A Basket Trial of Pembrolizumab in Patients With Advanced Solid Tumors and Genomic Instability
Phase: PHASE2
Conditions: BRCA1 Gene Mutation, BRCA2 Gene Mutation, Locally Advanced Solid Neoplasm, Metastatic Malignant Solid Neoplasm, POLD1 Gene Mutation, POLE Gene Mutation, Recurrent Malignant Solid Neoplasm, Recurrent Ovarian Carcinoma, Stage III Breast Cancer AJCC v7, Stage III Ovarian Cancer AJCC v8, Stage IIIA Breast Cancer AJCC v7, Stage IIIA Ovarian Cancer AJCC v8, Stage IIIB Breast Cancer AJCC v7, Stage IIIB Ovarian Cancer AJCC v8, Stage IIIC Breast Cancer AJCC v7, Stage IIIC Ovarian Cancer AJCC v8, Stage IV Breast Cancer AJCC v6 and v7, Stage IV Ovarian Cancer AJCC v8, Stage IVA Ovarian Cancer AJCC v8, Stage IVB Ovarian Cancer AJCC v8
Sponsor: Rutgers, The State University of New Jersey

 
 
Official Title: 
Pembrolizumab in Treating Participants With Metastatic, 
Recurrent or Locally Advanced Cancer and Genomic 
Instability 
NCT number: 
NCT03428802 
Document Type:  
Protocol SAP 
Date of the 
Document: 
02/22/2023 
 

