reports are to be telephoned or faxed  
(301-827-9796) to the FDA within 7 calendar days of first learning of the event.    
  
15 Calendar-Day Written Report:    
The IND Sponsor is required to notify the FDA of any serious adverse event that 
is unexpected and possibly related to the investigational agent in a written IND 
Safety Report.    
  
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 


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41 
should contain comments on the significance of the new event in light of the 
previous, similar reports.    
  
Written IND safety reports with Analysis of Similar Events are to be submitted to 
the FDA within 15 calendar days of first learning of the event.   
  
7.5.3.2 IND Annual Reports  
  
In accordance with the regulation 21 CFR § 312.33, the Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of 
the adverse events and progress of the investigation.  Please refer to Code of 
Federal Regulations, 21 CFR § 312.33 for a list of the elements required for the 
annual report.  All IND annual reports will be submitted to the FDA by the 
Sponsor-Investigator.  
  
8. PHARMACEUTICALINFORMATION (MK-3475)  
  
 
8.1  
Agent Accountability  
  
The sponsor/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.  
 
8.2  
Mode of Action  
  
 
  
 
8.3  
Description  
  
  
  
  
 
  
  
 
8.4  
Packaging and Labeling Information  
  
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Open label kits will be provided for patient dosing.   
 
 
 
 
  


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8.5  
Preparation  
  
Refer to Procedures Manual for preparation instructions.  
  
 
8.6  
Storage  
  
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of trial medication must be 
recorded by an authorized person at the trial site.   
  
Refer to Procedures Manual for Storage conditions.  
Clinical supplies may not be used for any purpose other than that stated in the protocol.  
  
 
8.7  
Stability  
  
Refer to Procedures Manual for Stability information.  
  
 
8.8  
Route of Administration  
  
The reconstituted product is intended for IV administration.   
  
 
8.9  
Patient Care Implications  
  


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8.11  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.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent Ordering  
8.10 
 
  
 
 
 
 
 


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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.  
  
9. CORRELATIVE/SPECIAL STUDIES  
  
Sample collection, storage, and shipment instructions will be provided in the Procedures 
Manual.  
  
 
9.1  
Tumor Tissue Studies  
  
Tumor biopsies will be collected (if a patient’s tumor is thought to be reasonably safe 
and easy to biopsy) at baseline and prior to Cycle 3 (4-6 cores per timepoint). Additional 
optional biopsies may be obtained later in the course of therapy. Archival tumor 
samples will also be collected for every patient (slides and/or blocks). Fine needle 
aspiration will not be acceptable. Additional archival tissue from patients no longer 
receiving treatment due to disease progression may also be collected in order to evaluate 
resistant lesions. Detailed instructions for tissue collection, processing and shipment are 
provided in the procedures manual.  
  
9.1.1 To explore the association of MSI positive, PD-L1 positivity, and tumor 
infiltrating lymphocyte characteristics with clinical responses, archived tumor tissue 
and tumor tissue obtained at baseline and during treatment (prior to cycle 3) will be 
compared. PD-L1 expression may predict response to anti-PD-1 [28, 51].  However, 
PD-L1 is also upregulated in response to IFN-γ released by infiltrating T cells and could 
potentially be a predictor of response to any active immunotherapy.  Pre and post-
treatment tumor biopsies will also be analyzed for PD-1 expression as well as 
infiltration of immune cells (effector T cells, Tregs, B cells, dendritic cells, etc).  
Characterization of immune checkpoint expression as well as immune infiltrates may 
be predictive of response to therapy and may also give insight into next generation 
combinatorial approaches.  Preliminary data from a pancreatic cancer immunotherapy 
study suggests that induction of a Th1and Th17 phenotype at the tumor itself predicts 
response.  Furthermore, upregulation of other inhibitory molecules such as IL-10 and 
TGF-β may identify other targets for combinatorial strategies.  
  
Slides from a newly obtained biopsy sample of at least one tumor lesion at baseline or 
from archived tissue will be submitted for PD-L1 and biomarker staining. Biopsy or 
archival tissue samples should have proper size to enable IHC analysis of PD-L1.   
  
9.1.2 The Ludwig Center for Cancer Genetics will perform whole-exome sequencing 
using next-generation sequencing on DNA from tumors and matched normal tissue.  As 
with all targeted therapies, we expect a subset of patients will respond to 


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45 
immunotherapy and there may be genetic determinants that define this response. These 
studies will define the genetic landscape of these tumors and may determine an 
‘immune responsive’ phenotype.  Furthermore, since each mutation is a potential neo-
antigen that may drive an immune response, we will evaluate each mutation for 
antigenic potential in our model [58].  
  
9.1.3 In cases, where the genes listed are known to be mutated, we will test for MSI 
status since there is a correlation between MSI status and these mutations.  
  
Deleterious mutations in the following genes:  
  
• 
MLH 1  
• 
MSH 2  
• 
MSH 6  
• 
PMS2  
• 
BRAF pV600E  
• 
TGFBR2  
  
 
9.2   Peripheral Blood Lymphocytes (PBLs)  
  
Post-treatment expression of PD-1 and other lymphocyte activation markers will be 
measured and correlated with OS and MSI positivity.  PBL will be collected as 
described in Section 10.  PBL are isolated and stored frozen until use.  
  
 
9.3   Serum and Plasma Marker Studies  
  
Sera and plasma will be collected as described in Section 10 to identify potential 
therapeutic targets, biomarkers, and predictors of response and autoimmune toxicity 
through proteomic approaches. In addition, we will look at alternative methods to 
identify MSI in circulating tumor DNA. Whole blood will be collected in a 10 milliliter 
Serum Separator Tube (SST tube) at the designated time points and processed using 
standard laboratory procedures.  Using a pipette, aliquots of 1 mL of serum should be 
transferred to cryogenic vials and stored at -80oC.  
  
We will also collect whole blood in two 10 mL plasma preparation tubes with EDTA 
(PPT, BD Vacutainer, Franklin Lakes, NJ) and gently swirl tubes to mix blood with 
EDTA.   Within two hours of collection, the sample will be processed using standard 
procedures for plasma separation.  Plasma will be divided into 1 mL aliquots and stored 
at -80oC.  Pellets from this separation procedure will be washed in PBS and then divided 
into aliquots and also stored at -80oC.  
  
 
9.4   Normal tissue based studies  
  
To assess the baseline characteristic of the subjects enrolled and to correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity.  DNA 


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Amendment 11/ Version 12/ December 1, 2017  
46 
will be extracted from whole blood (collection and processing described in 9.3) and 
used to evaluate for any germline mutations that may correlate with response or toxicity.  
A SNP array may be performed on each case using the Affymetrix Genomewide Human 
SNP Array 6.0 (Santa Clara, CA).  
  
 
9.5  
Diagnostic Tissue Samples  
  
Tissue, fluid, or blood may be collected from standard of care procedures used to treat 
or diagnoses immune related toxicities. Detailed instructions for tissue collection and 
shipment are provided in the procedures manual.  
  
