A Phase 2 Study of Pembrolizumab in Patients With Histiocyte/Dendritic Cell Neoplasms and Biologically Selected Subtypes of Relapsed/Refractory Aggressive Lymphomas
Phase: PHASE2
Conditions: Lymphoma, Histiocytic Sarcoma, Follicular Dendritic Cell Sarcoma, Interdigitating Dendritic Cell Sarcoma
Sponsor: Dana-Farber Cancer Institute

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
NCI Protocol #:
N/A
DF/HCC Protocol #: 17-448
TITLE:  A Phase 2 Study of pembrolizumab in patients with histiocyte/dendritic cell neoplasms 
and biologically selected subtypes of relapsed/refractory aggressive lymphomas.
Coordinating Center:
Dana-Farber Cancer Institute 
Principal Investigator (PI):
Eric Jacobsen, MD
Dana-Farber Cancer Institute
450 Brookline Avenue, Boston MA 02215
(p): 617-632-6633
(f): 617-582-8413
edjacobsen@partners.org
Other Investigators: 
MGH: Jeffrey Barnes, MD
Statistician:
Robert Redd
Dana-Farber Cancer Institute
Robert_Redd@DFCI.HARVARD.EDU
NCI-Supplied Agent(s):  N/A
Other Agent(s):  Pembrolizumab (investigational, provided by Merck)
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Version # / Version Date: Version 10 / April 29, 2022

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Protocol Date: April 29, 2022
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SCHEMA
1In certain circumstances, subjects will be allowed to continue treatment past PD (see Section 5.8)
2will still have survival follow-up; patients who are removed for reasons other than PD will also be followed for 
response
Relapsed/refractory
lymphoma or 
histiocyte/dendritic cell 
neoplasm meeting 
eligibility criteria 
Pembrolizumab q3 
weeks x 35 cycles 
(approximately2 
years)
Survival 
follow-up
PD1, 
toxicity, 
withdrawal 
of consent, 
PI 
discretion
Off 
treatment2
Completion of 
therapy

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................1
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objectives...................................................................................................5
1.3
Secondary Objectives...............................................................................................5
1.4
Exploratory Objectives ............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Study Diseases .........................................................................................................6
2.2
Study Agent .............................................................................................................8
2.3
Rationale ..................................................................................................................9
2.4
Correlative Studies Background ............................................................................10
3.
PARTICIPANT SELECTION...........................................................................................10
3.1
Eligibility Criteria..................................................................................................10
3.2
Exclusion Criteria ..................................................................................................12
3.3
Inclusion of Women and Minorities ......................................................................14
4.
REGISTRATION PROCEDURES ...................................................................................14
4.1
General Guidelines for DF/HCC Institutions ........................................................14
4.2
Registration Process for DF/HCC Institutions.......................................................15
4.3
General Guidelines for Other Investigative Sites ..................................................15
4.4
Registration Process for Other Investigative Sites.................................................15
5.
TREATMENT PLAN........................................................................................................15
5.1
Treatment Regimen................................................................................................15
5.2
Pre-Treatment Criteria ...........................................................................................16
5.3
Agent Administration.............................................................................................16
5.4
General Concomitant Medication and Supportive Care Guidelines......................17
5.5
Criteria for Taking a Participant off Protocol Therapy..........................................23
5.6
Duration of Follow Up...........................................................................................24
5.7
Criteria for Taking a Participant Off Study ...........................................................24
5.8
Treatment Past Disease Progression......................................................................25
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................30
7.1
Expected Toxicities................................................................................................31
7.2
Adverse Event Characteristics...............................................................................31
7.3
Expedited Adverse Event Reporting......................................................................31
7.4
Expedited Reporting to Hospital Risk Management .............................................38
7.5
Routine Adverse Event Reporting .........................................................................38
8.
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES..38