Product:  Pembrolizumab
Protocol/Amendment No.:  CINJ 051709 v5 01-04-2023 
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1
SPONSOR: Rutgers Cancer Institute of New Jersey
With funding support from Merck
TITLE: A Basket Trial of Pembrolizumab in Patients with Advanced Solid Tumors and 
Genomic Instability
IND NUMBER:
EudraCT NUMBER (Studies in Europe only):
Version Date: 04-January-2023
PROTOCOL AMENDMENTS
The current version of the protocol was released on 01-04-2023 and includes the following 
Amendments, 1-18 into the version approved by Rutgers IRB on 10/06/2017.
Amend-
ment #
Section
Page(s)
Protocol Change
1.
4.2.1
13
15
15
Insertions, “Alterations in DNA response and repair genes have been shown 
to correlate with clinical outcome to immune checkpoint therapy”
“There is mounting evidence that tumors with additional DNA repair defects 
will also be susceptible to immune checkpoint therapy.”
“As well,  reports examining the relationship between a panel of DNA 
damage and repair alterations and response to PD-1/PD-L1 blockade in 
bladder cancer suggested that the presence of any  DDR alteration was 
associated with a higher response rate, and that this was enhanced when 
tumors harbored known or likely deleterious DDR alterations compared with 
DDR alterations of unknown significance and in those whose tumors were 
wild-type for DDR genes, an observation that warrants additional study 
22,23. Thus, tumors with BRCA1 or BRCA2 mutations or DDR alterations 
will be explored in a second cohort.”
2.
5.1.2
17
18
#3 changed as “Have a diagnosis of a tumor with evidence of genomic 
instability or DNA repair deficiency on CLIA certified genomic testing, 
inclusive of mutations in POLE, POLD1 for Arm 1  and in  BRCA1 and 
BRCA2  for Arm 2 as well as additional DNA repair abnormalities 
including RAD51, FANCA or FANCC, ATM, ATR, PALB2.  In Arm 2, 
enrollment of breast and ovarian histologies will be limited to a total of 10 
patients. Non-BRCA DNA repair abnormalities will be reviewed in consult 
with the Precision Medicine Initiative at Rutgers to confirm suitability for 
inclusion.
#5 changed as “If adequate tissue is not present the patient may consent to 
a newly obtained biopsy in consultation with the PI and treating physician 
of risks and benefits of the biopsy”.
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2
3
5.1.3
19
#2 changed as “Has a diagnosis of immunodeficiency that consistently 
requires more than 10 mg daily of prednisone or equivalent or has resulted 
in life threatening episodes previously regardless of current treatment.”
4
5.1.3
20
#9 changed as
“Has active autoimmune disease which currently requires 
disease modifying agents that include corticosteroids > 10 mg of prednisone 
or equivalent 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.”
5
5.1.3
20
#10 changed as “Has a history of (non-infectious) pneumonitis that required 
steroids or has current pneumonitis.”
6
5.1.3
21
#19 changed as “Has a known history of Hepatitis B (defined as Hepatitis 
B surface antigen [HBsAg] reactive) or known active Hepatitis C virus 
(defined as HCV RNA [qualitative] is detected) infection.”
7
5.1.3
21
“MSI unknown will be excluded” appended to exclusion criteria #18
8
6.1
34
Table footnote modified for clarity
9
11.5.1.1
69
Blood collection into Red Top tubes added
10
11.5.1.2
69
Minor text edits on tumor tissue handling
11
11.5.2.1
70
Processing of peripheral blood into Red Top tubes appended (bullet b)©
12
11.5.2.2; 
bullet 
(a)
71
Genetic analyses specified (next generation sequencing)
13
11.5.2.2; 
bullet 
(e)
72
‘RNA later’ replaced with ‘TRIzol’
1411.5.2.2; 
Table 
9
73
Text modifications
15
11.5.3; 
bullet 
(e)
73
Address change
16
11.5.4.4
76
Appended “nanostring, single cell RNA-sequencing, exosome sequencing, 
multispecial immunostain”
17
2.1
6.1
7.1.2.6.2
10
37
38
43
Required number of slides updated to 15
Modified to read: Patients will be evaluated for response by RECIST 1.1 
and irRC criteria after every 9 weeks (3 cycles) of treatment until cycle 8,  
then subsequently after every 12 weeks (4 cycles) of treatment.
Updated the schedule for collection of Circulating cell-free DNA
Footnote #2 – added: All screening labs should be performed within 10 days 
of treatment initiation (refer to inclusion criteria #7, Table 1).  
Footnote #3 modified to read: “Prior to Cycles 4”
Footnote #6 – added: every 6 weeks of treatment
Deleted: Andrew Zloza, MD PhD
Added: Joshua Vieth, PhD, Managing
Deleted: a flow cytometry multiplex assay (LegendPlex) detecting IL-2, IL-
4, IL-10, IL-6, IL-17A, TNF-α, sFas, sFasL, IFN-γ, granzyme A, granzyme 
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3
7.2.3.1
10.7
11.5
44
51
63
B, perforin and granulysin
Added: Luminex Multiplexe Analysis against a panel of 48 human 
cytokines/chemokines.
Moved (insertion)
Added: “Rutgers Cancer Institute of New Jersey (Sponsor) Office of Human 
Research Services via OnCore within 24 hours of site notification. The 
completed SAE report (signed by the Investigator) must be sent to the 
Rutgers CINJ OHRS QA department.”
Deleted: Sites will contact the Rutgers Cancer Institute of New Jersey’s 
OHRS Registration Desk (732) 235-7530 and fax (732) 235-7690 to register 
subjects.
Added: Sites will register and enroll patients through OnCore® the Clinical 
Trials Management System for this study. 
Removed text from Sections 11.5, 11.5.1, 11.5.1.1, 11.5.1.2, 11.5.2, 
11.5.2.1, 11.5.2.2, Table 9, 11.5.3, 11.5.4, 11.5.4.1, 11.5.4.2, 11.5.4.3, 
11.5.4.4
Updated Section 11.5 with the biospecimen collection requirements and 
updated to include reference to the 051709 Correlative Research 
Laboratory Manual for collection, processing, and shipping details.
18
2.1
4.1
4.2.1
Changed irRC to iRECIST
Deleted: Refer to the Investigator’s Brochure (IB)/approved labeling for 
detailed background information on MK-3475.
Added: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) 
monoclonal antibody (mAb) with high specificity of binding to the programmed 
cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed 
cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  
Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD 1.  Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is 
indicated for the treatment of patients across a number of indications because 
of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure (IB).
Deleted: entire section 
Added: The planned dose of pembrolizumab for this study is 200 mg every 3 
weeks (Q3W).  Based on the totality of data generated in the Keytruda 
development program, 200 mg Q3W is the appropriate dose of pembrolizumab 
for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by:
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg 
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5.1.2
5.1.3
5.2.1.1.
5.2.1.2.
Q3W to 10 mg/kg every 2 weeks ( Q2W), , representing an approximate 5- to 
7.5-fold exposure range (refer to IB, Section 5.2.2)
• Population PK analysis showing that both fixed dosing and weight-based 
dosing provides similar control of PK variability with considerable overlap in 
the distributions of exposures, supporting suitability of 200 mg Q3W
• Clinical data showing meaningful improvement in benefit-risk including 
overall survival at 200 mg Q3W across multiple indications, and
• Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically-based PK [PBPK] analysis) at 200 mg Q3W
Deleted: without transfusion or EPO dependency (within 7 days of assessment)
Added: without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 2 weeks.
Changed ≥60 mL/min to ≥30 mL/min
Deleted Inclusion Criteria #10:  Male subjects should agree to abstinence or use 
of an adequate method of contraception starting with the first dose of study 
therapy through 120 days after the last dose of study therapy.
Exclusion criteria #4 modified to read: Has severe hypersensitivity (≥Grade 3) 
to pembrolizumab or any of its excipients.
Exclusion criteria #10 modified to read: Has a history of (non-infectious) 
pneumonitis/ interstitial lung disease that required steroids or has current 
pneumonitis/interstitial lung disease.
Deleted: or father children from exclusion criteria # 14.
Added to exclusion criteria #15: or with an agent directed to another stimulatory 
or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
Deleted from exclusion criteria #17: Note:  Seasonal influenza vaccines for 
injection are generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and 
are not allowed
Exclusion criteria # 17 modified to read: Has received a live vaccine or live-
attenuated vaccine within 30 days of planned start of study therapy. 
Administration of killed vaccines is allowed.
Deleted: Details on preparation and administration of pembrolizumab (MK-
3475) are provided in the Pharmacy Manual.  
Changed Section 5.2.1.2 heading to read: Dose Modification and toxicity 
management for immune-related AEs associated with pembrolizumab and 
combination therapy
Added: including coadministration with additional compounds,
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5
5.2.2
5.3.2.
5.4.1.
5.5.2.
6.1
7.1.2.1.
Added: and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications.  
Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, 
administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy 
may be included as part of the evaluation. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab/combination 
treatment are provided in Table 3 below.
Deleted: The Pharmacy Manual contains specific instructions for the 
preparation of the pembrolizumab infusion fluid and administration of infusion 
solution.
Added: Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
Deleted references to the ECI guidance document.
Added: in Section 5.2.1.2, Table 3.
Changed Management of Infusion Reactions section to read: Dose modification 
and toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions 
including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction are 
provided in Table 4.
Deleted: Furthermore, it is not known if pembrolizumab has transient adverse 
effects on the composition of sperm.  
Deleted: and male 
Deleted: or impregnating a partner, respectively
Added: PD-L1 analysis during screening
Added: footnote 7Refer to the MISP Sample Handling Manual for collection 
and shipping instructions.
Deleted: For subjects receiving treatment with pembrolizumab all AEs of 
unknown etiology associated with pembrolizumab exposure should be 
evaluated to determine if it is possibly an event of clinical interest (ECI) of a 
potentially immunologic etiology (termed immune-related adverse events, or 
irAEs); see the separate ECI guidance document regarding the identification, 
evaluation and management of potential irAEs.  
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6
7.1.2.5.4.
7.2.
7.2.1.
7.2.3.1.
Added: iRECIST is based on RECIST 1.1, but adapted to account for the unique 
tumor response seen with immunotherapeutic drugs. iRECIST will be used by 
the investigator to assess tumor response and progression and make treatment 
decisions. When clinically stable, participants should not be discontinued until 
progression is confirmed per iRECIST.
Added: If repeat imaging does not confirm PD per iRECIST (below), as 
assessed by the Investigator, and the participant continues to be clinically stable, 
study treatment may continue and follow the regular imaging schedule
Added: Confirmation of Progression per iRECIST
Progression is considered confirmed, and the overall response will be confirmed 
progressive disease per iRECIST (iCPD), if ANY of the following occurs:
• Any of the factors that were the basis for the initial unconfirmed progressive 
disease (iUPD) show worsening
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥ 5 mm from a 
prior iUPD time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions
• Any new factor appears that would have triggered PD by RECIST 1.1
Changed the Worldwide Product Safety; FAX to 215- 661-6229
Deleted: All reports of overdose with and without an adverse event must be 
reported within 24 hours to the Sponsor and within 2 working days hours to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
Added: o Medical or scientific judgment should be exercised in deciding 
whether SAE reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious.
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse.
Deleted: Additionally, any serious adverse event, considered by an investigator 
who is a qualified physician to be related to Merck product that is brought to 
the attention of the investigator at any time outside of the time period specified 
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Pa
Page
ge
ge
ge
ge
ge
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7
7.2.3.2.
10.6.1.
10.7.
11.3.2.
11.4.
11.5.
in the previous paragraph also must be reported immediately to the Sponsor and 
to Merck.
Deleted: recorded as such on the Adverse Event case report forms/worksheets 
and reported within 24 hours to the Sponsor (CINJ) and CINJ will report within 
2 working days  Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220)
Deleted: The trial site guidance for assessment and follow up of these criteria 
can be found in the Investigator Trial File Binder (or equivalent).
Deleted: 1.Additional adverse events: A separate guidance document has been 
provided entitled “Event of Clinical Interest Guidance Document” (previously 
entitled, “Event of Clinical Interest and Immune-Related Adverse Event 
Guidance Document”).  This document can be found in Appendix 4 and 
provides guidance regarding identification, evaluation and management of ECIs 
and irAEs.  
ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever 
is earlier, need to be reported within 24 hours to the Sponsor (CINJ) and CINJ 
will report within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220), regardless of attribution to study 
treatment, consistent with standard SAE reporting guidelines.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results 
should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought 
to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes.  If no 
other cause is found, then it is assumed to be immune-related.
Deleted: annual review
Added: quarterly review
Added: This protocol is available at the Rutgers Cancer Institute of New Jersey 
(CINJ)/Robert Wood Johnson University Hospital (RWJUH) in New 
Brunswick and NYU Langone Health.
Changed pulmonitis to pneumonitis
Deleted entire section
Changed the section numbering to 11.4 and subsections were updated to 11.4.1 
– 11.4.3
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8
19
2,3
4.2
5.1.2.
5.1.3.
16
22
23
27
Trial Diagram updated to reflect closure of arm 1
Added: Rationale for Protocol Modification 
In this modification (v.04JAN2023), we are closing Arm 1 due to low accrual 
and removing the limitation of enrollment of patients with breast and ovarian 
histologies in Arm 2. The power of study will not be affected since the study 
was not powered to pick up differences in response between breast/ovarian 
and non breast/ovarian patients.  There is no mention of breast/ovarian-to 
other cohort comparisons.  Mutations of HRD pathway are the scientific factor 
of interest, not ovarian/breast cohort, so there is not statistical issue with 
proposed change.
Removed: “POLE, POLD1 for Arm 1  and in” and “In Arm 2, enrollment of 
breast and ovarian histologies will be limited to a total of 10 patients.” from 
inclusion criteria #3.
Exclusion criteria 19 updated to read:
19. Has a known active history of Hepatitis B (defined as Hepatitis B surface 
antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV 
RNA [qualitative] is detected) infection.  If patient has past hepatitis B 
virus or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [HBcAb) and absence of HBsAg), patients may be enrolled 
provided that HBV DNA is negative.
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9
1.0
TRIAL SUMMARY ..................................................................................................14
2.0
TRIAL DESIGN ........................................................................................................14
2.1
Trial Design............................................................................................................14
2.2
Trial Diagram ........................................................................................................15
3.0
OBJECTIVE(S) & HYPOTHESIS(ES) ..................................................................15
3.1
Primary Objective(s) & Hypothesis(es)...............................................................15
3.2
Secondary Objective(s) & Hypothesis(es) ...........................................................16
3.3
Exploratory Objective...........................................................................................16
4.0
BACKGROUND & RATIONALE ..........................................................................17
4.1
Background ............................................................................................................17
4.1.1
Pharmaceutical and Therapeutic Background .....................................................17
4.1.2
Preclinical and Clinical Trial Data.......................................................................18
4.2
Rationale.................................................................................................................18
4.2.1
Rationale for the Trial and Selected Subject Population .....................................18
4.2.2
Rationale for Endpoints .......................................................................................21
4.2.2.1
Efficacy Endpoints........................................................................................21
4.2.2.2
Biomarker Research......................................................................................21
5.0
METHODOLOGY ....................................................................................................22
5.1
Entry Criteria ........................................................................................................22
5.1.1
Diagnosis/Condition for Entry into the Trial.......................................................22
5.1.2
Subject Inclusion Criteria ....................................................................................22
5.1.3
Subject Exclusion Criteria ...................................................................................23
5.2
Trial Treatments....................................................................................................25
5.2.1
Dose Selection/Modification ...............................................................................26
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1
5.2.1.1
Dose Selection ..............................................................................................26
5.2.1.2
Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab and combination therapy...........................26
5.2.2
Timing of Dose Administration...........................................................................28
5.2.3
Trial Blinding/Masking........................................................................................28
5.3
Concomitant Medications/Vaccinations (allowed & prohibited)......................28
5.3.1
Acceptable Concomitant Medications.................................................................28
5.3.2