 
9.6   Microbiome Studies  
  
Stool and saliva samples will be collected for microbiome studies at baseline and with 
each scan at select clinical trial sites. Detailed instructions for sample collection, 
processing, storage, and shipment are provided in the procedures manual.  
10. STUDY CALENDAR  
10.1  Cohorts A-C  
Study Procedures  
Pre-Study19  
Cycle (14 
days) 20 
20  
Weeks21  
Off 
Treatment  
Off 
Study24 
Visit Windows (days)1  
N/A -28 to -1 
+7  
+/- 14  
+/- 7  
+/- 14  
MK-3475  
  
  
X  
  
  
  
Pre-screening consent2  
  
X  
  
  
  
  
Informed consent  
  
X  
  
  
  
  
Inclusion/exclusion criteria  
  
X  
  
  
  
  
Demographics  
  
X  
  
  
  
  
MSI Testing  
X  
  
  
  
  
  
Medical history  
  
X  
  
  
  
  
Cancer History3  
  
X  
  
  
  
  
Concurrent meds  
  
X  
X  
X  
X22,23  
X  
Physical exam4  
  
X  
X  
X  
  
X  
Vital signs5  
  
X  
X  
X  
  
X  


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47 
Height  
X  
  
  
  
  
  
Weight  
  
X  
X  
X  
  
X  
Performance status (PS)  
  
X  
X  
X  
  
X  
Hematology profile6, 12  
  
X  
X  
X  
X22,23  
X  
Chemistry profile7, 12  
  
X  
X  
X  
X22,23  
X  
TSH, T3, FT48, 12  
  
  
X  
X  
X22,23  
X  
Urinalysis9, 12  
  
X  
  
  
  
  
B-HCG10, 12  
  
X  
  
  
  
  
Serum Tumor Markers11, 12  
  
X  
X  
X  
X22,23  
X  
Adverse event evaluation  
  
  
X  
X  
X22,23  
X  
Radiologic evaluation13  
  
X  
X  
X  
X23  
X  
Tumor measurements13  
  
X  
X  
X  
  
X  
Whole blood for PBL14  
  
  
X  
X  
X23  
  
Serum (approximately 10cc) 14  
  
  
X  
X  
X23  
  
Whole Blood Sample for Plasma  
(approximately  20cc) 14  
  
  
X  
X  
X23  
  
Stool/Saliva Sample15  
  
X  
X  
  
  
  
Archival Tissue16  
  
X  
X  
  
X  
X  
Tumor Biopsies17  
  
X  
X  
  
  
  
Buccal Swab/purple top tube18  
  
X  
X  
  
  
  
1: Longer delays to be approved by the IND Sponsor.  
2: Pre-screening informed consent for MSI testing (Cohort C only).   
3: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, 
histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy regimens.  
4: Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter.  
Exams, concomitant medication, AE assessments can be made up to 3 days prior to infusion.  
5: Temperature, respiration rate, blood pressure, and pulse should be taken at baseline, prior to MK-3475 infusion, and 
at the end of the infusion.  Pulse oximetry should be taken at baseline and prior to each MK-3475 infusion.  
6: CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets.  


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48 
7: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.  
8: TSH, Total T3, and Free T4 will be collected at baseline (Day -28 to Day 1), 12 weeks (+/- 2 week), every 8 weeks 
(+/- 2 week) through week 52, and then every 12 weeks (+/- 2 week) thereafter including the off study evaluation. 
Weeks are in reference to calendar week and should not be adjusted due to dosing delays.   
9: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity.  
10:  Serum or urine pregnancy test (women of childbearing potential).  
11: Disease specific tumor markers where appropriate.   
12: Labs may be collected within a window of up to 3 days prior to dosing.  
13: Radiologic evaluations and tumor measurements will be performed at baseline (within 14 days prior to the first dose 
of MK-3475), 12 weeks (+/- 2 week), every 8 weeks (+/- 2 week) through week 52, and then every 12 weeks (+/- 2 
week) thereafter including the off study evaluation. Weeks are in reference to calendar week and should not be 
adjusted due to dosing delays.  
14: See Correlative Studies table below for further details.  
15: Samples to be obtained at baseline and with each scan [12 weeks (+/- 2 week), every 8 weeks (+/- 2 week) through 
week 52, and then every 12 weeks (+/- 2 week) thereafter] at select clinical trial sites. Detailed instructions regarding 
collection and processing are located in the Procedures Manual.   
16: Attempts to obtain archival tumor samples will be made for every patient until the sample is obtained or 
documentation that the sample cannot be obtained. The tissue sample should have proper size to enable IHC analysis 
of PD-L1. Fine needle aspirates will not be acceptable. Detailed instructions for tissue collection, processing and 
shipment are provided in the Procedures Manual.   
17:  Tumor biopsies to be taken (if a patient’s tumor is thought to be reasonably safe and easy to biopsy) at baseline 
and prior to Cycle 3 (4-6 cores per timepoint). The biopsy performed prior to Cycle 3 has a -7 day window prior to 
the Cycle 3 visit. Additional optional biopsies may be obtained later in the course of therapy. The tissue sample 
should have proper size to enable IHC analysis of PD-L1. Fine needle aspiration will not be acceptable. Detailed 
instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  
18: Buccal swabs and/or purple top tube will be obtained only for those patients who do not have enough normal tissue 
for MSI testing.  This collection can occur any time after consent.  
19: Patients who stop MK-3475 with SD or better may be eligible for up to one year of additional MK-3475 therapy if 
they progress after stopping MK-3745, they meet the criteria listed in Section 5.7.2, and undergo the following 
evaluations: interval medical and cancer history, physical exam, vitals, weight, PS, hematology and chemistry 
profile, autoimmune and endocrine panel, urinalysis, serum or urine pregnancy test, serum tumor markers, 
radiographic evaluations, and tumor measurements. The following samples will be collected at baseline and while 
on study: peripheral blood, serum, whole blood for plasma, and biopsy. Subjects who restart treatment after relapse 
should resume at the same dose and cycle interval which they were receiving prior to discontinuation.  
20: For cycle 1, study procedures do not need to be repeated if they were conducted within 3 days of the pre-study 
evaluations.  
21: Week 20 evaluations (calculated from the date of the first dose), which include additional blood, CT/MRI scans and 
tumor measurements, may coincide with a cycle visit.   All week 20 evaluations must be completed at the Week 20 
time point.  
22: Patients will undergo the Off Treatment Evaluation 30 days (+/- 7 days) after the last infusion of MK-3475 if they 
completed 24 months of MK-3475 treatment or the patient has discontinued MK-3475 after an investigator 
determined confirmed CR (Section 5.7.1). The assessment of AEs and medications can be made either as part of a 
clinical visit or over the phone. Patients will also continue to be monitored for the resolution of drug-related AEs to 
≤ Grade 1. SAEs that occur within 90 days of the last infusion of MK-3475 or before initiation of a new 
antineoplastic treatment should also be followed and recorded.  
23: While off treatment (Section 5.7.1), patients should continue to be monitored for disease status by radiologic 
imaging and tumor marker(s) every 12 weeks (+/- 2 weeks) for 1 year starting from the last scan. After 1 year, 
disease status should be evaluated every 24 weeks (+/- 2 weeks). These evaluations can be done locally if approved 
by the IND Sponsor. In addition, we will also continue to collect clinical labs, as well as peripheral blood, serum, 
and plasma samples every 12 weeks (+/- 2 weeks) for 1 year starting from the last research blood draw as described 
below. After 1 year, clinical labs and research bloods should be collected every 24 weeks (+/- 2 weeks).  
24:  30 days after their last dose of study drug or within 7 days prior to initiation of a new anti-cancer treatment, 
whichever comes first. Patients who come off study should continue to be followed as described in Section 5.9.   