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8.1
Investigational Product ..........................................................................................38
8.2
Packaging and Labeling Information.....................................................................39
8.3
Clinical Supplies Disclosure..................................................................................39
8.4
Storage and Handling Requirements .....................................................................39
8.5
Returns and Reconciliation....................................................................................39
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................39
9.1
Correlative Studies.................................................................................................39
10.
STUDY CALENDAR .......................................................................................................40
11.
MEASUREMENT OF EFFECT .......................................................................................43
11.1
Response Criteria...................................................................................................43
11.2
Evaluation of Best Overall Response ....................................................................43
12.
DATA REPORTING/REGULATORY REQUIREMENTS.............................................44
12.1
Data Reporting.......................................................................................................44
12.2
Data Safety Monitoring..........................................................................................44
12.3
Multicenter Guidelines...........................................................................................45
13.
STATISTICAL CONSIDERATIONS...............................................................................45
13.1
Study Design/Endpoints ........................................................................................45
13.2
Sample Size, Accrual Rate and Study Duration ....................................................45
13.3
Stratification Factors..............................................................................................46
13.4
Interim Monitoring Plan ........................................................................................46
13.5
Analysis of Primary Endpoints..............................................................................46
13.6
Analysis of Secondary Endpoints..........................................................................46
13.7
Reporting and Exclusions ......................................................................................47
14.
PUBLICATION PLAN .....................................................................................................47
15.
REFERENCES ..................................................................................................................48
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................52
APPENDIX B 
LUGANO AND LYRIC RESPONSE CRITERIA (31, 32)......................53
APPENDIX C
DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING 
PLAN
....................................................................................................................54
1
INTRODUCTION .............................................................................................................54
1.1
Purpose...................................................................................................................54
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..................................54
2
GENERAL ROLES AND RESPONSIBILITIES .............................................................55
2.1
DF/HCC Sponsor...................................................................................................55
2.2
Coordinating Center...............................................................................................56
2.3
Participating Institution..........................................................................................56

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3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................57
3.1
Protocol Distribution..............................................................................................57
3.2
Protocol Revisions and Closures ...........................................................................57
3.3
Informed Consent Requirements ...........................................................................58
3.4
IRB Documentation ...............................................................................................58
3.5
IRB Re-Approval...................................................................................................58
3.6
Participant Confidentiality and Authorization Statement......................................59
3.7
DF/HCC Multi-Center Protocol Registration Policy.............................................59
3.8
DF/HCC Protocol Case Number............................................................................60
3.9
Safety Assessments and Toxicity Monitoring .......................................................61
3.10
Data Management..................................................................................................62
4
REQUISITIONING INVESTIGATIONAL DRUG..........................................................63
5
MONITORING: QUALITY CONTROL..........................................................................63
5.1
Ongoing Monitoring of Protocol Compliance.......................................................63
5.2
Monitoring Reports................................................................................................64
5.3
Accrual Monitoring................................................................................................64
6
AUDITING: QUALITY ASSURANCE ...........................................................................64
6.1
DF/HCC Internal Audits........................................................................................64
6.2
Audit Notification..................................................................................................64
6.3
Audit Reports.........................................................................................................65
6.4
Participating Institution Performance ....................................................................65

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1.
OBJECTIVES
1.1
Study Design
This is a phase II, open-label, non-randomized study of pembrolizumab in patients with 
histiocyte/dendritic cell neoplasms or relapsed or refractory biologically selected subsets 
lymphoma.  Pembrolizumab 200 mg IV will be administered every 3 weeks for 35 cycles 
(approximately 2 years) or until disease progression, toxicity precluding treatment, sustained CR, 
withdrawal of consent, and/or investigator discretion.
1.2
Primary Objectives
•
To examine the efficacy (overall response rate) of pembrolizumab in patients with 
biologically selected subsets of relapsed/refractory (R/R) biologically selected 
subgroups of lymphoma, using 2014 Lugano criteria (31, appendix C).
1.3
Secondary Objectives
•
To examine the rates of complete response, partial response, stable disease, and 
progressive disease with pembrolizumab in the group of patients with biologically 
selected subsets of R/R biologically selected subgroups of lymphoma and 
histiocyte/dendritic cell neoplasms, using the 2014 Lugano criteria (31, appendix C) 
•
To examine the efficacy (overall response rate) of pembrolizumab in patients with 
histiocytic sarcoma, follicular dendritic cell sarcoma, and interdigitating dendritic cell 
sarcoma using 2014 Lugano criteria (31, appendix C).
•
To examine the duration of response, duration of complete response, and progression-
free survival associated with pembrolizumab treatment in this patient population, 
using the 2014 Lugano criteria (31, appendix C).
•
To examine the rates of overall, complete and partial response as well as stable 
disease, progression-free survival and duration of remission using the LyRIC criteria 
[32, appendix B]
•
To examine the safety and toxicity of pembrolizumab in patients with biologically 
selected subsets of R/R lymphoma and histiocyte/dendritic cell neoplasms.
1.4
Exploratory Objectives
•
To evaluate the expression of PD-L1, genetic integrity of PD-L1/2 locus, and latent 
viral infection in a selected subset tumors, and preliminarily correlate those with 
clinical outcome.
•
To study the immune microenvironment and circulating lymphocyte subsets in 
patients before and after pembrolizumab, and preliminarily correlate those with 
clinical outcome.
2.
BACKGROUND
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 