Prohibited Concomitant Medications ..................................................................29
5.4
Rescue Medications & Supportive Care..............................................................30
5.4.1
Supportive Care Guidelines.................................................................................30
5.5
Diet/Activity/Other Considerations .....................................................................33
5.5.1
Diet.......................................................................................................................33
5.5.2
Contraception.......................................................................................................34
5.5.3
Use in Pregnancy .................................................................................................35
5.5.4
Use in Nursing Women........................................................................................35
5.6
Subject Withdrawal/Discontinuation Criteria....................................................36
5.6.1
Discontinuation of Study Therapy after CR ........................................................37
5.7
Subject Replacement Strategy..............................................................................37
5.8
Clinical Criteria for Early Trial Termination ....................................................37
6.0
TRIAL FLOW CHART............................................................................................38
6.1
Study Flow Chart...................................................................................................38
7.0
TRIAL PROCEDURES ............................................................................................41
7.1
Trial Procedures ....................................................................................................41
7.1.1
Administrative Procedures...................................................................................41
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7.1.1.1
Informed Consent .........................................................................................41
7.1.1.2
Inclusion/Exclusion Criteria .........................................................................41
7.1.1.3
Medical History ............................................................................................42
7.1.1.4
Prior and Concomitant Medications Review................................................42
7.1.1.5
Disease Details and Treatments....................................................................42
7.1.1.6
Assignment of Screening Number................................................................42
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other)....................................42
7.1.2
Clinical Procedures/Assessments ........................................................................43
7.1.2.1
Adverse Event (AE) Monitoring ..................................................................43
7.1.2.2
Full Physical Exam.......................................................................................43
7.1.2.3
Vital Signs ....................................................................................................43
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ............43
7.1.2.5
Tumor Imaging and Assessment of Disease.................................................43
7.1.2.6
Tumor Tissue Collection and Correlative Studies Blood Sampling.............46
7.1.3
Laboratory Procedures/Assessments ...................................................................48
7.1.4
Withdrawal/Discontinuation................................................................................50
7.1.5
Visit Requirements ..............................................................................................50
7.1.5.1
Screening Period...........................................................................................50
7.1.5.2
Treatment Period ..........................................................................................50
7.1.5.3
Post-Treatment Visits ...................................................................................51
7.1.5.4
Follow-up Visits ...........................................................................................51
7.1.5.5
Second Course Phase (Retreatment Period) .................................................52
7.2
Assessing and Recording Adverse Events ...........................................................53
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7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck..........................................................................................54
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck..................54
7.2.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck ..............55
7.2.3.1
Serious Adverse Events ................................................................................55
7.2.3.2
Events of Clinical Interest ............................................................................56
7.2.4
Evaluating Adverse Events..................................................................................56
7.2.5
Sponsor Responsibility for Reporting Adverse Events .......................................60
8.0
STATISTICAL ANALYSIS PLAN .........................................................................60
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................61
9.1
Investigational Product .........................................................................................61
9.2
Packaging and Labeling Information..................................................................61
9.3
Clinical Supplies Disclosure..................................................................................61
9.4
Storage and Handling Requirements...................................................................61
9.5
Returns and Reconciliation...................................................................................62
10.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................62
10.1
Confidentiality .......................................................................................................62
10.2
Compliance with Financial Disclosure Requirements .......................................62
10.3
Compliance with Law, Audit and Debarment ....................................................62
10.4
Issues with Minors.................................................................................................64
10.5
Compliance with Trial Registration and Results Posting Requirements.........65
10.6
Quality Management System................................................................................65
10.6.1 Data Safety Monitoring Board.............................................................................65
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10.6.2 Monitoring ...........................................................................................................65
10.7
Registration ............................................................................................................66
10.8
Data Management ................................................................................................66
10.8.1 Study Documentation ..........................................................................................66
10.8.2 Case Report Forms (CRFs)..................................................................................67
10.8.3 Data Management Procedures and Data Verification..........................................67
10.8.4 Study Closure.......................................................................................................67
10.9
Data Safety Monitoring Plan................................................................................67
11.0
APPENDICES ..........................................................................................................68
11.1
ECOG Performance Status...................................................................................68
11.2
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ...............68
11.3
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors.................................................................68
11.3.1 Measurable Disease .............................................................................................69
11.3.2 Non-measurable Disease......................................................................................69
11.3.3 Target Lesions......................................................................................................69
11.3.4 Non-target Lesions...............................................................................................70
11.3.5 Evaluation of Target Lesions...............................................................................70
11.3.6 Evaluation of Non-Target Lesions.......................................................................70
11.3.7 Evaluation of New Lesions..................................................................................70
11.3.8 Evaluation of Best Overall Response ..................................................................71
11.4
Collection, Processing and Shipping of Blood and Tumor Tissue and 
Correlative Science*..............................................................................................71
11.4.1 Tissue Collection .................................................................................................72
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11.4.1.1 Analysis of PD ligand expression (Qualtek analysis)...................................72
11.4.1.2 Tissue for Correlative Research....................................................................72
11.4.1.3 Tissue Collection Priority.............................................................................72
11.4.2 Blood Collection..................................................................................................72
11.4.3 Safety Precautions................................................................................................72
12.0
references....................................................................................................................74
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1.0 TRIAL SUMMARY
Abbreviated Title
Basket Trial of Pembrolizumab
Trial Phase
II
Clinical Indication
BRCA,  POLE and POLD1 mutant tumors
Trial Type
Therapeutic
Type of control
None
Route of administration
IV
Trial Blinding
None
Treatment Groups 
BRCA,  POLE and POLD1 mutant tumors
Number of trial subjects
40
Estimated 
enrollment 
period
18-24 months
Estimated duration of trial 30-36 months
Duration of Participation
30-36 months
2.0 TRIAL DESIGN
2.1
Trial Design
This will be a phase II trial that will enroll two cohorts of patients: a) Patients with advanced 
solid tumors with POLE and POLD1 mutations whose tumors exhibit a microsatellite stable 
phenotype and b) Patients with advanced solid tumors with BRCA1/2 mutations. The primary 
endpoint will be response rate, which we anticipate to be higher than that seen historically in 
unselected solid tumors. Progression free survival will also be measured. 
Patient Selection and Recruitment: Patients referred for this trial must submit pre-treatment 
tumor specimens for next generation sequencing analysis to characterize the presence of 
POLE, POLD1, or BRCA1/2 mutations. Enrollment will be guided by presence of tumor 
mutations (as opposed to tumor histology). Patients with BRCA1/2 mutations will be identified 
through standard of care testing for these mutations. If Foundation One next generation 
sequencing panel, or other similarly validated analysis, is ordered commercially prior to the 
patient’s referral for study this analysis will be acceptable for enrollment to this protocol. 
Patients with POLE/POLD1 mutations will likely be identified through Foundation One next 
generation sequencing panel, or other similarly validated analysis, ordered commercially prior 
to the patient’s referral for study. This analysis will be acceptable for enrollment to this 
protocol. Tumors harboring hotspot mutations in POLE/POLD1 that result in a hypermutator 
phenotype are expected to be microsatellite stable (MSS). Testing for microsatellite instability 
will be done in all POLE mutant cases prior to enrollment. Tumors harboring non-hotspot 
POLE or POLD1 mutations that show clear evidence of MSI will be excluded.
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Archived tumor tissue will be retrieved for correlative analyses from each patient (20 unstained 
slides preferred, minimum of 15 required). If inadequate archived tissue is available, a fresh 
tumor biopsy must be performed. 
Mandatory tumor assessments include collection of archived or fresh tumor at baseline and a 
biopsy of tumor upon progression. Fresh tumor biopsies or archived tumor tissue will be 
collected at baseline as well as peripheral blood mononuclear cell (PBMC) samples. Patients 
will be treated with pembrolizumab dosed at 200 mg intravenous infusion every three weeks 
(1 cycle = 21 days). Patients will be evaluated for response by RECIST 1.1 and iRECIST 
criteria after every 9 weeks (3 cycles) of treatment until cycle 8,  then subsequently after every 
12 weeks (4 cycles) of treatment. PBMCs (tumor optional) will be sampled to assess treatment 
effect on the immune response at the following time points: baseline and after week 4 of 
pembrolizumab. Mandatory submission of PBMC tumor biopsies at progression will occur 
provided that the biopsy of the progressing tumor does not impose significant risk in the 
opinion of the investigator. Plasma samples for analysis of cell-free DNA will also be collected 
prior to initiation of treatment, and every 6 weeks of treatment. The above design and 
assessments are depicted in the schema below.
2.2
2.3
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate the response rate of pembrolizumab in patients with evidence of 
genomic instability classified as follows: 1) All solid tumors with POLE and POLD1 
mutations 2) All solid tumors with BRCA1/2 mutations
Arm 1 is closed 
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Hypothesis:  Tumors with evidence of genomic instability such as those with mutations in 
POLE, POLD1 and BRCA1 and BRCA2 will have higher response rates than tumors that 
do not exhibit these mutations.1-7
3.2
Secondary Objective(s) & Hypothesis(es)
(1) Objective:  To compare the complete and partial response rate, and response durability 
(immune related progression free survival), to historical cohort information of 
unselected patients treated with pembrolizumab
(2) Hypothesis:  PFS rate will be improved in patients whose tumors have POLE and 
POLD1 mutations, or BRCA1/2 mutations, compared with unselected patients 
3.3
Exploratory Objective
(1) Objective: To evaluate potential tumor and T cell biomarkers predictive of response 
through the following correlates: 
-
To evaluate the CD4+ and CD8+ T cell response in the tumor 
microenvironment and peripheral blood of patients treated on this study 
as well as the frequencies, activation/differentiation, functionality, and 
co-inhibitory molecule expression of immune cell populations in 
peripheral blood and tumor, before and after treatment with systemic 
pembrolizumab
-
To measure PD-L1 expression in pretreatment tumor biopsies and in 
post treatment tumor tissue, as well as on biopsies taken at progression, 
to capture data on the relationship between PD-L1 expression and 
patient outcome
-
To perform deep sequencing for detection of PD-1 and PD-L1 
polymorphisms that may correlate with clinical outcomes as well as 
identification of mutations in immunoregulatory genes that are potential 
predictors of response to these therapies.
-
To perform exome sequencing of pre-treatment tumor specimens to 
determine if the presence of immunogenic neoantigens is associated 
with response.
-
To perform RNA sequencing to determine if expression of checkpoint 
genes, immune-regulatory modules, or non-coding RNAs including 
repetitive RNAs and retroelements are associated with response.
(2) Hypothesis: POLE, POLD1 and BRCA1/2 deficient tumors will have high incidence 
of expression of PD-L1 and evidence of CD8+ lymphocyte infiltration, levels and 
intensity of which will correlate with clinical benefit obtained. Responses will be 
associated with specific immune-related gene expression and effector T cell patterns 
and function.
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4.0 BACKGROUND & RATIONALE
4.1
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications because of its mechanism of action to bind the PD-1 receptor 
on the T cell.  For more details on specific indications refer to the Investigator brochure (IB).
4.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
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receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma.  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, 
and for non small cell lung cancer which express PD-L1 and are refractory to chemotherapy, 
and for head and neck squamous carcinomas that are refractory to platinum based 
chemotherapy.
4.1.2
Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
Tumors with intrinsic defects in DNA repair mechanisms may have a high burden of 
potentially immunogenic mutations and thus be vulnerable to immune checkpoint blockade, a 
hypothesis that is the subject of multiple current investigations1-3. We hypothesize that 
patients with mutations in DNA Polymerase Epsilon (POLE), part of the DNA 
polymerase complex responsible for DNA replication during S-phase, and POLD1, which 
is part of the main lagging strand polymerase, will result in a “hyper-mutator” phenotype. 
Similarly, cancers with mutations in BRCA1/2 also have an underlying mutator 
phenotype which may lead to generation of immunogenic mutations. Thus, these tumors 
will be rendered especially vulnerable to therapy with pembrolizumab.
Mutational Burden and Immunogenic Neo-epitopes. Immune checkpoint therapy with 
antibodies to programmed cell death receptor-1 (PD-1) can lead to prolonged remissions in 
multiple tumor types8-16, but many do not benefit. While programmed death-ligand 1 (PD-L1) 
expression may predict response, it is not definitive, and its accuracy may be enhanced by the 
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discovery of additional predictors17. This is critical as combination therapy with checkpoint 
inhibitors enters the landscape of treatment for lung and melanoma cancers18,19. This approach 
raises the response and durable remission rate, but is complicated by a significantly higher 
incidence of grade 3 or 4 side effects; as well, increased financial burden is conferred. Thus, 
elucidating predictive biomarkers for response is enormously beneficial, particularly if 
patients who require single agent PD-1 blockade for treatment of their disease could be 
identified.
Acquired or germline defects in DNA repair pathways can result in very high mutational 
burdens. DNA repair defects in human cancer, include defects in mis-match repair (MMR) 
that result in a micro-satellite instability (MSI) phenotype, are associated with robust 
lymphocytic infiltration with CD8+ T-cells and evidence of immune checkpoint 
engagement20,21.  Alterations in DNA response and repair genes have been shown to correlate 