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49 
  
Correlative Studies While On study   
 
 
 
 
  
Baseline  
2  
Weeks  
4  
Weeks  
12 
Weeks  
20 
Weeks  
Q 8 Weeks  
(Weeks 28- 
52)  
Q 12 Weeks  
(week 64 
and beyond)  
Whole blood for PBL 1  
X2  
X2  
X2  
X3  
X3  
X3  
X3  
Serum (approximately  
10cc) 1  
X  
X  
X  
X  
X  
X  
X  
Whole Blood Sample 
for Plasma  
(approximately  20cc)  
1 
  
X  
X  
X  
X  
X  
X  
X  
  
1: Blood and serum samples will be collected at baseline (Day -28 to Day 1), 2 weeks (+/- 1  week), 4 weeks (+/- 
1  week), 12 weeks (+/- 2 week), every 8 weeks (+/- 2 week) through week 52, and then every 12 weeks (+/- 2 
week) thereafter. Weeks are in reference to calendar week and should not be adjusted due to dosing delays. 2: 
Up to 64 cc  
3: Up to 100 cc  
  
Correlative Studies While Off Treatment (per Section 5.7.1) 
  
Q 12 Weeks  
(for first 52 weeks off treatment)  
Q 24 Weeks  
(after first 52 weeks off treatment)  
Whole blood for PBL (up to 
100cc)  
X  
X  
Serum (approximately 10cc)   
X  
X  
Whole Blood Sample for Plasma  
(approximately  20cc)   
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
10.2  Cohort D  
Study Procedures  
Pre-Study19  
Cycle (21 
days) 20 
21  
Weeks21  
Off 
Treatment  
Off 
Study24 


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Visit Windows (days)1  
N/A -28 to -1 
-3/+7  
+/- 14  
+/- 7  
+/- 14  
MK-3475  
  
  
X  
  
  
  
Pre-screening consent2  
  
X  
  
  
  
  
Informed consent  
  
X  
  
  
  
  
Inclusion/exclusion criteria  
  
X  
  
  
  
  
Demographics  
  
X  
  
  
  
  
MSI and mutator phenotype testing  
X  
  
  
  
  
  
Medical history  
  
X  
  
  
  
  
Cancer History3  
  
X  
  
  
  
  
Concurrent meds  
  
X  
X  
X  
X22,23  
X  
Physical exam4  
  
X  
X  
X  
  
X  
Vital signs5  
  
X  
X  
X  
  
X  
Height  
X  
  
  
  
  
  
Weight  
  
X  
X  
X  
  
X  
Performance status (PS)  
  
X  
X  
X  
  
X  
Hematology profile6, 12  
  
X  
X  
X  
X22,23  
X  
Chemistry profile7, 12  
  
X  
X  
X  
X22,23  
X  
TSH, T3, FT48, 12  
  
  
X  
X  
X22,23  
X  
Urinalysis9, 12  
  
X  
  
  
  
  
B-HCG10, 12  
  
X  
  
  
  
  
Serum Tumor Markers11, 12  
  
X  
X  
X  
X22,23  
X  
Adverse event evaluation  
  
  
X  
X  
X22,23  
X  
Radiologic evaluation13  
  
X  
X  
X  
X23  
X  
Tumor measurements13  
  
X  
X  
X  
  
X  


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Whole blood for PBL14  
  
  
X  
X  
X23  
  
Serum (approximately 10cc) 14  
  
  
X  
X  
X23  
  
Whole Blood Sample for Plasma  
(approximately  20cc) 14  
  
  
X  
X  
X23  
  
Stool/Saliva Sample15  
  
X  
X  
  
  
  
Archival Tissue16  
  
X  
X  
  
X  
X  
Tumor Biopsies17  
  
X  
X  
  
  
  
Buccal Swab/purple top tube18  
  
X  
X  
  
  
  
1: Longer delays to be approved by the Sponsor or Protocol Chair.  
2: Pre-screening informed consent for MSI testing (Cohort C only).   
3: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, 
histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy regimens.  
4: Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter.  
Exams, concomitant medication, AE assessments can be made up to 3 days prior to infusion.  
5: Temperature, respiration rate, blood pressure, and pulse should be taken at baseline, prior to MK-3475 infusion, and 
at the end of the infusion.  Pulse oximetry should be taken at baseline and prior to each MK-3475 infusion.  
6: CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets.  
7: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.  
8: TSH, Total T3, and Free T4 will be collected at baseline (Day -28 to Day 1), 12 weeks (+/- 2 week), every 9 weeks 
(+/- 2 week) through week 57, and then every 12 weeks (+/- 2 week) thereafter including the off study evaluation. 
Weeks are in reference to calendar week and should not be adjusted due to dosing delays.   
9: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity.  
10:  Serum or urine pregnancy test (women of childbearing potential).  
11: Disease specific tumor markers where appropriate.   
12: Labs may be collected within a window of up to 3 days prior to dosing.  
13: Radiologic evaluations and tumor measurements will be performed at baseline (within 14 days prior to the first dose 
of MK-3475), 12 weeks (+/- 2 week), every 9 weeks (+/- 2 week) through week 57, and then every 12 weeks (+/- 2 
week) thereafter including the off study evaluation. Weeks are in reference to calendar week and should not be 
adjusted due to dosing delays.  
14: See Correlative Studies table below for further details.  
15: Samples to be obtained at baseline and with each scan [12 weeks (+/- 2 week), every 9 weeks (+/- 2 week) through 
week 57, and then every 12 weeks (+/- 2 week) thereafter] at select clinical trial sites. Detailed instructions regarding 
collection and processing are located in the Procedures Manual.   
16: Attempts to obtain archival tumor samples will be made for every patient until the sample is obtained or 
documentation that the sample cannot be obtained. The tissue sample should have proper size to enable IHC analysis 
of PD-L1.  Fine needle aspirates will not be acceptable. Detailed instructions for tissue collection, processing and 
shipment are provided in the Procedures Manual.   
17:  Tumor biopsies to be taken (if a patient’s tumor is thought to be reasonably safe and easy to biopsy) at baseline 
and prior to Cycle 3 (4-6 cores per timepoint). The biopsy performed prior to Cycle 3 has a -7 day window prior to 
the Cycle 3 visit. Additional optional biopsies may be obtained later in the course of therapy. The tissue sample 
should have proper size to enable IHC analysis of PD-L1. Fine needle aspiration will not be acceptable. Detailed 
instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  
18: Buccal swabs and/or purple top tube will be obtained only for those patients who do not have enough normal tissue 
for MSI testing.  This collection can occur any time after consent.  