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on pembrolizumab (MK-3475).
2.1
Study Diseases
The current standard of care for patients with DLBCL who are refractory to or who relapse after 
first line therapy consists of salvage chemotherapy and, if a remission is achieved, consolidation 
by high-dose therapy with autologous stem cell transplantation (ASCT).  This is typically 
considered the last chance at curative therapy.  Unfortunately, many patients are not candidates 
for ASCT.  Also, the majority of patients who relapse after modern first-line therapy may not 
achieve the remission needed to proceed to ASCT.  Even among patients who do proceed to 
ASCT many will relapse.  For patients with primary refractory disease or patients who relapse 
after ASCT, the outcomes are dismal.  Thus, relapsed/refractory DLBCL represents an urgent, 
unmet clinical need.
Immune checkpoint blockade is a promising strategy in DLBCL.  Immune checkpoint blockade 
has already established a favorable track record in the treatment of DLBCL.  The anti-PD1 
antibody pidilizumab administered to patients with DLBCL after ASCT proved to be safe and 
associated with promising response rate and progression-free survival especially among the 
higher risk subgroup of patients on the trial1.  In a phase 1b study of patients with hematologic 
malignancies, another anti-PD1 antibody, nivolumab, was associated with a response rate of 36% 
in DLBCL2.
It is possible to select a subset of DLBCL tumors which may be particularly vulnerable to PD-1 
blockade.  In two independent phase 1 studies of PD-1 blockade (one using the monoclonal 
antibody nivolumab and one using pembrolizumab), patients with heavily pre-treated 
relapsed/refractory classical Hodgkin lymphoma had remarkably high response rates (87% and 
65%, respectively) 3,4.  This validated the pre-clinical work showing that HL tumor cells very 
frequently over-express the PD-1 ligands PD-L1 and PD-L2 on the cell surface, most often as a 
result of genetic amplification events at the 9p24.1 locus5.  These results lend credence to the 
hypothesis that some hematologic malignancies such as HL may have particularly strong 
dependence on the PD-1 pathway for survival, and that those tumors are ideal targets for PD-1 
blockade.  In the case of DLBCL, PD-L1 expression on the tumor cell surface, while 
encountered occasionally, is not a universal event, and that genetic events such as occur in HL 
are rare.  This difference may explain the variation in response rates between the two histologies 
seen in clinical studies.  It also suggests that selecting DLBCL subtypes with a dependence on 
PD-1 could result in significantly higher response rates.  
Recent work has demonstrated that there are indeed subtypes of DLBCL that seem to have a high 
frequency of PD-L1 surface over expression, implying a larger reliance on checkpoint blockade 
for survival and a higher vulnerability to PD-1 blockade.  One of those subtypes is primary 
mediastinal B-cell lymphoma (PMBL), which like HL frequently harbors genetic amplification 
at 9p246,7.  The susceptibility of this entity to pembrolizumab is being tested in an ongoing phase 
II trial.  The other DLBCL subtypes with frequent PD-L1 over expression are EBV-positive 
DLBCL, post-transplant lymphoproliferative disease (PTLD), plasmablastic lymphoma, and the 
histological variant of DLBCL T-cell/histiocyte rich DLBCL (TCRLBCL) 8,9.  These DLBCL 
subtypes represent 30% of unselected DLBCLs. 