with clinical outcome to immune checkpoint therapy 22,23, and clinical trials in malignancies 
with specific MMR repair deficiencies revealed that MMR repair status predicted clinical 
benefit3. 
A specific class of potentially predictive DNA repair defects includes defects in proofreading 
function of DNA polymerases, such as DNA polymerase Epsilon and DNA polymerase Delta 
(POLE and POLD1). Missense mutations in POLE and POLD1 are seen as rare germline 
mutations associated with variant Lynch syndrome, or as acquired somatic mutations. Loss of 
POLE or POLD1 proofreading function leads to an “ultra-mutator” phenotype with a mutation 
burden that exceeds even that seen in tumors with MSI phenotype4. POLE mutations occur in 
up to 10% of endometrial cancers, and are also found in colon, lung, breast and glial tumors. 
POLE mutant tumors show immune activation with a brisk lymphocytic infiltration and high 
expression of immune checkpoint genes such as PD-L121,24-27. 
We identified a patient with POLE mutant endometrial cancer who experienced an 
exceptional response to pembrolizumab, supporting the hypothesis that POLE mutant 
cancers may be susceptible to immune checkpoint therapy28. Our patient’s primary tumor 
showed a readily apparent peritumoral lymphocytic infiltrate (Fig 1 A, B26 ). She experienced 
immediate, sustained partial response to therapy still ongoing after 10 months (Fig. 1D26). The 
POLE mutation was identified through clinical grade targeted genomic profiling (Foundation 
OneTM) of a pre-treatment tumor sample. This tumor was associated with an ultramutator 
phenotype, with 32 likely pathogenic sequence variants in the primary tumor and 33 potentially 
pathogenic variants identified in the LN recurrence; 28 changes were present in both samples. 
Both samples harbored a mutation in the exonuclease domain of POLE that affects 
proofreading function (V411L) as well as a separate nonsense mutation in POLE (R114*), 
consistent with inactivation of the wild-type allele; these features are associated with an 
ultramutator phenotype20,25. In addition, there were a large number of single nucleotide variants 
classified as “variant of unknown significance” (VUS): 116 in the primary sample, and 159 in 
the recurrence, with only 83 shared between the tumors (Fig. 1E26 ). For comparison in 252 
deidentified endometrioid endometrial cancers that underwent genomic profiling with the 
Foundation OneTM assay, 23 (9.1%) had sequence variants in POLE. Indeed, POLE mutant 
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endometrial cancers from TCGA have the highest mutation burden (Fig 2A26). Clustering 
analysis using a set of immune-related genes (Fig. 2B26) demonstrated that POLE-mutant 
endometrioid endometrial cancers have high expression of a large set of immunerelated genes 
compared with MSS cancers; MSI tumors appear to have an intermediate phenotype. To 
further determine if POLE mutant cancers were associated with an immune signature, analysis 
of RNA sequencing data from endometrioid endometrial cancers in TCGA was performed. 
POLE mutant cancers have higher expression of several genes encoding for immune 
checkpoint-related proteins, including PD-L1 and PD-L2, than either MSI or microsatellite 
stable (MSS) endometrioid cancers (Fig. 3A,B26). POLE mutant cancers also showed higher 
expression of T-cell markers such as CD8A, CD3G, PD-1 and CTLA-4, suggesting the 
presence of a preexisting T-cell infiltrate. Analysis of histologic image data from TCGA 
confirmed that POLE mutant cancers had presence of a robust lymphocytic infiltrate (Fig 3C26 
). It is of note that at least half of POLE mutant cancers, and the majority of those with hotspot 
mutations in the proofreading domain, do not show an MSI phenotype and thus would not be 
detected just by using an MSI assay. Importantly, the mutation burden conveyed by 
POLE/POLD1 mutations is often several orders of magnitude higher than those noted in 
MSI phenotype cancers27, implying these tumors may be even more sensitive to 
pembrolizumab than MSI phenotype tumors. Thus POLE mutation identifies a subset of 
micro-satellite stable cancers with a high mutational burden. These tumors may be 
excellent candidates for immune checkpoint therapy. These POLE  and POLD1  mutant 
tumors that are microsatellite stable mutant tumors will be the focus of one of the cohorts of 
our trial. 
There is mounting evidence that tumors with additional DNA repair defects will also be 
susceptible to immune checkpoint therapy. Defects in the BRCA1/2 related homologous 
recombination (HR)-mediated DNA repair pathway represent a separate category of 
tumors which may have genomic instability and thus, respond well to checkpoint 
inhibitor therapy. Loss of BRCA1/2 function is a hallmark of tumor that arises in germline 
carriers of BRCA1/2 mutation, but functional loss of BRCA1/2 is also seen in a subset of 
sporadic cancers as well. Tumors that lack BRCA1/2 have a profound defect in homology-
mediated DNA repair (HMDR) and show evidence of dramatic genomic instability. 
Interestingly BRCA1/2 mutant tumors have a huge burden, not of point mutations, but of gross 
chromosomal rearrangements, and copy number variants. The junctions of rearrangement 
events can lead to fusion proteins and deletions/truncations that can have novel, potentially 
immunogenic junction sequences. Similar to MMR-deficient tumors, BRCA1 mutant tumors 
show brisk lymphocytic infiltrate and expression of immune checkpoint proteins6,7,29. These 
data suggest that BRCA1/2 mutant cancers may also be good candidates for immune checkpoint 
blockade.  As well,  reports examining the relationship between a panel of DNA damage 
and repair alterations and response to PD-1/PD-L1 blockade in bladder cancer suggested 
that the presence of any  DDR alteration was associated with a higher response rate, and 
that this was enhanced when tumors harbored known or likely deleterious DDR 
alterations compared with DDR alterations of unknown significance and in those whose 
tumors were wild-type for DDR genes, an observation that warrants additional study 
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22,23. Thus, tumors with BRCA1 or BRCA2 mutations or DDR alterations will be explored in 
a second cohort. 
Rationale for Dose Selection/Regimen/Modification 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by:
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg every 2 weeks ( Q2W), , representing an approximate 5- to 7.5-fold exposure range 
(refer to IB, Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Rationale for Protocol Modification 
In this modification (v.04JAN2023), we are closing Arm 1 due to low accrual and removing 
the limitation on enrollment of patients with breast and ovarian histologies in Arm 2. The 
power of the study will not be affected since the study was not powered to pick up differences 
in response between breast/ovarian and non breast/ovarian patients.  There is no mention of 
breast/ovarian-to other cohort comparisons.  Mutations of HRD pathway are the scientific 
factor of interest, not ovarian/breast cohort, so there is not statistical issue with proposed 
change.
4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
It has been published in a phase 2 trial of pembrolizumab that tumors with defects in mismatch 
repair deficiency have superior response rates and immune related progression free survival 
compared with tumors that are mismatch repair proficient3. We similarly expect that tumors 
with POLE, POLD1 and BRCA1/2 mutations will have superior response rates and progression 
free survival compared with cohorts of patients whose tumors are not selected for genomic 
instability. We have thus selected the primary clinical endpoint of response rate and secondary 
endpoints of immune related progression free survival to be evaluated in this basket trial. 
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4.2.2.2
Biomarker Research
We expect that tumors which are POLE, POLD1 and BRCA1/2 deficient will have high 
incidence of expression of PD-L1 and evidence of CD8+ lymphocyte infiltration, levels and 
intensity of which will correlate with clinical benefit obtained and that responses will be 
associated with specific immune-related gene expression and effector T cell patterns and 
function. We also expect patients whose tumors harbor high mutational loads to benefit most 
from immunotherapy. Mutational load may be both point mutations (seen in POLE and POLD1 
mutants) as well as genomic rearrangements, duplications and deletions (seen in BRCA1/2 
mutants).  We will examine immunologic parameters that may indicate response to treatment 
using advanced multi-parameter flow cytometric approaches and immunochemistry. We will 
employ genomic sequencing analyses of pre-treatment specimens and specimens collected at 
progression. This is important information to collect as analysis may lead to the selection of 
biomarkers that will further assist in the selection of patients for immunotherapeutic 
approaches and as well, will allow us to potentially develop markers to assist in monitoring of 
response durability in patients on therapy. 
We will also evaluate plasma samples collected before and during treatment with 
pembrolizumab for presence of circulating cell-free tumor DNA. We will evaluate the 
measurement of mutant-tumor DNA allele-fractions as a surrogate marker of response or 
progression to immune therapy. Several studies have shown that quantitative assessment of 
tumor-DNA in plasma can herald progression; this may allow one to separate radiographic 
pseudo-progression from true progression.
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be  18 years of age on day of signing informed consent.
3. Have a diagnosis of a tumor with evidence of genomic instability or DNA repair 
deficiency on CLIA certified genomic testing, inclusive of mutations in BRCA1 and 
BRCA2  for Arm 2 as well as additional DNA repair abnormalities including RAD51, 
FANCA or FANCC, ATM, ATR, PALB2.  Non-BRCA DNA repair abnormalities will 
be reviewed in consult with the Precision Medicine Initiative at Rutgers to confirm 
suitability for inclusion. 
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4. Have advanced cancer (metastatic, recurrent or locally advanced) and measurable 
disease based on RECIST 1.1.  
5. Be willing to provide archived tumor tissue. Tissue from the most obtained core or 
excisional biopsy of a tumor lesion is preferred. 20 unstained slides are preferred but a 
minimum of 15 slides will be acceptable. If adequate tissue is not present the patient 
may consent to a newly obtained biopsy in consultation with the PI and treating 
physician of risks and benefits of the biopsy.
6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation. 
Table 1.  Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without erythropoietin dependency and 
without packed red blood cell (pRBC) transfusion within last 2 
weeks.
Renal
Serum creatinine OR
Measured 
or 
calculateda 
creatinine 
clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥30 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.  
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9. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.5.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency that consistently requires more than 10 mg daily 
of prednisone or equivalent or has resulted in life threatening episodes previously 
regardless of current treatment. 
3. Has a known history of active TB   (Bacillus Tuberculosis)
4. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
-
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study.
-
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer, or 
malignancies that have been inactive for three years or exceptionally indolent. Any 
current diagnosis of second malignancy requires approval from Principal Investigator 
and Sponsor. 
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8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline) and have no evidence of new or enlarging brain metastases.  Patients who had 
oligometastatic disease treated with stereotactic radiation or gamma knife therapy may 
receive treatment 14 days after therapy as long as they are not requiring steroids. This 
exception does not include carcinomatous meningitis, which is excluded regardless of 
clinical stability.  
9. Has active autoimmune disease which currently requires disease modifying agents that 
include corticosteroids > 10 mg of prednisone or equivalent 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. 
10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of 
the trial, starting with the pre-screening or screening visit through 120 days after the 
last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX 40, CD137).
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start 
of study therapy. Administration of killed vaccines is allowed.
18. Tumors harboring non-hotspot POLE or POLD1 mutations that show clear evidence of 
MSI will be excluded. In addition, MSI unknown will also be excluded. 
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19. Has a known active history of Hepatitis B (defined as Hepatitis B surface antigen 
[HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA 
[qualitative] is detected) infection.  If patient has past hepatitis B virus or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [HBcAb) and absence 
of HBsAg), patients may be enrolled provided that HBV DNA is negative.
5.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 2
Table 2.  Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 week cycle
Experimental
5.2.1
Dose Selection/Modification
5.2.1.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background & Rationale.  
.  
5.2.1.2
Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab and combination therapy
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or several months after 
the last dose of treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab/combination treatment, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab/combination 
treatment are provided inTable 3 below. 
Table 3.  Dose Modification Guidelines for Drug-Related Adverse Events
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Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Discontinue Subject
2-3
Toxicity resolves to Grade 
0-1.
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
Diarrhea/
Colitis
4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose.
AST, 
ALT, 
or 
Increased 
Bilirubin
3-4
Permanently discontinue
(see exception below)1
Permanently discontinue
Type 1 diabetes 
mellitus 
(if new onset) or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
with evidence of beta cell 
failure. 
Resume pembrolizumab when patients are 
clinically and metabolically stable.
2-3
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
Hypophysitis
4
Permanently discontinue
Permanently discontinue
3
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
2-4
Therapy 
with 
pembrolizumab 
can 
be 
continued while treatment 
for the thyroid disorder is 
instituted
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted.
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
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Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Discontinue Subject
3 or Severe
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks.
All Other Drug-
Related Toxicity2
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event.
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline patients should hold therapy and have imaging to assess for 
progression. If no progression is seen and abnormalities persist for at least 1 week then patients should be 
discontinued.
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment 
with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (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 Sponsor. The reason for 
interruption should be documented in the patient's study record.
5.2.2
Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle. Patients may 
be seen separately for physical exam and treatment evaluations if needed no more than 48 
hours apart, and a repeat toxicity assessment by study staff must occur on day of treatment.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
5.2.3
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
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or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. 
5.3.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2.
5.3.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
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Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.4
Rescue Medications & Supportive Care
5.4.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in Section 5.2.1.2, Table 
3. Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.   Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: if after the evaluation the event is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance. Refer to the details below and 
Section 5.2.1 for dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Pneumonitis: 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks.
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed.
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration.
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
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All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis.
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral corticosteroids. 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)
For T1DM or Grade 3-4 Hyperglycemia
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
Hypophysitis:
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy.
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, 
is indicated per standard of care.
Grade 3-4 hyperthyroidism 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
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less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered.
Hepatic:
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly).
Treat with IV or oral corticosteroids
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks.
Renal Failure or Nephritis:
For Grade 2 events, treat with corticosteroids.
For Grade 3-4 events, treat with systemic corticosteroids.
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 4. 
Table 4. Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
Grade 1
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
None
Grade 2
Requires 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
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).
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NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
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.
Acetaminophen 
500-1000 
mg po (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from 
further 
trial 
treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration.
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NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
5.5
Diet/Activity/Other Considerations
5.5.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
5.5.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female subjects of reproductive potential must agree to avoid becoming pregnant while 
receiving study drug and for 120 days after the last dose of study drug by complying with one 
of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
 