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52 
19: Patients who stop MK-3475 with SD or better may be eligible for up to one year of additional MK-3475 therapy if 
they progress after stopping MK-3745, they meet the criteria listed in Section 5.7.2, and  undergo the following 
evaluations: interval medical and cancer history, physical exam, vitals, weight, PS, hematology and chemistry 
profile, autoimmune and endocrine panel, urinalysis, serum or urine pregnancy test, serum tumor markers, 
radiographic evaluations, and tumor measurements. The following samples will be collected at baseline and while 
on study: peripheral blood, serum, whole blood for plasma, and biopsy. Subjects who restart treatment after relapse 
should resume at the same dose and cycle interval which they were receiving prior to discontinuation.  
20: For cycle 1, study procedures do not need to be repeated if they were conducted within 3 days of the pre-study 
evaluations.  
21: Week 21 evaluations (calculated from the date of the first dose), which include additional blood, CT/MRI scans and 
tumor measurements, may coincide with a cycle visit.   All week 21 evaluations must be completed at the Week 21 
time point.  
22: Patients will undergo the Off Treatment Evaluation 30 days (+/- 7 days) after the last infusion of MK-3475 if they 
completed 24 months of MK-3475 treatment or the patient has discontinued MK-3475 after an investigator 
determined confirmed CR (Section 5.7.1). The assessment of AEs and medications can be made either as part of a 
clinical visit or over the phone. Patients will also continue to be monitored for the resolution of drug-related AEs to 
≤ Grade 1. SAEs that occur within 90 days of the last infusion of MK-3475 or before initiation of a new 
antineoplastic treatment should also be followed and recorded.  
23: While off treatment (Section 5.7.1), patients should continue to be monitored for disease status by radiologic 
imaging and tumor marker(s) every 12 weeks (+/- 2 weeks) for 1 year starting from the last scan. After 1 year, 
disease status should be evaluated every 24 weeks (+/- 2 weeks). These evaluations can be done locally if approved 
by the IND Sponsor. In addition, we will also continue to collect clinical labs, as well as peripheral blood, serum, 
and plasma samples every 12 weeks (+/- 2 weeks) for 1 year starting from the last research blood draw as described 
below. After 1 year, clinical labs and research bloods should be collected every 24 weeks (+/- 2 weeks).  
24:  30 days after their last dose of study drug or within 7 days prior to initiation of a new anti-cancer treatment, 
whichever comes first. Patients who come off study should continue to be followed as described in Section 5.9.  
  
Correlative Studies While On Study   
 
 
 
  
  
Baseline  
3  
Weeks  
6  
Weeks  
12 
Weeks  
21 
Weeks  
Q 9 Weeks  
(Weeks 30- 
57)  
Q 24 Weeks  
(week 81 and 
beyond)  
Whole blood for PBL 1  
X2  
X2  
X2  
X3  
X3  
X3  
X3  
Serum (approximately  
10cc) 1  
X  
X  
X  
X  
X  
X  
X  
Whole Blood Sample 
for Plasma  
(approximately  20cc)  
1 
  
X  
X  
X  
X  
X  
X  
X  
  
1: Blood and serum samples will be collected at baseline (Day -28 to Day 1), 3 weeks (+/- 1  week), 6 weeks (+/- 
1  week), 12 weeks (+/- 2 week), every 9 weeks (+/- 2 week) through week 57, and then every 12 weeks (+/- 2 
week) thereafter. Weeks are in reference to calendar week and should not be adjusted due to dosing delays. 2: 
Up to 64 cc  
3: Up to 100 cc   
  
  
Correlative Studies While Off Treatment (per Section 
5.7.1 
) 


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
 
Amendment 11/ Version 12/ December 1, 2017  
53 
  
Q 12 Weeks  
(for first 52 weeks off treatment)  
Q 24 Weeks  
(after first 52 weeks off 
treatment)  
Whole blood for PBL (up to  
100cc)  
X  
X  
Serum (approximately 10cc)   
X  
X  
Whole Blood Sample for Plasma  
(approximately  20cc)   
X  
X  
  
  
11. MEASUREMENT OF EFFECT  
  
11.1 Antitumor Effect – Solid Tumors  
  
For the purposes of this study, patients should be evaluated for response at the 12 week 
timepoint, every 8 weeks through week 52, and then every 12 weeks thereafter 
including the off study evaluation.  Response and progression will be evaluated in this 
study using the new international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Appendix E] and the 
immune related Response criteria (irRC)  [Appendix F].  Tumor assessments in the 
second expansion cohort will be evaluated by RECIST 1.1 criteria only. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. RECIST 
and irRC response assessments will be performed locally for the trial and may be 
requested for central review.  
  
11.1.1 Definitions  
  
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with MK-3475.  
  
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one dose of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.)  
  
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease reevaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.   
  
11.1.2 Methods for Evaluation of Measurable Disease  
  


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All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
  
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).    
  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible.  
  
PET-CT:  A PET-CT can be used to obtain the images as long as the CT is of 
diagnostic quality.    
  
11.1.3  Duration of Response as per RECIST 1.1 and irRC  
  
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  
  
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.   
  


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Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. In order to be considered durable, Stable Disease must be 
maintained for at least 6 weeks (this will be attained by the 9 week time point).  
  
11.1.4 Progression-Free Survival (PFS) as per RECIST 1.1 and irRC  
  
PFS is defined as the duration of time from start of treatment to time of first 
documented progression or death, whichever occurs first.  
  
 
  
11.1.5 Overall Survival (OS)  
  
  
  
OS is defined as the duration of time from start of treatment to time of death.  
  
 
12.   
DATA REPORTING / REGULATORY REQUIREMENTS  
  
Adverse event guidelines and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements).  
  
12.1 Data Management  
  
All information will be collected on study-specific case report forms (CRFs) by study 
staff. These data will be reviewed for completeness and accuracy by the Principal 
Investigator at each site.   
  
Protocol Chair  
The Protocol Chair is responsible for performing the following tasks:  
• Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments.  
• Assuring that all participating institutions are using the correct version of the protocol.  
• Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study.  
• Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 Reviewing 
data from all sites.  
  
Coordinating Center  
The Coordinating Center is responsible for performing the following tasks:  
• Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site.  
• Managing central patient registration.  
• Collecting and compiling data from each site.  


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• Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties.  
• Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites.  
  
Participating Sites  
Participating sites are responsible for performing the following tasks:  
• Following the protocol as written, and the guidelines of Good Clinical Practice (GCP).  
• Submitting data to the Coordinating Center.  
• Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly.  
• Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol.  
• Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center.  
• Collecting and submitting data according to the schedule specified by the protocol.  
  
12.2 Safety Meetings  
  
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), data manager(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings matters related to the following will be 
discussed: safety of protocol participants, validity and integrity of the data, enrollment 
rate relative to expectation, characteristics of participants, retention of participants, 
adherence to protocol (potential or real protocol violations), data completeness, and 
progress of data for objectives.  
  
Monthly teleconferences will be scheduled to include the Investigator and Merck 
representatives. During these meetings, the Investigator shall provide Merck with study 
progress updates.  The Investigator will provide a summary of key points from the 
weekly meetings with a focus on safety of the protocol participants, enrollment status, 
and progress of data for objectives.  In addition, Merck will provide safety and 
applicable program updates to the Sponsor.  
  
12.3  Monitoring  
  
This is a DSMP Level II study under the Johns Hopkins Sidney Kimmel Comprehensive 
Cancer Center (SKCCC) Data Safety Monitoring Plan (DSMP, 12/6/2012, Appendix 
G). Eligibility for all sites will be monitored by the JHU SKCCC CRO. Data monitoring 
of this protocol will occur on a regular basis with the frequency dependent on the rate 
of subject accrual and the progress of the study.  Additional data and safety monitoring 
oversight will also be performed by the SKCCC Safety Monitoring Committee (SMC - 
as defined in the DSMP). The protocol will be monitored internally by the Principal 


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Investigator at each site. External monitoring will occur according to the following 
guidelines:  
  
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO 
in accordance with SKCCC guidelines. Trial monitoring and reporting will be done 
through the Safety Monitoring Committee (SMC) at SKCCC.   
  