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Histiocyte and dendritic cell neoplasms. Histiocytic sarcoma (HS) is an extremely rare and 
generally aggressive malignancy for which no standard therapy exists.  Patients with unifocal 
disease amenable to surgical resection and/or radiation with curative intent are thought to have a 
better prognosis, although in one series of 15 patients there was no difference in survival between 
those with localized disease and those with disseminated disease (33). Unfortunately, histiocytic 
sarcoma generally does not respond well to cytotoxic chemotherapy and the outcome for patients 
with multifocal disease is poor. No standard systemic therapy exists and most clinicians utilize 
regimens developed for aggressive non-Hodgkin lymphomas. Some of the responses described 
with these regimens originate from a time when limited diagnostic techniques were available and 
aggressive lymphomas may have been misdiagnosed as histiocytic sarcoma. Nonetheless, these 
regimens remain widely used. The two most commonly utilized regimens are cyclophosphamide, 
doxorubicin, vincristine, and prednisone (CHOP) or ifosfamide, carboplatin, and etoposide with 
mesna (ICE) though response rates are poor (33). 
BRAF V6000E mutations do occur in a small subset of histiocytic sarcoma and there are case 
reports describing responses to BRAF inhibitors in histiocytic sarcoma (34). More recently, PD–
L1 expression has been demonstrated in 50% of cases of histiocytic sarcoma creating the 
possibility that immunotherapy with PD–L1 or PD–1 inhibitors may be a potential option (35). At 
present, however, there is no published clinical experience with these immunotherapies in 
histiocytic sarcoma. 
Follicular dendritic cell sarcoma (FDCS) is a very rare disease of mesenchymal origin (36).  The 
optimal therapy for FDCS remains unknown. In a pooled analysis that included 343 cases of 
FDCS, 31% of patients presented with isolated nodal disease, 58% had isolated extranodal 
involvement and only 10% had both nodal and extranodal involvement. With a median follow-up 
of 20 months, local recurrences or distant metastases occurred in approximate 45% of patients 
after initial treatment. FDCS is amenable to surgical resection and/or radiation when localized but 
does not often respond well to chemotherapy as evidenced by 2 year survival rates of 82.4% for 
early disease, 80% for locally advanced disease, but only 42.8% for metastatic disease (37).  Copy 
number gains in 9p24 and expression of PD-L1 have been reported, making immunotherapy with 
PD-1 or PD-L1 blockade a therapeutic possibility though there are no clinical reports 
demonstrating efficacy (38).
Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare disease arising from 
interdigitating dendritic cells are found in the paracortex of lymph nodes. Pooled data from 
reported cases demonstrated a significantly lower overall survival in patients with metastatic 
disease (38.46% at 1 year) compared to local disease (84.8% at 1 year). The median survival for 
patients with metastatic disease was 9 months. The majority of patients with local disease were 
still alive at last follow up (82%) and median survival was not reached (39). The SEER registry 
data revealed a similar pattern with a median survival of 10 months in patients with metastatic 
disease while the median survival was not reached in those with localised disease (40). Surgery is 
the mainstay of treatment in patients with localised disease. Patients with metastatic disease are 
usually treated with chemotherapy.  A range of chemotherapy treatments have been reported but 
responses are often absent/short-lived and outcomes remain poor. Chemotherapy regimens 
reported include ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine); CHOP 
(cyclophosphamide, doxorubicin, vincristine and prednisolone); docetaxel + gemcitabine; IE 
(ifosfamide and eoposide). In the absence of consistent reports of successful treatment with 