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
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•
contraceptive rod implanted into the skin
 
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study.
5.5.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
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immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2.
5.5.4
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
5.6
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be discontinued from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject may 
be withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, 
the trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 
7.1.2.5.4 A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved.

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.5
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3

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first.
5.6.1
Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks or PR for 48 weeks with pembrolizumab and 
had at least two treatments with pembrolizumab beyond the date when the initial response was 
declared.  Subjects who then experience radiographic disease progression may be eligible for 
up to one year of additional treatment with pembrolizumab via the Second Course Phase at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5.
5.7
Subject Replacement Strategy
5.8
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART 
6.1
Study Flow Chart
Trial Period:
Treatment Cycles
End of Treatment
To 
be 
repeated 
beyond 8 cycles
Treatment Cycle/Title:
Screening 1
2 
3
4
5
6
7
8
Discont
inue5
Safety Follow-
up5
Long 
term 
Follow up
Scheduling Window (Days):
-28
± 
3
d
± 
3d
± 
3d
± 
3d
± 
3d
± 
3d
± 
3d
± 3d
At time 
of 
Discont
inue
30 
days 
post 
discontinue
Q12 weeks from 
Safety F/U visit
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics 
and 
Medical 
History
X
Prior 
and 
Concomitant 
Medication Review
X
X X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X X
X
X
X
X
X
X
Post-study anticancer therapy 
status
X
X
Survival Status
X
Review Adverse Events
X
X X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X X
X
X
X
X
X
X1
X
X
Vital Signs and Weight
X
X X
X
X
X
X
X
X
X.
X.
ECOG Performance Status
X
X X
X
X
X
X
X
X
X
X
Pregnancy Test – Urine or Serum X
PT/INR and aPTT2
X
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Trial Period:
Treatment Cycles
End of Treatment
To 
be 
repeated 
beyond 8 cycles
Treatment Cycle/Title:
Screening 1
2 
3
4
5
6
7
8
Discont
inue5
Safety Follow-
up5
Long 
term 
Follow up
Scheduling Window (Days):
-28
± 
3
d
± 
3d
± 
3d
± 
3d
± 
3d
± 
3d
± 
3d
± 3d
At time 
of 
Discont
inue
30 
days 
post 
discontinue
Q12 weeks from 
Safety F/U visit
CBC with Differential2
X
X X
X
X
X
X
X
X
X
X
CMP, LDH, Uric Acid, Phos, 
Mg, D. Bili (if t.bili > ULN)2
X
X X
X
X
X
X
X
X
X
X
Urinalysis
X
T3, FT4 and TSH2
X
X X
X
X
X
X
X
Tumor Imaging3
X
X
X
X
Tumor Markers
X
X
X
X
PD-L1 analysis
X7
Archival or Newly Obtained  
Tissue Collection4
X
X4
X4
Correlative 
Studies 
Blood 
Collection (PBMC and serum)
X
X4
X4
Circulating Cell-free tumor DNA 
(Plasma)
X
X
X
X6
X
1After 24 weeks, PE to be performed once every six weeks.
2 All screening labs should be performed within 10 days of treatment initiation (refer to inclusion criteria #7, Table 1). CBCD, CMP to 
be performed prior to each treatment. See Table 5 for complete list of chemistries. After cycle 4, thyroid function tests to be performed 
every six weeks.
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3Tumor imaging (CT chest/abdomen/pelvis preferred; MRI may be used in select instances if felt to be clinically appropriate by 
investigator) to be performed after every three cycles until commencement of eight cycles, when imaging will be performed after every 
four cycles (Prior to Cycles 4 and 7, then prior to Cycles 11, 15, 19, etc). Tumor imaging to be completed within 7 days of next scheduled 
cycle. Patients who enroll with known prior disease will require MRI brain repeat imaging every 12 weeks. 
4 Archived tumor tissue is required for enrollment of all patients (20 unstained slides preferred, minimum of 15 required). Newly 
obtained biopsy may occur if inadequate tissue is available. Optional biopsies will be obtained after 4 weeks and at mandatory biopsies 
at progression. PBMCs will be drawn at baseline, Cycle 2, and at progression. Correlative tumor and blood may be collected within a 
+/- 7 day window. 
5Tumor imaging and RECIST measurements will continue past end of treatment until time of progression. 
6Plasma samples for circulating cell-free tumor DNA will be collected every 6 weeks of treatment, whenever scheduled times coincide, 
at the time of PBMC or standard of care blood draws. Samples may be collected within a +/- 7 day window. 
7Refer to the MISP Sample Handling Manual for collection and shipping instructions.
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. A copy of the signed and dated consent form 
should be given to the subject before participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  The informed consent will adhere to IRB/ERC requirements, applicable 
laws and regulations and Sponsor requirements.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
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7.1.1.3
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
7.1.1.4
Prior and Concomitant Medications Review
7.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
7.1.1.5
Disease Details and Treatments
7.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up. 
7.1.1.6
Assignment of Screening Number
The coordinating site will assign each patient a screening number. 
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other)
The investigator or qualified designee will review trial compliance regarding medication, 
contraception, scheduled assessments, other. 
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7.1.2
Clinical Procedures/Assessments
All clinical procedures/assessments will be performed according to the Trial Flow Chart 
(Section 6.0). 
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart (Section 6.0) and more frequently if 
clinically indicated.  Adverse experiences will be graded and recorded throughout the study 
and during the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and 
action taken with regard to trial treatment. 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart (Section 6.0).  
7.1.2.5
Tumor Imaging and Assessment of Disease
All tumor assessments will be performed according to the Trial Flow Chart (Section 6.0). If a 
patient discontinues treatment for any reason other than progression, tumor assessments will 
be done every 12 weeks (± 14 days) for duration of study disease monitoring of 24 months 
unless after cycle 8 in which case they will be performed every 16 weeks (+.14 days).  
7.1.2.5.1 Methods of Tumor Assessment 
The preferred imaging modality is CT scan. Other modalities (MRI, PET-CT, ultrasound, 
endoscopy, laparoscopy, cytology, histology) may be used as adjuncts. If there is a compelling 
reason to do PET/CT scans or MRI (e.g. patient has allergy to iodinated contrast), the PI should 
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be contacted for permission. 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
The same method of assessment and the same technique must 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. Combinations of clinically measurable and 
radiographically measurable are permissible. For example, the patient may have dermal lesions 
that are most accurately measured by clinical evaluation with a ruler or calipers, and lymph 
nodes that are most accurately measured on CT scan. 
Cytology and histology may be helpful to differentiate a complete response from a partial 
response. 
7.1.2.5.2 RECIST version 1.1 
The primary set of response criteria for this trial is RECIST v1.130. See Appendix 11.3 for 
criteria for complete response (CR), partial response (PR), stable disease (SD), and progressive 
disease (PD). 
RECIST v1.1 will be modified for this trial. To account for tumor pseudo-progression that can 
sometimes occur with immunotherapy, it is required that RECIST PD be confirmed on a 
subsequent assessment performed 4-6 weeks later (see Section 7.1.2.5.4 for details). 
7.1.2.5.3 Evaluation of Best Overall Response (BOR) 
The best overall response is the best response (Target + non-target lesions) recorded from the 
start of the treatment until disease progression/recurrence or non-protocol therapy (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.
 