Participating site(s): The protocol will be monitored by the internal CRO at each site. 
A report of the reviews will be submitted to the Johns Hopkins principal investigator 
and SKCCC CRO.  
  
Authorized representatives of the Coordinating Center may visit the satellite sites to 
perform audits or inspections, including source data verification. The purpose of these 
audits or inspections is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements.  
  
Dr. Le is holding the IND for this study.  She will comply with all regulated reporting 
requirements to the FDA.  
  
13. STATISTICAL CONSIDERATIONS  
  
13.1 Study Design/Endpoints  
  
This is a multicenter, open-label, two-stage, phase 2 study to evaluate the clinical 
activity of MK-3475 in MSI positive and MSI negative solid tumors.  We will enroll 
three cohorts of patients:  patients with MSI positive colorectal adenocarcinomas 
(Cohort A); patients with MSI negative colorectal adenocarcinomas (Cohort B); and 
patients with MSI positive solid tumor malignancies but not colorectal adenocarcinoma 
(Cohort C); all cohorts will receive MK-3475. Each cohort will be assessed separately.  
This design aims to evaluate MSI as a biomarker and evaluate treatment benefit 
simultaneously.  
  
The primary endpoints for Cohorts A and B are immune-related progression-free 
survival (irPFS) rate at 20 weeks and objective response rate (irORR) assessed using 
immune related response criteria (irRC); irPFS is defined as the proportion of subjects 
alive and free of disease progression at 20 weeks per irRC; and irORR is the proportion 
of subjects whose best overall response is a CR or PR.  
  
The primary endpoint for Cohort C is immune-related progression-free survival (irPFS) 
rate assessed using immune related response criteria (irRC) at 20 weeks, defined as the 
proportion of subjects alive and free of disease progression at 20 weeks per irRC.  Each 
cohort will be assessed separately.   
  


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The primary endpoint for Cohort D will be objective response rate (ORR), which is 
defined as the proportion of subjects who have response of CR or PR.    
  
The secondary efficacy endpoints include overall survival, progression-free survival 
according to RECIST 1.1 (PFS), best overall response (BOR), duration of objective 
response (DOOR), time to objective response (TDOR), and disease control rate (DCR) 
per RECIST 1.1, and irPFS, irBOR,  irDOOR, irTDOR, irDCR per irRC.   
  
We will also evaluate safety and toxicity of MK-3475. We will evaluate exploratory 
endpoints of pharmacogenomics and predictive biomarkers for responses.   
  
   
  
13.2 Sample Size/Accrual Rate  
  
For Cohort A and B, a total of 25 evaluable patients are planned.   
  
MK-3475 will be considered to be inactive and of no interest for further evaluation if  
the irPFS rate at 20 weeks is 5% (p10) or less or irORR is 5% (p20) or less, and considered 
active if the irPFS rate at 20 weeks is 25% or greater (p11) and irORR is 21% or greater 
(p21). We will apply a step-down gatekeeping procedure to preserve a study-wise type 
I error rate at 0.05 when evaluating co-primary endpoints of irPFS and irORR for 
Cohort A and B. Specifically, the endpoints will be tested in the hierarchical order first 
with irPFS at 20 weeks. If the null hypothesis of 20-week irPFS being 5% is rejected 
(i.e. the result reaches statistical significance), we will proceed to test for irORR. If 
irPFS is not significant at the 0.05 level (one-sided test), the statistical testing for irORR 
will not occur. Twenty-five patients in Cohort A and B would provide 90% power to 
detect an improved irPFS rate at 20 weeks from 5% to 25%, a 20% increase, at 
significance level of 0.05 based on a one-sided test.  For an improved irORR from 5% 
to 21%, a total of 25 patients would provide 80% power to detect an of 16% increase 
using a one-sided exact binomial test at a 0.05 significance level.   
  
For Cohort A and B, there will be 1 interim and 1 final analysis for irPFS, and 1 final 
analysis of irORR.  An interim analysis will be conducted in order to assess futility after 
irPFS at 20 weeks are available for the first 15 evaluable patients. According to Green-
Dahlberg design, if 0 irPFS are observed, enrollment in that cohort will be terminated. 
If at least one patient is free of disease progression at 20 weeks per irRC, an additional 
10 evaluable subjects will be enrolled into that cohort. If 3 or fewer patients are 
progression free at 20 weeks in the total of 25 evaluable patients enrolled in that cohort, 
then the regimen will be considered inactive. If 4 or more patients are progression free 
at 20 weeks, we proceed to test for the endpoint of irORR for that cohort. If 4 or more 
responders (CR or PR) are observed, we conclude the regimen is promising with that 
cohort and warrants further study.  
  
There is a 1.3% probability of stopping for futility under the alternative hypothesis p11 
(i.e. incorrectly stopping at the interim when the drug is efficacious) and a 46% 


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probability of stopping for futility under the null hypothesis p10 (i.e. correctly stopping 
at the interim when the drug is not efficacious).  
  
For Cohort D, the regimen would be considered of insufficient activity for further study 
if the response rate is 5% or less, and the minimum required level of efficacy that would 
warrant further study with the proposed regimen is a 21% response rate. A two-stage 
Green-Dahlberg design is planned. A total of 20 subjects will be entered in the first 
stage. If zero response is observed, that cohort will be terminated and we will conclude 
the regimen is ineffective. If >1 subjects respond, then additional 15 subjects will be 
studied for that cohort.  If < 4 subjects respond in stage one and two combined, we 
consider this regimen ineffective. If >5 responses are observed, we conclude the 
regimen is promising and warrant further study. Each cohort could also be terminated 
as soon as 5 responses are observed before the total cohort is enrolled or evaluated in 
that cohort. The maximum sample size will be 35 for each cohort. This design provides 
90% power to detect an absolute difference of 16% of response with a type I error of 
0.05. There is a 36% chance to stop the trial early for futility under 5% response rate.  
Tumor assessments for Cohort D will be evaluated by RECIST 1.1 criteria only.  
  
For Cohort C, a total of 21 evaluable patients are planned, respectively. MK-3475 will 
be considered to be inactive and of no interest for further evaluation if the irPFS rate at 
20 weeks is 5% (p0) or less and considered active if the irPFS rate at 20 weeks is 25% 
or greater (p1).   
  
A two-stage Green-Dahlberg design is used for Cohort C. An interim analysis will be 
conducted in order to assess futility after irPFS at 20 weeks are available for the first 14 
evaluable patients. If 0 irPFS are observed, enrollment in Cohort C will be terminated. 
If at least one patient is free of disease progression at 20 weeks per irRC, an additional 
7 evaluable subjects will be enrolled into Cohort C. If 3 or fewer patients are progression 
free at 20 weeks in the total of 21 evaluable patients enrolled in Cohort C, then the 
regimen will be considered inactive in that cohort. If 4 or more patients are progression 
free at 20 weeks, we conclude the regimen is promising and warrants further study this 
patient population.  
  
This design provides 81% power to detect an improved irPFS rate at 20 weeks from 5% 
to 25% in Cohort C respectively, a 20% increase, with a type I error of 0.05. There is a 
1.8% probability of stopping for futility under the alternative hypothesis p1 (i.e. 
incorrectly stopping at the interim when the drug is efficacious) and a 49% probability 
of stopping for futility under the null hypothesis p0 (i.e. correctly stopping at the interim 
when the drug is not efficacious).  
  