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specific regimens it is not possible to make definitive treatment recommendations and responses 
to chemotherapy are typically poor (39, 40).   Data on PD-L1 expression in IDCS is limited but 
PD-L1 expression was demonstrated in 40% of cases tested in one small series (35).
T cell lymphomas: Peripheral T-cell lymphomas (PTCL) account for ~10% of all cases of non-
Hodgkin’s lymphoma (NHL) diagnosed in North America and Western Europe (41). Although 
initial response rates with anthracycline based chemotherapy with or without autologous stem cell 
transplantation are high, relapses are extremely common (42). Patients with relapsed/refractory 
PTCL have a poor prognosis and most patients die within one year (43).With notable exceptions 
as discussed below, approximately 30% of PTCLs will be characterized by EBV and/or PD-L1 
expression (44).  However, angioimmunoblastic T cell lymphoma (AITL) is almost always 
characterized by PD-1 expression and is frequently associated with a clonal EBV+ B cell infiltrate 
which is of unknown significance in the pathophysiology of the disease (45).  Additionally, 
extranodal NK/T cell lymphoma is universally EBV+ and frequently expresses PD-L1 (46).  PD-
1 inhibition has been studied in a small, unselected subset of PTCL as well as cutaneous T cell 
lymphoma and has demonstrated responses (2,47).  Selecting histologies with biologic rationale 
predicting response to pembrolizumab warrants further study.
In summary, the group of tumors included in this protocol represents a very promising target for 
anti-PD-1 therapy.  This hypothesis can be readily tested in a phase 2 study of pembrolizumab in 
patients with subtypes of relapsed/refractory lymphomas and histiocyte/dendritic cell neoplasms 
expected to have a high frequency of PD-L1 surface over expression.  If the hypothesis is 
confirmed, it could define a subset of lymphoma and histiocyte/dendritic cell patients in whom 
pembrolizumab is a therapeutically useful agent leading to further study as a single agent or in 
combination with other therapies in this subgroup of patients.  We therefore propose a 
multicenter phase 2 trial of pembrolizumab in patients with biologically selected subtypes of 
lymphoma and histiocyte/dendritic cell neoplasms to establish the efficacy of pembrolizumab in 
these patient populations.
2.2
Study Agent
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades10.  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 tumors11-15.
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)16-17.  The structure of murine PD-1 has 
been resolved18.  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 

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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 cascade16,19-21.  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 proteins22,23.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells24,25.  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells26.  
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 tumors22; 27-29.  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues22.  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 melanoma30.  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 been approved in the United Stated for the 
treatment of select patients with unresectable or metastatic melanoma, non-small cell lung 
cancer, and squamous cell carcinoma of the head and neck.  
2.3
Rationale
It is possible to select a subset of lymphomas as well as histiocyte/dendritic cell neoplasms that 
frequently over-expresses PD-L1 or, in the case of AITL, are characterized by near universal PD-
1 expression.  Such selection could significantly increase the response rate to PD-1 blockade 
compared to that of an unselected population.  If the hypothesis is confirmed, it could define a 
subset of patients in whom pembrolizumab is a therapeutically useful agent.  We therefore 
propose a multicenter phase 2 trial of pembrolizumab in patients with biologically selected 
subtypes of lymphoma and histiocyte/dendritic cell neoplasms.  The goal of this study is to lay 
the groundwork for a new treatment paradigm in this lymphoma subgroup.
The choice of the 200 mg Q3W as an appropriate dose for is based on simulations performed using 
the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks 
will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose 

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every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.
2.4
Correlative Studies Background
The scientific basis for PD-1 blockade in biologically selected subtypes of lymphoma and 
histioctye/dendritic cell neoplasms has been discussed above. We propose to conduct correlative 
studies examining the relationship between PD-1/PD-L1/PD-L2 expression and treatment 
outcome and on possible mechanisms of immune escape after PD-1 blockade in patients who 
relapse in whom a post-relapse tumor biopsy can be obtained.  The exact studies to be performed 
are subject to sample and funding availability.
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria
3.1.1
Be willing and able to provide written informed consent for the trial.
3.1.2
Histologically confirmed diagnosis of a histiocyte/dendritic cell neoplasm or 
relapsed/refractory aggressive lymphoma with at least one of the following 
features (with review required at a participating study center):

Diffuse large B-cell lymphoma with EBV positive tumor cells (defined as 
positive EBV-encoded RNA in tumor cells)

Diffuse large B-cell lymphoma, leg type (DLBCL-LT)

Plasmablastic lymphoma

T cell/histiocyte rich DLBCL

EBV+ T cell lymphoma of any histology; note, patients with 
angioimmunoblastic T cell lymphoma will be eligible regardless of EBV 
status

Histiocytic sarcoma 

Follicular dendritic cell sarcoma 

Interdigitating dendritic cell sarcoma
3.1.3
For patients with histiocytic sarcoma, interdigitating dendritic cell sarcoma, or 
follicular dendritic cell sarcoma only: disease that is not amenable to surgical 
resection and/or radiation therapy with curative intent.