7.1.2.5.4 Confirmation of PD 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed per iRECIST. Allowing patients to 
continue treatment despite the initial radiologic progression takes into account the observation 
that some patients can have a transient tumor flare in the first few months after start of 
immunotherapy with subsequent disease response. The minimal criteria must be met to 
continue treatment in patients with radiological PD. Such criteria may include the following: 
1. No symptoms or signs (including worsening of laboratory values) indicating disease 
progression 
2. No decline in ECOG performance status or symptomatic clinical deterioration 
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3. No evidence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention 
If a patient does not meet all of the requirements above, the patient should be removed from 
trial immediately for unconfirmed PD with clinical demise. Every effort should be made to 
document the objective progression even after discontinuation of treatment. Patients with a 
global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time (not evaluated by confirmatory scan) should be 
reported as “symptomatic clinical deterioration.” 
For patients who are clinically well and meet the criteria above, the patient may remain on 
treatment at the discretion of the investigator, and imaging should be repeated no less than 4 
weeks but no more than 6 weeks later (4-6 weeks). If repeat imaging does not confirm PD per 
iRECIST (below), as assessed by the Investigator, and the participant continues to be clinically 
stable, study treatment may continue and follow the regular imaging schedule.
If the repeat assessment shows demonstrates PD (relative to baseline or the nadir tumor burden, 
whichever is smaller) as per iRECIST criteria below, treatment will be discontinued. The 
development of confirmed PD and/or the development of symptomatic clinical deterioration 
constitutes confirmed progressive disease. In the case of confirmed progressive disease, study 
treatment should be discontinued. 
Confirmation of Progression per iRECIST
Progression is considered confirmed, and the overall response will be confirmed progressive 
disease per iRECIST (iCPD), if ANY of the following occurs:
• Any of the factors that were the basis for the initial unconfirmed progressive disease 
(iUPD) show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 
mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions
• Any new factor appears that would have triggered PD by RECIST 1.1
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7.1.2.5.5 Confirmation of PR or CR 
The subject’s first instance of a PR or CR should be confirmed on a repeat assessment no less 
than 4 weeks later (4-6 weeks); however, it is acceptable to delay the repeat assessment until 
the next scheduled interval imaging study (12 weeks ± 7 days) at the discretion of the treating 
investigator, or if the patient prefers not to have an extra CT scan for this purpose. A biopsy of 
any residual lesion may be used to confirm a CR at the discretion of the treating investigators. 
7.1.2.5.6 Determining the date of progression or response 
For all patients who experience disease progression on study, the date noted for disease 
progression is the time of the scan when it was originally determined, and not the later date of 
the confirmatory scan. 
For all patients who experience complete or partial response on study, the date noted for disease 
response is the time of the scan when it was originally determined, and not the later date of the 
confirmatory scan. 
7.1.2.6
Tumor Tissue Collection and Correlative Studies Blood Sampling
7.1.2.6.1 Genomics/Sequencing: 
In collaboration with Shridar Ganesan, MD, PhD, Director of the Functional Genomics Shared 
Resource, we propose to perform genomic sequencing analysis of pre-treatment biopsy 
specimens, and specimens, if available at progression. Next generation DNA sequencing of 
exomes will commence, and RNA sequencing will evaluate selected gene expression. Tumor 
samples, and where available, matched normal tissue or peripheral blood lymphocytes, will be 
assayed by whole exome sequencing to determine the set and amount of genomic variants 
present. In addition to standard variant analysis, we will also implement algorithm such as 
NASeek to look for presence of immunogenic neo- antigens. For cancer specimens from 
BRCA1/2 mutation carriers, where there is likely a high burden of genomic rearrangements, 
we will also look for presence of gene fusion using the NUGEN SPET approach. BRCA1/2 
mutant specimens will also be analyzed by CGH to assay for specific patterns of gross genomic 
alterations (allelic imbalance, large scale transitions, etc). By this approach we hope to 
determine if the nature and/or pattern of genomic changes present, as well as the presence of 
potential immunogenic neoantigens, will correlate with response to pembrolizumab. 
7.1.2.6.2 Tissue/Blood: 
In collaboration with Joshua Vieth, PhD, Managing Director of the Immune Monitoring Core, 
we propose to assess the frequencies, activation/differentiation, functionality, and co-
inhibitory molecule expression of immune cell populations in peripheral blood and tumor, 
before and after treatment with systemic pembrolizumab. We will measure the following 
immunologic parameters that may be indicative of responsiveness to treatment using advanced 
multi-parameter flow cytometric approaches and immunohistochemistry: 
1)  The frequencies of T and NK cell subsets will be analyzed by flow cytometry using 
antibodies for CD3, CD4, CD8, CD11b, CD11c, CD14, CD16, CD19, CD25, CD56, 
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and FoxP3. Special attention will be paid to CD8 T cell:CD4 Treg and NK:CD4 Treg 
cell ratios. We hypothesize that increased effector (CD8 and NK cell subsets versus 
Treg subsets) following pembrolizumab administration will be a biomarker positively 
associated with responsiveness to treatment and other major prognostic indicators for 
survival.  
2)  Activation and differentiation of T cell subsets will be analyzed by flow cytometry 
using additional antibodies for HLA- DR, CD38, CD57, CCR7, CD45RA and 
CD45RO. We hypothesize that activation and differentiation toward effector and 
memory responses versus exhaustion following pembrolizumab administration will be 
a biomarker positively associated with responsiveness to treatment and other major 
prognostic indicators for survival.
3)  Immune cell functionality before and after pembrolizumab will be analyzed by 
assessing intracellular cytokines and effector molecules in serum via Luminex 
Multiplexe Analysis against a panel of 48 human cytokines/chemokines. We 
hypothesize that increased expression of immune-stimulatory cytokines and effector 
molecules (versus inhibitory cytokines) following pembrolizumab administration will 
be a biomarker positively associated with responsiveness to treatment and other major 
prognostic indicators for survival. 
4)  Expression of the T cell inhibitory molecules PD-1, TIM-3, 2B4, Lag-3, and CTLA-
4 on CD8+ T cells and their ligands (PD-L2, Gal9, CD48, CD80, CD86) will be 
evaluated on antigen presenting cells (MHC-II+) and tumor cells (CD45-) using 
respective monoclonal antibodies to these molecules and analyzed by flow cytometry. 
PD-L1 
will 
be 
assessed 
from 
formalin-fixed 
paraffin-embedded 
by 
immunohistochemistry via Qualtek/Dako assay (Carpinteria, CA). We hypothesize that 
reduced expression of other T cell co-inhibitory molecules will be seen following 
pembrolizumab administration.
If samples are available, some or all of the following analyses may also be performed: 
nanostring, single cell RNA-sequencing, exosome sequencing, multispecial immunostain, 
proteomics and grafting of fresh tissue into experimental animals using blood and tumor tissue. 
The experimental protocol will follow laboratory SOPs and published procedures.
Leftover research specimens will be stored for future research for subjects who have provided 
permission.
7.1.2.6.3 Plasma cell-free DNA:
Samples of plasma will be collected prior to treatment, then every 6 weeks. Plasma will be 
analyzed for quantitative presence of circulating cell-free tumor DNA (ctDNA). This will be 
done either by custom quantitative PCR assays for presence of known tumor-associated 
mutations identified on tumor sequencing, or using panel sequencing platforms such as 
Guardant360. Correlation of level of ctDNA with clinical and radiographic response will be 
determined. The aim is to determine if ctDNA can be a sensitive early predictor of response 
and resistance to pembrolizumab, and whether it can differentiate true progression from 
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radiographic pseudoprogression.
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.

Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)

Laboratory tests for hematology, chemistry, urinalysis, and others are specified in 
Table 5.  
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Table 5.  Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum 
β-human 
chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
  (β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)
WBC (total and differential)
Aspartate aminotransferase (AST)
Specific gravity 
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3)
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Free tyroxine (T4)
Absolute Lymphocyte Count
  (CO2 or biocarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Uric Acid
PK
Calcium
Chloride
Blood for correlative studies
Glucose
 
Phosphorus
 
Potassium  
 
Sodium
 
Magnesium
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. 
‡ If considered standard of care in your region.
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment. 
7.1.4
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 12 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4).
7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening Period
During the screening period (28 days prior to treatment initiation), the following data will be 
collected and assessed for each patient: informed consent, whether the patient meets the 
inclusion and exclusion criteria of the trial, demographics and medical history, a review of 
prior or concomitant medications, a post-study anticancer therapy status, the patient’s survival 
status, a review of adverse events, a full physical examination of the patient, vital signs and 
weight, ECOG performance status, a pregnancy test assessing urine or serum β-HCG, 
prothrombin time (PT)/international normalized ratio (INR) and activated partial 
thromboplastin time (aPTT), a complete blood count (CBC) with differential, a comprehensive 
metabolic panel (CMP), a urinalysis, a test of triiodothyronine (T3), free throxine (FT4), and 
thyroid stimulating hormone (TSH), tumor imaging, an MRI of the brain, and archival of newly 
obtained tissue (preferably 20 unstained slides but minimum of 10; exceptions may be allowed 
at discretion of PI in conjunction with study sponsor; newly obtained biopsy may commence 
if inadequate tissue).  Peripheral blood mononuclear cells (PBMCs) will be drawn at baseline, 
after 4 weeks of therapy, and at progression(s). Plasma will be drawn at baseline, after 4 weeks 
of therapy, then aligning with blood draws every six weeks. Correlative tumor and blood may 
be collected with a +/- 7 day window.
7.1.5.2
Treatment Period
The treatment period consists of 8 treatment cycles, which repeat from cycle 5 if treatment 
continues beyond cycle 8.  At each cycle throughout the treatment period, the following are to 
be performed and/or assessed for each patient: a review of prior and concomitant medications, 
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administration of trial treatment, survival status, a review of adverse events, a full physical 
examination (after 24 weeks, a physical exam will be performed once every 6 weeks), the 
patient’s vital signs and weight, the patient’s ECOG performance status, CBC with differential, 
and CMP (both to be performed prior to each treatment).  T3, FT4, and TSH will be measured 
at cycle 1 through cycle 4 (after cycle 4, these thyroid function tests are to be performed every 
6 weeks).  Tumor imaging (CT chest/abdomen/pelvis preferred; MRI may be used in select 
instances if felt to be clinically appropriate by investigator) is to be performed after every 3 
cycles until commencement of 8 cycles, after which time imaging will be performed after every 
4 cycles.  An MRI of the brain will be required every 12 weeks for patients who enroll with 
known prior disease. Optional biopsies will be obtained after 4 weeks and at mandatory 
biopsies at progression.  PBMCs will be drawn after 4 weeks of therapy, and at progression. 
Correlative tumor and blood may be collected with a +/- 7 day window.
7.1.5.3
Post-Treatment Visits
Visits following trial treatment will assess the following conditions for each patient at the time 
of treatment discontinuation: a review of prior and concomitant medications, survival status, a 
review of adverse events, a full physical examination, vital signs and weight, ECOG 
performance status, CBC with differential, and CMP.
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase.  During the safety follow-up, the 
following conditions will be assessed for each patient: a review of prior and concomitant 
medications, survival status, a review of adverse events, a full physical examination, vital signs 
and weight, ECOG performance status, CBC with differential, CMP, and analysis of T3, FT4, 
and TSH.  
7.1.5.4
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 12 weeks (72 ± 7 days) by radiologic 
imaging to monitor disease status. Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.5.5. Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated.
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Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  During the follow-up visits, the following conditions will be 
assessed for each patient: a review of prior and concomitant medications, survival status, a 
review of adverse events, a full physical examination, vital signs and weight, ECOG 
performance status, CBC with differential, and CMP.  
7.1.5.4.1 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first. During the survival follow-up, the following conditions will 
be assessed for each patient: survival status and any new cancer therapy received.
7.1.5.5
Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy

Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 12 months of study 
therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab

Did not receive any anti-cancer treatment since the last dose of pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.2
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
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.5.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year. 

Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.  

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator.
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use.
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Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)
7.2.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose of pembrolizumab;

Is another important medical event 
o
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious.
o
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
Refer to Table 6 for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported to the Rutgers Cancer Institute of New Jersey (Sponsor) Office of Human Research 
Services via OnCore within 24 hours of site notification. The completed SAE report (signed 
by the Investigator) must be sent to the Rutgers CINJ OHRS QA department. Rutgers CINJ 
will report within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. SAE reports and any other relevant safety information 
are to be forwarded to the Merck Global Safety facsimile number:  +1-215-661-6229
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The Sponsor will forward a copy of all 15 Day Reports and Annual Progress Reports is 
submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices 
agency (PMDA) or other local regulators. Investigators will cross reference this submission 
according to local regulations to the Merck Investigational Compound Number (IND, CSA, 
etc.) at the time of submission.  Additionally investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215-661-6229) at the time of 
submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to Merck. 
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor and to Merck, that is not associated 
with clinical symptoms or abnormal laboratory results. 
2.  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.  
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 6.  Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred 
(Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including 
hospitalization for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse 
event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse 
event. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be 
reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Merck product to be discontinued?
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Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality 
was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse 
event 
based 
upon 
the 
available 
information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the Merck product 
caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Merck 
product
(continued) 
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) 
Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial 
is a single-dose drug trial); or (3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK 
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
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RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product 
or drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to 
his/her best clinical judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck 
product relationship).
Yes, there is a reasonable 
possibility of Merck product 
relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable.  The AE is more likely explained by the Merck product than by 
another cause.
No, there is not a reasonable 
possibility 
Merck 
product 
relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the 
Merck product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with 
overdose without an associated AE.)
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7.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
8.0 STATISTICAL ANALYSIS PLAN
Sample size justification. To address the primary objective, we have calculated the 95% 
confidence intervals (CI’s) to assess precision of expected response rate of pembrolizumab in 
treating patients with specified mutant tumors (e.g., POLE, POLD1, and BRCA1 and 2). 
Responses to single agent PD-1 inhibition are not seen in the majority of patients; available 
published data in pretreated triple negative breast, lung, ovarian tumors, histologies likely to 
be enrolled to this trial, have ranged from 11-19% in small studies16,31. Based on the data in 
MSI high tumors by Le et al3, responses can be expected to rise significantly in tumors with 
genomic instability, with the lowest rate of 40% in their published series. We thus assume that 
the response rate of pembrolizumab in our trial, treating patients with POLE (or POLD1) 
and/or BRCA1/2 mutant tumors, will similarly be at about 40%. For n=23 patients for each 
type of tumors ([POLE or POLD1] and [BRCA1 and 2]), we expect to yield a 95% CI of (0.20, 
0.60), within the 40%+/- 20% range (Table 7). This confidence interval is above the response 
rate of using standard therapy in treating unselected cancer patients suggesting significant 
improvement of pembrolizumab over standard therapies.
To address the secondary objective, we used the same 95% CI calculations (Table 7), assuming 
no loss of follow-up, to assess the precision of expected PFS rate of pembrolizumab at 6 
months in treating patients with specified mutant. Based on the data in Le et al3 (Panel C Fig 
2), the PFS rate at 6 months was at least 35% while the immune-related PFS at 20 weeks was 
at least 67%. Assuming the 6-month PFS rates in our study will be similarly at least 35%. With 
n=23 patients for each type of tumors ([POLE or POLD1] and [BRCA1 and 2]), we expect to 
yield a 95% CI of (0.15,0.55) for PSF of 35% and (0.46,0.84) for PSF of 65%, both within the 
+/- 20% range. 
Table 7. 95% Confidence Intervals for Response and/or PFS* Rate Based on Estimated 
Rate (P) and Sample Size (n) for a Specific Mutant Tumor.
P
n
0.25
0.30
0.35
0.40
0.50
0.65
0.75
20
(0.06,0.44)
(0.10,0.50)
(0.14,0.56)
(0.18,0.62)
(0.28,0.72)
(0.44,0.86)
(0.56,0.94)
23
(0.07,0.43)
(0.11,0.49)
(0.15,0.55)
(0.20,0.60)
(0.29,0.71)
(0.46,0.84
)
(0.57,0.93)
25
(0.08,0.42)
(0.12,0.48)
(0.16,0.54)
(0.20,0.60)
(0.30,0.70)
(0.46,0.82
)
(0.58,0.92)
26
(0.08,0.42)
(0.12,0.48)
(0.16,0.54)
(0.21,0.59)
(0.30,0.70)
(0.48,0.82
)
(0.59,0.91)
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28
(0.09,0.4)
(0.13,0.47)
(0.17,0.53)
(0.21,0.59)
(0.31,0.69)
(0.47,0.83
)
(0.59,0.91)
30
(0.10,0.40)
(0.13,0.47)
(0.18,0.52)
(0.22,0.58)
(0.32,0.68)
(0.48,0.82
)
(0.60,0.90)
*CI calculations for PFS assumed no loss of follow-up.
        
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by Merck as summarized in Table 8.
Table 8.  Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
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9.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Subjects’ identities, names or any identifying characteristics will not be disseminated in 
publications, nor made public. The data forms will be de-identified, meaning that the patients 
identifying information will be matched to the research number, in a separate file. 
10.2 Compliance with Financial Disclosure Requirements 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, 
and local regulations regarding reporting and disclosure of conflict of interest. Conflicts of 
interest may arise from situations in which financial or other personal considerations have the 
potential to compromise or bias professional judgment and objectivity. Conflicts of interest 
include but are not limited to royalty or consulting fees, speaking honoraria, advisory board 
appointments, publicly-traded or privately-held equities, stock options, intellectual property, 
and gifts. 
The Rutgers University’s Office of Research and Economic Development Integrity Office 
(RIO) reviews and manages research-related conflicts of interest. The Principal Investigator 
and Sub-Investigators must report conflicts of interest annually and within 30 days of a change 
in status, and when applicable, must have a documented management plan that is developed in 
conjunction with the Rutgers RIO and approved by the IRB/IEC. 
Dr. Salma Jabbour, a sub-investigator on this study, has a financial relationship with Merck 
& Co., the company that provides the study drug, Pembrolizumab (KEYTRUDA).  Please 
feel free to ask any further questions you might have about this matter.
10.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
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Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial. 
All revisions to the protocol must be discussed with, and be prepared by, Rutgers Cancer 
Institute of New Jersey. The investigator should not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB approval/favorable opinion, as soon as possible the deviation or change will 
be submitted to: 

IRB for review and approval/favorable opinion

Merck Sharp Dohme Corp

Regulatory Authority(ies), if required by local regulations
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must 
be sent to Rutgers Cancer Institute of New Jersey Office of Human Research Services. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form 
must be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
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and worksheets/case report forms. The investigator must maintain copies of all documentation 
and records relating to the conduct of the trial in compliance with all applicable legal and 
regulatory requirements. This documentation includes, but is not limited to, the protocol, 
worksheets/case report forms, advertising for subject participation, adverse event reports, 
subject source data, correspondence with regulatory authorities and IRBs/ERCs, consent 
forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures and laboratory director curriculum vitae. By signing 
this protocol, the investigator agrees that documentation shall be retained until at least 2 years 
after the last approval of a marketing application in an ICH region or until there are no pending 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention period 
and upon request, will provide guidance to the investigator when documents no longer need to 
be retained. The sponsor also recognizes that documents may need to be retained for a longer 
period if required by local regulatory requirements. All trial documents shall be made available 
if required by relevant regulatory authorities. The investigator must consult with and obtain 
written approval by the Sponsor prior to destroying trial and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. The investigator 
will promptly inform the Sponsor of any regulatory authority inspection conducted for this 
trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB. 
The rights, safety, and well-being of the study subjects are the most important considerations 
and should prevail over interests of science and society.
 
10.4 Issues with Minors 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. The explicit wish of a minor, 
who is capable of forming an opinion and assessing this information to refuse participation in, 
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or to be withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent. 
10.5 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
10.6 Quality Management System 
10.6.1 Data Safety Monitoring Board 
The Rutgers Cancer Institute Human Research Oversight Committee is responsible for 
quarterly data and safety monitoring of DUHS sponsor-investigator phase I and II, therapeutic 
interventional studies that do not have an independent Data Safety Monitoring Board (DSMB). 
The primary focus of the SOC is review of safety data, toxicities and new information that may 
affect subject safety or efficacy. Safety reviews includes but may not be limited to review of 
safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference 
literature, and interim analyses as provided by the sponsor- investigator. The HROC in concert 
with the Quality Assurance Monitoring Team oversees the conduct of Rutgers CINJ cancer-
related, sponsor-investigator therapeutic intervention and prevention intervention studies that 
do not have an external monitoring plan, ensuring subject safety and that the protocol is 
conducted, recorded and reported in accordance with the protocol, standing operating 
procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements. 
10.6.2 Monitoring 
The Rutgers Cancer Institute of New Jersey’s (Rutgers CINJ) Quality Assurance Monitoring 
Team will conduct monitoring visits to ensure subject safety and to ensure that the protocol is 
conducted, recorded, and reported in accordance with the protocol, standard operating 
procedures, good clinical practice, and applicable regulatory requirements. As specified in the 
Rutgers CINJ Data and Safety Monitoring Plan, the Quality Assurance Monitoring Team will 
conduct routine monitoring after the third subject is enrolled, followed by annual monitoring 
of 1 – 3 subjects until the study is closed to enrollment and subjects are no longer receiving 
study interventions that are more than minimal risk. 
The Rutgers CINJ Human Research Oversight Committee (HROC) will perform annual 
reviews on findings from the quality Assurance Monitoring Team visit and additional safety 
and toxicity data submitted by the Principal Investigator. 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon 
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request of Rutgers CINJ leadership, the Scientific Review Committee, the Human Research 
Oversight Committee (HROC), the sponsor, the Principal Investigator, or the IRB. All study 
documents must be made available upon request to the DCI Monitoring Team and other 
authorized regulatory authorities, including but not limited to the National Institute of Health, 
National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
 
10.7 Registration 
This protocol is available at the Rutgers Cancer Institute of New Jersey (CINJ)/Robert Wood 
Johnson University Hospital (RWJUH) in New Brunswick and NYU Langone Health. 
A copy of the institution’s IRB-approved informed consent document and written justification 
for any changes made to the informed consent for this protocol will be on file at Rutgers Cancer 
Institute of New Jersey’s Office of Human Research Services (OHRS) before any participating 
institutions may enter patients. 
Sites will register and enroll patients through OnCore® the Clinical Trials Management 
System for this study. Registration/Enrollment process: 

Registration: Any subject that has signed the consent will be entered into OnCore®. 