As of 28Jan2015, four irPFS at 20 weeks and four responses have been observed in 
each Cohort A and Cohort C. Since the emerging clinical data suggest promising 
clinical activity, up to an additional 50 patients will be enrolled in each of these cohorts 
under a second expansion in Amendment 7. Tumor assessments in the second expansion 
cohort will be evaluated by RECIST 1.1 criteria only.  


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13.3 Stratification Factors  
  
We will enroll four cohorts of patients based on disease and MSI or mutator phenotype 
status: patients with MSI positive colorectal adenocarcinomas (Cohort A); patients with 
MSI negative colorectal adenocarcinomas (Cohort B); and patients with MSI positive 
solid tumor malignancies but not colorectal adenocarcinoma (Cohort C); and patients 
with MSI negative solid tumor malignancies that have a documented mutation burden 
level measured at > 20 mutations per megabase pairs (MB) (Cohort D).  
  
13.4 Analysis of Primary Endpoints  
  
For Cohort A and B, immune-related progression-free survival (irPFS) rate at 20 weeks 
and objective response rate (irORR) assessed using immune related response criteria 
(irRC) are co-primary endpoints.  irPFS rate at 20 weeks will be estimated as the 
proportion of patients alive and free of disease progression at 20 weeks per irRC, along 
with its 95% confidence interval (CI); irORR will be estimated as the proportion of 
subjects whose best overall response is either a CR or PR with corresponding 95% CI. 
The patients who drop out of the study due to toxicity and do not have a follow-up scan 
will be considered non-responders. The formal statistical testing for irORR will take 
place only if 20-week irPFS is statistically significant. For Cohort C, irPFS will be the 
primary endpoint.   
  
As of 28Jan2015, four irPFS at 20 weeks and four responses have been observed in 
each Cohort A and Cohort C. Since the emerging clinical data suggest promising 
clinical activity, up to an additional 50 patients will be enrolled in each of these cohorts 
under a second expansion in Amendment 7. Tumor assessments in the second expansion 
cohort will be evaluated by RECIST 1.1 criteria only, and ORR will be the primary 
endpoint for the expanded Cohort A and Cohort C.   
  
On 23May2017, FDA approved MK-3475 (pembrolizumab) for the treatment of adult 
and pediatric patients with unresectable or metastatic solid tumors that are MSI-H or 
mismatch repair deficient. The recommended dose is 200mg for adults every 3 weeks. 
After the approval patients may receive this new lower dose. We will continue follow-
up of the patients for disease progression and death after FDA approval. The analysis 
for PFS will be performed in two ways; the primary analysis will censor all patients at 
the date of the last tumor assessment prior to starting the treatment at the FDA-approved 
lower dose, if they do not have disease progression at or prior to that date. A secondary 
analysis will define PFS as the time from the first day of study treatment to the date of 
the first documented tumor progression or death due to any cause, whichever occurs 
first, during the entire follow-up period. Subjects who did not progress or die will be 
censored on the date of their last evaluable tumor assessment.         
  
The evaluable population includes all subjects who receive at least one dose of MK3475 
and have MSI results confirmed using the MSI Analysis System from Promega (section 


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3.4). This test will determine MSI status through the insertion or deletion of repeating 
units in the five nearly monomorphic mononucleotide repeat markers (BAT-25, BAT-
26, MON0-27, NR-21 and NR-24). At least 2 MSI loci are required to be evaluable in 
Cohorts A and C. Patients may be assigned to a new cohort and/or replaced based on 
the Promega test results. With amendment 9, the decision was made to not require 
retesting with Promega if MSI status is confirmed by IHC or other PCR.   
  
The primary endpoint for Cohort D will be response rate. The evaluable population for 
Cohort D includes all subjects who receive at least one dose of MK-3475 and have solid 
tumors that have a documented mutation burden level measured at > 20 mutations per 
megabase pairs (MB) using the Foundation Medicine  
(FoundationOne.com) targeted sequencing panel.   
  
13.5 Analysis of Secondary Endpoints  
  
Overall survival (OS) is the time from the first day of study treatment with MK-3475 
to the date of death due to any cause. A subject who has not died will be censored at 
last known date alive. Kaplan-Meier curves will be used to summarize OS.  
  
The analyses described below will be conducted on the basis of responses as assessed 
by both RECIST v1.1 and irRC. Summary statistics will be provided for each cohort as 
well as for each tumor type for Cohort C. The analysis will also be conducted in PD-
L1+ versus PD-L1- protein expression subgroups.  
  
PFS is defined as the time from the first day of study treatment to the date of the first 
documented tumor progression or death due to any cause, whichever occurs first. 
Subjects who did not progress or die will be censored on the date of their last evaluable 
tumor assessment. Kaplan-Meier curves will be used to summarize PFS.  
  
ORR is defined as the proportion of subjects whose best overall response (BOR) from 
baseline is either a CR or PR. BOR is determined by the best response designation 
recorded between the date of the first study treatment and the date of objectively 
documented progression or the date of subsequent anti-cancer therapy, whichever 
occurs first. For subjects without documented progression or subsequent anticancer 
therapy, all available response designations will contribute to the BOR determination. 
For subjects who continue MK-3475 beyond progression, the BOR should be 
determined based on response designations recorded at the time of the initial 
progression. DCR is the proportion of patients with CR, PR, or SD.    
  
Among patients with an objective response, DOOR is defined as the time between the 
date of initial complete or partial response to the date of the first documented tumor 
progression or death due to any cause. Subjects who neither progress nor die will be 
censored on the date of their last assessment. TTOR is defined as the time from the first 
day of study treatment to the date of the first documented CR or PR. DOOR and TTOR 
will be evaluated for responders (CR or PR) only.   


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13.6 Safety Analysis  
  
The safety analysis will be performed in all treated subjects. Toxicity will be tabulated 
by type and grade.   
  
13.7 Biomarker Analysis  
  
Potential relationships between biomarker data and efficacy or safety endpoints will be 
investigated as part of an analysis plan aimed at identifying baseline biomarkers that 
may be used to prospectively identify subjects likely (or not likely) to respond toMK-
3475 and to identify subjects who may be predisposed to having adverse reactions to 
treatment. These exploratory predictive biomarker analyses will be completed with 
biomarkers measured in blood and in tumor samples and will focus primarily- as 
outlined in the exploratory objectives- on germline mutations and SNPs, and on MSI 
positive, PD-L1 positivity, and tumor infiltrating lymphocyte in tumor specimens. 
Similar analyses will be completed with peripheral blood samples. We will also explore 
standard protein biomarkers such as CEA, CA19-9, and other exploratory circulating 
biomarkers.   
  
Associations between biomarkers and efficacy measures will be analyzed on all subjects 
with available biomarker data. Efficacy measures will include OS and standard and 
immune criteria of response and PFS. Demographic and case-history factors will be 
examined to determine whether stratification or adjustments should be made within the 
subsequent statistical analyses, and if necessary, the appropriate stratification or 
adjustment will be made. Biomarkers will be summarized graphically as they relate to 
efficacy and safety endpoints, as applicable. Summary statistics will be tabulated. The 
relationships between binary measures (e.g. response) and candidate biomarkers will 
be investigated using logistic regression. Associations will be summarized in terms of 
point and interval estimates of hazard ratios, odds ratios, or other statistics, as 
appropriate for the analyses completed. Models to predict clinical activity based on 
combinations of biomarkers may also be investigated.  
  