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3.1.4
For lymphoma patients only: At least one prior systemic chemotherapy including 
an alkylating agent and anthracycline (unless contraindicated), and an anti-CD20 
monoclonal antibody if the tumor is CD20+. Prior treatment with anthracycline 
and alkylating agent is not required for patients with NK/T cell lymphoma but 
prior treatment with platinum-based chemotherapy and/or l-asparaginase is 
required.
3.1.5
For lymphoma patients only: Participants must have received and relapsed after 
autologous stem cell transplantation (ASCT), or be ineligible for ASCT 
(including on the basis of refractory disease), or have declined ASCT
3.1.6
Age 18 years or older at the time of signing consent.  
3.1.7
 ECOG performance status of 0 or 1 (Karnofsky ≥70%, see Appendix A)
3.1.8
Participants must have normal organ and marrow function as defined below:

absolute neutrophil count ≥ 500/mcL

platelets ≥75,000/mcL (> 30,000 if there is bone marrow involvement with 
lymphoma)

total bilirubin < 1.5 times the institutional upper limit of normal (ULN) OR 
direct bilirubin < the normal in subjects with total bilirubin >1.5 times the ULN

AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or < 5 times ULN in 
patients with known hepatic involvement with lymphoma                                         

albumin > 2.5 mg/dl

creatinine < 1.5 times the normal upper institutional limit OR creatinine 
clearance ≥60 mL/min/1.73 m2 in participants with creatinine levels > 1.5 times 
the normal upper institutional limit 

INR, aPTT or PT < 1.5 times the ULN unless subject is receiving 
anticoagulation therapy as long as PT or aPTT are within therapeutic range of 
intended use of anticoagulant
3.1.9
Be willing to provide tissue from a newly obtained core needle or excisional 
biopsy. Newly-obtained is defined as a specimen obtained up to and including 90 
days prior to treatment day 1. Subjects for whom newly obtained samples cannot 
be provided may be enrolled only with agreement by the overall PI.
3.1.10 No prior allogeneic transplant unless all of the following apply:

At least 5 years from time of transplant

Absence of clinically significant graft-versus-host disease (GVHD)

Not on immune suppression

Approval of overall PI

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3.1.11 Not a candidate for potentially curative therapy at the time of   enrollment
3.1.12 Measurable disease per the Lugano criteria.
3.1.13 Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test 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.  
3.1.14 Female subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Section 5.4.3 – Contraception for the 
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
3.1.15 Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.4.3- Contraception, starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject
3.1.16 The effects of pembrolizumab on the developing human fetus are unknown.  
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.  
3.2
Exclusion Criteria

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13
3.2.1
Prior treatment with a PD-1, PD-L1 or PD-L2 inhibitor
3.2.2
Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study 
day 1 or has not recovered (i.e., < grade 1 or at baseline) from adverse events due 
to a previously administered agent.
3.2.3
Participants who have had chemotherapy, targeted small molecule therapy, or 
radiotherapy within 2 weeks prior to study day 1 (6 weeks for nitrosoureas or 
mitomycin C) or who has not recovered (i.e., < grade 1 or at baseline) from 
adverse events due to previously administered agents. Note: subjects with < grade 
2 peripheral neuropathy are an exception to this criterion and may qualify for the 
study.
3.2.4
Radiation therapy within 2 weeks of study treatment 
3.2.5
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.
3.2.6
Has a known history of active tuberculosis.
3.2.7
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
3.2.8
Has an active infection requiring systemic therapy.
3.2.9
Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e., with the use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal her pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.
3.2.10 Has a diagnosis of immunodeficiency or is receiving any form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment 
or is taking chronic systemic steroids (in doses exceeding 10 mg daily of 
prednisone equivalent) within 7 days prior to the first dose of trial treatment.  
Note: Subjects with asthma or chronic obstructive pulmonary disease that require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections are 
not excluded from the study.
3.2.11 Has a history of non-infectious pneumonitis that required systemic corticosteroid 
treatment or has active pneumonitis.
3.2.12 Known active central nervous system involvement and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
4 weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment. This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.