Enrollment: Once eligibility has been confirmed the subject will be enrolled (indicated 
as “On Study”) through OnCore®. The completed, signed and dated eligibility 
checklist and supporting source documents (de-identified for participating centers) will 
be uploaded into OnCore®. 

Patients will not start protocol treatment prior to enrollment.
Trial treatment should begin within 10 days of registration or as close as possible to the date 
on which treatment is allocated/assigned. 
10.8 Data Management
10.8.1 Study Documentation 
Study documentation includes but is not limited to source documents, case report forms, 
monitoring logs, appointment schedules, study team correspondence with sponsors or 
regulatory bodies/committees, and regulatory documents that can be found in the DCI- 
mandated “Regulatory Binder”, which includes but is not limited to signed protocol and 
amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA 
laboratory certifications, and clinical supplies receipts and distribution records. 
Source documents are original records that contain source data, which is all information in 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. Source documents include but are not limited 
to hospital records, clinical and office charts, laboratory notes, memoranda, subjects‟ diaries 
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or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved 
in the clinical trial. When possible, the original record should be retained as the source 
document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact 
duplication of the original document. 
10.8.2 Case Report Forms (CRFs) 
The electronic CRF stored in Oncore® will be the primary data collection document for the 
study. The CRFs will be updated in a timely manner following acquisition of new source data. 
Only the key personnel delegated on the delegation of authority log are permitted to make 
entries, changes, or corrections in the CRF. 
  
An audit trail will be maintained automatically by the electronic CRF management system. All 
users of this system will complete user training, as required or appropriate per regulations. 
10.8.3 Data Management Procedures and Data Verification 
Users of the electronic CRF will have access based on their specific roles in the protocol. 
Completeness of entered data will be checked automatically by the eCRF system, and users 
will be alerted to the presence of data inconsistencies. Additionally, the data manager and 
project manager will cross-reference the data to verify accuracy. Missing or implausible data 
will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, 
correction of data, completion or confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure, and will be closed only 
after resolution of all remaining queries. An audit trail will be kept of all subsequent changes 
to the data. 
10.8.4 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following 
activities: 
- Data clarification and/or resolution- Accounting, reconciliation, and destruction/return of 
used and unused study drugs - Review of site study records for completeness- Shipment of all 
remaining laboratory samples to the designated laboratories
10.9 Data Safety Monitoring Plan 
The Rutgers Cancer Institute of New Jersey (RCINJ) has established a Data and Safety 
Monitoring Plan (DSMP) for the conduct of clinical trials in patients with cancer. The DSMP 
is enacted in part by the Human Research Oversight Committee (HROC). HROC is an 
established group within the Office of Human Research Services, and it is responsible for 
oversight of all therapeutic and non-therapeutic clinical trials conducted by RCINJ and it meets 
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regularly to review deviations. HROC will serve as the Data Safety Monitoring Board (DSMB) 
for this clinical trial. All unexpected and serious adverse events will be reported to the DSMB 
(as well as each institutional IRB and study sponsor) according to the reporting requirements 
detailed in Section 7.2 of this protocol and per the Rutgers University DSMP. 
 
11.0 APPENDICES
11.1 ECOG Performance Status 
Grade
Description
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more 
than 50% of waking hours. 
3 
 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- 
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1 will be used in this study for assessment of tumor response, with one 
modification. To account for tumor pseudo-progression that can sometimes occur with 
immunotherapy, it is required that RECIST PD be confirmed on a repeat scan before a patient 
is removed from study (see Section 7.1.2.5 for details). 
For full details, refer to the manuscript as published in the European Journal of Cancer30: 
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E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
  
11.3.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT 
scan, or ≥ 10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters. 
NOTE: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable. 
NOTE: Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
11.3.2 Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 15 mm short 
axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, and lymphangitis cutis/pneumonitis, are considered as non-
measurable. Non-measurable also includes lesions that are < 20 mm by chest x-ray. 
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. 
11.3.3 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 of the 
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diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
 
11.3.4 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 or absence of unequivocal 
progression of each should be noted throughout follow-up. 
11.3.5 Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
Note: the appearance of one or more unequivocal new lesions is 
also considered progression. 
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. 
11.3.6 Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis) 
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. 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
 
11.3.7 Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
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A growing lymph node that did not meet the criteria for reporting as a measurable or non- 
measurable lymph node at baseline should only be reported as a new lesion (and therefore 
progressive disease) if it a) increases in size to ≥ 15 mm in the short axis, or b) there is new 
pathological confirmation that it is disease (regardless of size). 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
11.3.8 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence or non-protocol therapy (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. 
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non- PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD 
or 
not 
all 
evaluated
No
PR
SD
Non-PD 
or 
not 
all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
11.4  Collection, Processing and Shipping of Blood and Tumor Tissue and Correlative 
Science*
Samples will be processed at CINJ according to the 051709 Correlative Research 
Laboratory Manual. 
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Participating centers (non-CINJ sites) will not be processing specimens locally. All samples 
will be shipped and processed at CINJ according to the 051709 Correlative Research 
Laboratory Manual. 
11.4.1 Tissue Collection
11.4.1.1 Analysis of PD ligand expression (Qualtek analysis)
Formalin-fixed tissue (archival tissue collected at baseline, if adequate tissue is not present the 
patient may consent to a newly obtained biopsy) will be utilized for analysis of PD-L1. PD-L1 
will be detected using the Dako IHC assay for PD-L1 developed by Qualtek (Santa Barbara, 
CA). Kits must be requested from Qualtek. 
11.4.1.2 Tissue for Correlative Research 
Tissue will be collected according to the 051709 Correlative Research Laboratory Manual.   
Newly obtained biopsy may occur if inadequate tissue is available. An optional biopsy will be 
obtained after 4 weeks and a mandatory biopsy at progression. 
11.4.1.3 Tissue Collection Priority
The priority for tissue collection shall be as follows when tissue is available:
1) Diagnostic (non-research; sent to pathology)
2) Collection in HTS-FRS Media for processing and Genomic Analysis
3) Placed in formalin for IHC
4) Placed in HTS-FRS for TIL isolation and flow cytometry
11.4.2 Blood Collection
Blood samples will be collected for correlative research studies (PBMC and serum isolation) 
at baseline, C2 (after 4 weeks of treatment) and at discontinuation of treatment. 
Blood samples will be collected for circulating cell-free tumor DNA at baseline, every 6 weeks 
during treatment and at discontinuation of treatment. 
All blood samples will be collected according to the 051709 Correlative Research Laboratory 
Manual.  
11.4.3 Safety Precautions
Universal precautions (i.e., a method of infection control in which all human blood and 
body fluids are treated as if they are infectious for Hepatitis viruses, Human 
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Immunodeficiency virus (HIV), and other known and unknown infectious agents) will be 
utilized when handling all unfixed cells and tissues.
a.
Hepatitis B and Hepatitis C viruses may be transmitted through blood and other 
body fluids, and are associated with acute hepatitis, chronic liver disease, and 
hepatocellular carcinoma in humans. The probability of seroconversion after 
needlestick exposure is estimated at 7%. Untreated virus can persist for up to one 
week at room temperature. All staff who work with human tissue must provide 
evidence of Hepatitis B vaccination.
b. HIV is a retrovirus that causes severe immunodeficiency. Infection increases the 
risk of developing malignancies, infection by opportunistic organisms, and death. 
The probability of seroconversion after needlestick exposure is estimated at 0.5%. 
Infectivity of untreated virus persists for up to one week at room temperature.
c.
Other potentially infectious agents, both known and unknown, pose hazards to 
those working with human tissue. Included are tuberculosis, HTLV1, 
Coccidiomycosis, Creutzfeldt-Jacob disease, among others.
d. Individual institutional and OSHA guidelines must be followed when handling 
human cells and tissues, and referred to for additional information on blood-borne 
pathogens, laboratory safety, chemical safety, and biohazardous waste disposal. 
Briefly:
i.
Personal protective equipment (PPE) must be used at all times while working 
with human tissue. These include disposable latex or nitrile gloves, face 
shield, protective splash-resistant laboratory coat (disposable preferred), and 
covered protective shoes.
ii.
Gloves should be immediately removed and replaced in the event that they 
become torn or perforated. Gloves must be removed prior to leaving the work 
area, and disposed of in an appropriate waste disposal container. Hands must 
be washed in a "clean" sink after removal of gloves.
iii.
Face shields, goggles and masks should be worn whenever a potential for 
exposure to splashes, spray, splatter, droplets, aerosols of blood or tissue 
fluid, or other potentially infectious materials may be generated, and if there 
is a potential for eye, nose or mouth contamination. They should be worn at 
all times while handling tissue in the for processing.
iv.
Protective lab coats, preferably disposable types, must be donned while 
working with tissue. Contaminated clothing must be removed prior to leaving 
the work area, and appropriately laundered or discarded, as per individual 
institutional guidelines.
v.
All waste must be disposed of prior to leaving the work area. Biohazardous 
sharps must be properly disposed of in an approved "sharps" container. All 
other non-sharp waste must be disposed of in an approved orange or red 
biohazardous waste disposal bag.
vi.
After completion of work with human tissue, all work surfaces must be 
disinfected with a product that has been demonstrated to be effective against 
bacteria, viruses, pseudomonas, tuberculosis and fungi. Product literature 
should be referred to for appropriate use.
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Any injuries or exposure to human tissue or potentially infectious biologic agents must be.
12.0 REFERENCES
1.
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 
2015;348(6230):124-128.
2.
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-
4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-2199.
3.
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. N Engl J Med. 2015;372(26):2509-2520.
4.
Heitzer E, Tomlinson I. Replicative DNA polymerase mutations in cancer. Curr Opin 
Genet Dev. 2014;24:107-113.
5.
Albertson TM, Ogawa M, Bugni JM, et al. DNA polymerase epsilon and delta 
proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad 
Sci U S A. 2009;106(40):17101-17104.
6.
Basu GD GA, Gatalica Z, Anderson KS, McCullough AE, Spetzer DB, Pockaj BA. 
Expression of novel immunotherapeutic targets in triple-negative breast cancer. J Clin 
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