The dynamics of tumor growth trajectories are often ignored in evaluation of treatment 
efficacy, which often leads to underpowered studies and biased comparisons. To 
address this issue, we constructed a Bayesian mixture model of tumor growth based on 
longitudinal measures of serum biomarkers. This model assumes natural growth and 
drug induced decay are two independent latent processes underlying tumor growth 
among responders of treatment, whereas the growth process is the sole driver of tumor 
growth among non-responders. The data we obtained from collaboration will be used 
to test the effectiveness of the proposed method in comparing treatment effects based 
on longitudinal serum biomarkers. This dataset will also help us to develop novel 
statistical methods to better identify subgroups that are more responsive to a given 
treatment, where patient subgroup is often defined based on genetic profiles. This work 


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will be done in collaboration with the Medical University of South Carolina (Dr. 
Elizabeth Garrett-Mayer and Wei Wei).  
  
Additional post hoc statistical analyses not specified in the protocol, such as alternative 
modeling approaches may be completed. All analyses described in this section are based 
on the availability of the data.  
  
  
  
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16. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients 
with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.    
17. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer. Clin Cancer Res 2007;13(7):2151-7   
18. Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 
significantly associates with tumor aggressiveness and postoperative recurrence in human 
hepatocellular carcinoma. Clin Cancer Res 2009;15(3):971-9.     
19. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. PNAS 2007;104(9):3360-5.    
20. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell expression of 
programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 
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21. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a regulator of 
NYESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 2009;182:5240-
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22. Cai G, Karni A, Oliveira EML, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, negative 
regulators for activation of naïve, memory, and recently activated human CD4+ T cells. Cell 
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PNAS 2002;99(19):12293-7.    
25. Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, et al. Predominant expression 
of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol 
2006;42:268-74.    
26. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic factors. 
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tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 and anti-CTLA-4 
[Abstract]. J Immunol 2007;178:48.37  
28. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of AntiPD-1 antibody in cancer. N Engl J Med 2012:doi: 
10.1056/NEJMoa1200690.    
29. Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al. 2012 ASCO 
Annual Meeting:  Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with 
advanced solid tumors, 2012.     
30. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 
2010;363(8):711-23.    
31. Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. Improved survival 
with vemurafenib in melanoma with BRAF V600E mutation. New Engl J Med 
2011;346(26):2507-16.    
32. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med  
2011;364(26):2517-26.    
33. Bellati F, Visconti V, Napoletano C, Antonilli M, Frati L, Benedetti Panici P, et al. Immunology 
of gynecologic neoplasms: analysis of the prognostic significance of the immune status. Curr 
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34. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: 
polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 2010;21:3-10.    


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36. Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The prognistic 
value of intraepithelial and stromal CD3-, CD117- and CD138-positive cells in non-small cell 
lung carcinoma. APMIS 2010;118:371-82.    
37. Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: 
insights from genetically engineered mouse models of cancer. Cancer Lett 2009;279:1-7.    
38. Diederichsen ACP, Hjelmborg JvB, Christensen PB, Zeuthen J, Fenger C. Prognostic value of 
the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLADR 
expression on tumour cells. Cancer Immunol Immunother 2003;52:423-8.    
39. Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance of regulatory 
and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. 
J Clin Oncol 2007;25(18):2586-93.    
40. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, 
et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in 
primary cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-106.    
41. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells at the invasive 
margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastatsis: a 
longitudinal study. Lancet Oncol 2009;10:877-84.    
42. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic value of 
peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 
expression in clear cell renal cell carcinoma. BJU Intern 2008;103:399-405.    
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44. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival of 
a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30.    
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value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential 
immune response. J Surg Oncol 2003;84:224-8.    
46. Piersma SJ, Welters MJP, van der Burg SH. Tumor-specific regulatory T cells in cancer 
patients. Human Immunol 2008;69:241-9.    
47. Rao UNM, Lee SJ, Luo W, Mihm Jr. MC, Kirkwood JM. Presence of tumor-infiltrating 
lymphocytes and a dominant nodule within primary melanoma are prognostic factors for 


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relapse-free survival of patients with thick (T4) primary melanoma: pathologic analysis of the 
E1690 and E1694 intergroup trials. Am J Clin Pathol 2010;133:646-53.    
48. Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of 
tumorinfiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma. EJSO 
2008;34:173-9.    
49. Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral infiltrated Foxp3+ 
Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable 
gastric cancer. J Cancer Res Clin Oncol 2010;136:1585-95.    
50. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. 
Int J Clin Oncol 2010;15:544-51.    
51. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study 
of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010: 28:3167-
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52. Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer 
medulloblastoma. Science 2011;331:435-9.  
53. Berger MF, Hodis E, Heffernan TP, et al. Melanoma genome sequencing reveals frequent 
PREX2 mutations. Nature 2012:485:502-6.  
54. Lee W, Jiang Z, Liu J, et al. The mutation spectrum revealed by paired genome sequences from 
a lung cancer patient. Nature 2010:465:473-7.  
55. Timmermann B, Kerick M, Roehr C, et al. Somatic mutation profiles of MSI and MSS 
colorectal cancer identified by whole exome next generation sequencing and bioinformatics 
analysis. PLoS One 2010:5:e15661.  
56. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma 
Multiforme. Science 2008:321:1807-12.  
  
57. Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, et al. Durable Cancer 
Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody. 
Clin Cancer Res. 2013:19:462-8.  
  
58. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope 
landscape in breast and colorectal cancer. Cancer Res. 2008: 68:889-92.   
  
  
  
  
  
  
APPENDIX A: Performance Status Criteria  
  


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ECOG Performance Status Scale  
Karnofsky Performance Scale  
Grade  
Descriptions  
Percent  
Description  
0  
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.  
100  
Normal, no complaints, no evidence 
of disease.  
90  
Able to carry on normal activity; 
minor signs or symptoms of disease.  
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).  
80  
Normal activity with effort; some 
signs or symptoms of disease.  
70  
Cares for self, unable to carry on 
normal activity or to do active 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.  
60  
Requires occasional assistance, but is 
able to care for most of his/her 
needs.  
50  
Requires considerable assistance and 
frequent medical care.  
3  
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.  
40  
Disabled, requires special care and 
assistance.  
30  
Severely disabled, hospitalization 
indicated.  Death not imminent.  
4  
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund, fatal processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
  
  
  
  
  
  
  
  
  
  
  


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APPENDIX B: Foundation One Tumor Mutational Burden (TMB) Testing   
  
  
  
 


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APPENDIX C: Adverse Event of Clinical Interest (ECI) Reporting Form  
  
  
  
 


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Adverse Event of Clinical Interest (ECI) Reporting Form  
  
Please notify: 
  
  
Protocol Title:  
  
  
Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) 
Tumors  
Protocol Number 
(MK-3475-016):  
  
Signature of PI:  
  
  
  
Principal Investigator:  
  
Date:  
  
  
  
Report Type:  
  
Initial          
Follow-up          
Final Follow-up          
Addendum to:  
  
  
  
Section A: Subject Information  
Subject ID:  
Subject Initial:  
  
Subject Gender:  
Male  
Female  
  
Section B: Event Information  
Event diagnosis or symptoms:  
  