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14
3.2.13 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
3.2.14 Active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., 
hepatitis C virus RNA detectable).
3.2.15 Human immunodeficiency virus (HIV 1/2).
3.2.16 Is pregnant or breast-feeding or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit until 120 days 
after the last dose of trial treatment.
3.2.17 Has received a live vaccine within 30 days of planned start of study therapy. 
(Note: seasonal influenza vaccines for injection are allowed as they are 
inactivated; however, intranasal influenza vaccines are live attenuated vaccines 
and are NOT allowed)
3.2.18 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pembrolizumab.
3.2.19 Baseline pulse oximetry <94% or requires oxygen supplementation of any kind
3.2.20 If subject underwent major surgery they must have recovered adequately from the 
toxicity and/or complications from the procedure prior to starting therapy.
3.2.21 Uncontrolled intercurrent illness including, but not limited to symptomatic 
congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 

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15
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the DF/HCC by the Project Manager.  
All sites should call the Project Manager at 617-632-2328 to verify study slot availabilities.  
Following registration, participants should begin protocol therapy within 5 days. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Project Manager should be notified of cancellations as soon as possible.
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and  e-mailed to the DFCI Project Manager:

Copy of required laboratory tests including: All screening evaluations.

Signed informed consent document

HIPAA authorization form (if separate from the informed consent document)

Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration form)
The research nurse or data manager at the participating site will then call 617-632-2328 or e-mail 
Megan_Forsyth@DFCI.HARVARD.EDU to verify eligibility.  To complete the registration 
process, the Coordinator will follow DF/HCC Standard Operating Procedure for Human Subject 
Research Titled Subject Protocol Registration (SOP #: REGIST-101) and register the participant 
on the protocol.  The coordinator will fax or e-mail the participant study number, and if 
applicable the dose treatment level, to the participating site.  The coordinator will also call the 
research nurse or data manager at the participating site and verbally confirm registration
5.
TREATMENT PLAN
5.1
Treatment Regimen
The rationale for selection of doses to be used in this trial is provided in Section 2.3 – Rationale.  
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.  
Pembrolizumab will be administered once every 3 weeks, with 21 consecutive days defined as a 
treatment cycle (unless the treatment cycle length is increased for adverse effect, as detailed in 
Section 6).  Treatment will be administered on an outpatient basis. Reported adverse events and 

DF/HCC Protocol #: 17-448
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16
potential risks are described in Section 7. No dose reductions are allowed. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the participant's malignancy.
All participants will receive pembrolizumab at a fixed dose of 200 mg intravenously every 3 
weeks for up to 35 cycles (approximately 2 years) or until disease progression, prohibitive 
toxicity, withdrawal of consent, or investigator discretion.  
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1
In order to receive the first dose of study treatment, the participant must meet all of the eligibility 
criteria. All study therapy will occur in the outpatient setting.
5.2.2
Subsequent Cycles 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed in the study calendar (Section 10).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
or logistical reasons.  
A bone marrow biopsy at screening will only be required if patients have unexplained cytopenias 
of grade 2 or greater at baseline or if PET/CT is suggestive of bone marrow involvement.  
As detailed in Section 6, pembrolizumab administration should be held for grade 4 hematologic 
events or grade 3 non-hematologic events, if the event is judged to be at least possibly related to 
study drug. In all cases, dose delay, treatment discontinuation, and toxicity management for 
immune-related adverse events should follow the guidelines in Section 6. In addition, treatment 
should be delayed if the subject’s resting oxygen saturation is <94% while breathing ambient air.  
Criteria to resume treatment are also listed in Section 6.
5.3
Agent Administration
The general instructions for study drug preparations can be found in the MK-3475 Pharmacy 
Manual.
The drug will be provided as a solution for infusion, 100mg/vial. MK-3475 Solution for Infusion 
vials should be stored at refrigerated conditions (2 – 8 °C) and protected from light. Note: vials 
should be stored in the original box to ensure the drug product is protected from light. Parenteral 
drug products should be inspected visually for particulate matter and discoloration prior to 
administration. Discard the drug product vial if opaque or extraneous particulate matter other 
than proteinaceous particles is observed. In addition, the following precautions should be 
observed:

Do not shake or freeze the vial(s).

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17

Do not administer the product as an intravenous (iv) push or bolus.