Date of First Dose (MK-3475):  
  
Action taken with the study 
drug (MK-3475):  
  
None  
Interrupted  
Discontinued  
Delayed  
  
Date of Last Dose (MK-3475) prior to 
Event:  
  
Number of Total Doses (MK-3475):  
  
Event Onset Date:  
Event End Date:  
  
  
  
Date Event Discovered:  
  
Relationship to:  
MK-3475  
Underlying Disease  
Unrelated  
  
  
Probably Unrelated  
  
  
 


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Possible Related  
  
  
Probably Related  
  
  
Definitely Related  
  
  
Section C: Brief Description of the Event: (please include relevant procedures and laboratory values)  
  
Section D: Relevant Medical History  
  
Section E: Concomitant Drug (Not related to ECI)  
Name of the Drug  
Start Date 
Stop Date 
Route  
Dose 
Freque 
ncy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Section F: Comments  
  
Additional Documents:    Please specify  
  
  
  


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APPENDIX D: SAE Reporting Form  
  
    
 


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Serious Adverse Event Reporting Form  
  
Please notify: 
  
  
Protocol Title:  
  
  
Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) 
Tumors  
Protocol Number 
(MK-3475-016):  
  
Signature of PI:  
  
  
  
Principal Investigator:  
  
Date:  
  
  
  
Report Type:  
Initial     
Follow-up  
Final Follow-up  
Death  
Addendum to:  
  
Serious Criteria (check all 
that apply):  
Death     
Life-threatening  
 Hospitalization or Elongation of  
Existing Hospitalization  
 Persistent or Significant 
Disability  
 Congenital Anomoly  
 Other Important Medical Event  
 Cancer  
 Overdose  
  
Hospital Admission 
Date:   
  
  
  
Hospital Discharge 
Date:  
Date Event  
Discovered:  
Section A: Subject Information  
 
Subject ID: Subject Initial: Subject Gender:  
 Male  
Female  
Section B: Event Information  
Event diagnosis or 
symptoms:  
  
Date of First Dose (MK-3475):  
  
Action taken with the study drug 
(MK-3475):  
  
None  
Interrupted  
Discontinued  
Delayed  
  
Date of Last Dose (MK-3475) 
prior to Event:  
  
Number of Total Doses 
(MK3475):  
  
 
 


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Event Onset Date:  
Event End Date:  
Relationship to:  
MK- 475  
Underlying Disease  
Unrelated  
  
  
Probably Unrelated  
  
  
Possible Related  
  
  
Probably Related  
  
  
Definitely Related  
  
  
Section C: Brief Description of the Event:  
  
Section D: Relevant Medical History  
  
Section E: Concomitant Drug (Not related to  SAE)  
Name of the Drug  
Start  Date 
Stop Date 
Route  
Dose 
Frequ 
ency 
  
  
  
  
  
  


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Section F: Comments  
  
Additional Documents:  
Please specify  
  
  
  
  
APPENDIX E: 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 used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.    
Disease Parameters  
  
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with 
CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  
  
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. Malignant 
lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 


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be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.  
  
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.  
  
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  
  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.  
  
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected.  A sum of the diameters (longest 
for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
  
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.   
  
Evaluation of Target Lesions  
  
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  
  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters.  
  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 


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increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions).  
  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study.  
  
Evaluation of Non-Target Lesions  
  
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis).  
  
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.  
  
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.      
  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).  
  
Evaluation of Best Overall Response  
  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
  
For Patients with Measurable Disease (i.e., Target Disease)  
  
Target 
Lesions  
Non-Target 
Lesions  
New  
Lesions  
Overall 
Response 
Best Overall  
Response when  
Confirmation is  
Required*  
CR  
CR  
No  
CR  
>4 wks.  
Confirmation**  
CR  
Non-
CR/NonPD  
No  
PR  
>4 wks.  
Confirmation**  


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79 
CR  
Not evaluated  
No  
PR  
PR  
Non-CR/Non- 
PD/not 
evaluated  
No  
PR  
SD  
Non-CR/Non- 
PD/not 
evaluated  
No  
SD  
Documented at least 
once >4 wks. from 
baseline**  
PD  
Any  
Yes or 
No  
PD  
no prior SD, PR or CR  
Any  
PD***  
Yes or 
No  
PD  
Any  
Any  
Yes  
PD  
*  
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion.  
**  
Only for non-randomized trials with response as primary endpoint.  
***  
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.  
  
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
  
Reference  
  
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 tumours: Revised RECIST guideline (version 
1.1).  Eur J Cancer. 2009 Jan;45(2):228-47.  
  
  
  
APPENDIX F: Immune Related Response Criteria  
  
For all patients who experience disease progression on study, the date noted for of disease 
progression is the time of the scan where it is originally detected, and not the following date of the 
confirmatory scan.   
Definitions of measurable and non-measurable disease   
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane perpendicular 
diameters. Both its longest diameter and its longest perpendicular must be greater than or equal to 


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10 mm. Lymph nodes must have a short-axis line-length of ≥ 15 mm.  Malignant lymph nodes must 
be measurable in 2 perpendicular diameters. Both its longest diameter and its longest perpendicular 
must be greater than or equal to 15 mm.  The quantitative endpoint will be defined as the product 
of the longest diameter with its longest perpendicular.   
Non-measurable disease: Non-measurable lesions are those that are not suitable for quantitative 
assessment over time. These include:  
1) Neoplastic masses that are too small to measure, because their longest uninterrupted diameter 
or longest perpendicular are less than 10 mm.  
2) Neoplastic masses whose boundaries cannot be distinguished.  This includes masses which 
cannot be demarcated from surrounding tissue because of inadequate contrast, masses with 
overly complex morphology, or those with highly heterogeneous tissue composition.    
3) Other types of lesions that are confidently felt to represent neoplastic tissue, but difficult to 
quantify in a reproducible manner. These include bone metastases, leptomeningeal metastases, 
malignant ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, ill-defined abdominal masses, etc.  
For irRC, only target lesions selected at baseline and measurable new lesions are taken into 
account.   
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.    
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions 
(≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are 
added together to provide the total time-point tumor burden.  
  
  
Overall response using irRC:  
 Complete Response (irCR): Complete disappearance of all tumor lesions (whether 
measureable or not, and no new lesions).  CR must be confirmed by repeated, consecutive 
assessments made no less than 4 weeks from the date first documented.   
 Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive assessment 
at least 4 weeks after first documentation.   
 Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.    
 Progressive Disease (irPD): At least 25% increase in SPD relative to nadir (minimum 
recorded tumor burden) Confirmation by a repeat, consecutive assessment no less than 4 
weeks from the data first documented.    
Please note other key differences between irRC and the original WHO criteria:  


Phase 2 Study of MK-3475 in Patients with Microsatellite Unstable (MSI) Tumors  
 
Amendment 11/ Version 12/ December 1, 2017  
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New measurable lesions will be incorporated into the SPD   
New non measurable lesions do not define progression but preclude irCR  
Non-index lesions contribute to defining irCR (complete disappearance required).  
REFERENCE  
IrRC for the current protocol is adopted from the following reference:  
Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy Activity 
in Solid Tumors: Immune-Related Response Criteria. Clinical Cancer Research, 2009 Dec 
1;15(23):7412-20.  Epub 2009 Nov 24.  
  
  
  
APPENDIX G: Data Safety Monitoring Plan (DSMP)