Do not combine, dilute or administer it as an infusion with other medicinal products.
5.3.1
Dose calculation
The dose on this trial is a flat dose of 200 mg for all patients regardless of weight or body surface 
area.
5.3.2
Drug Administration
Pembrolizumab infusions will be administered as a 30 minute IV infusion, with a window of -5 
and +10 minutes, using an infusion pump. A central catheter is not required for infusion; 
however if a subject has a central venous catheter in place, it is recommended that it be used for 
the infusion.  No pre-hydration is necessary. The pharmacy manual contains specific instructions 
for the preparation of the pembrolizumab infusion fluid and administration of the infusion 
solution.
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
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 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. 
The following concomitant treatments are prohibited during the treatment phase of this study:

Anti-neoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy except in selected cases, radiation to a localized area(s) of 
symptomatic disease may be allowed, after consultation with the study chair, and if the 
radiated lesions are not the target lesions for response assessment.  In such cases, 
pembrolizumab treatment will be interrupted during the radiotherapy.

Live vaccines within 30 days prior to starting treatment and while receiving study 
treatment.

Immunosuppressive therapy.

Systemic glucocorticoids for any purpose. The use of physiologic doses of 
corticosteroids may be approved after consultation with the overall Principal 
Investigator.  NOTE: Systemic steroids can be given as premedication for blood 
products, treatment of adverse events, and/or contrast media for imaging procedures.

Intravenous immune globulin is allowed at the discretion of the treating physician for 
replacement of immune globulin deficiencies. 

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
18
Subjects who, in the assessment of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. 
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.
The exclusion criteria describe other medications which are prohibited in this trial.
There are no prohibited therapies during the post-treatment follow-up phase. 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic therapy per 
standard institutional practice. Subjects should be strongly encouraged to maintain liberal oral 
fluid intake.
Infection: Subjects with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating investigator for 
a given infectious condition, according to standard institutional practice.
Cytopenias: growth factors and blood product transfusion support are allowed on this trial.
5.4.2
Supportive Care Guidelines and Management Adverse Immune-Related Adverse Events (irAEs)
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 6 for dose 
modification. 

DF/HCC Protocol #: 17-448
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19
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
20
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
21

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion. 
Table 1 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 1. Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequentdosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires infusion interruption but responds 
promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration.
Subject may be premedicated 1.5h (± 30 
minutes) prior to infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic).
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.
Detailed guidelines for management of irAEs are provided in Table 3.

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
22
5.4.3
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if
pembrolizumab has transient adverse effects on the composition of sperm. 
For this trial, male subjects will 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 and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
(1) Practice abstinence† from heterosexual activity;  
OR
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
 
(1) Single method (one of the following is acceptable):
(a) Intrauterine device (IUD)
(i) Vasectomy of a female subject’s male partner 
(ii) Contraceptive rod implanted into the skin
 
(2) Combination method (requires use of two of the following):
(a) diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
(b) cervical cap with spermicide (nulliparous women only)  
(c) contraceptive sponge (nulliparous women only) 

DF/HCC Protocol #: 17-448
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23
(d) male condom or female condom (cannot be used together)
(e) 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.  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 enrolled on the study.
5.4.4
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 principal investigator and to Merck without 
delay and within 24 hours to the principal investigator 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 Merck.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the principal investigator and to Merck and followed as described above 
and in Section 7.3.4.
5.4.5
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.
5.5
Criteria for Taking a Participant off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
24
35 cycles until one of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event(s)
•
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements
•
Participant decides to withdraw from the protocol therapy
•
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Eric Jacobsen at 617-632-6633 (pager 41475). 
5.6
Duration of Follow Up
Participants will be followed for survival every 12 weeks (+ 14 days) for 24 months after 
completion of protocol therapy, discontinuation of protocol therapy or until death, whichever 
occurs first.  Survival follow-up may be conducted by telephone or email contact with the 
participant or his/her primary physician. Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event regardless of the duration of follow-up required.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
•
Completion of all study-related activities
•
Lost to follow-up
•
Withdrawal of consent 
•
Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 

DF/HCC Protocol #: 17-448
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25
5.8
Treatment Past Disease Progression
It is now increasingly recognized that patterns of response may differ with immunotherapeutic 
anti-cancer agents, compared with patterns seen with conventional cytotoxic agents. In 
particular, in patients receiving checkpoint blockade therapy for solid tumors, the phenomenon 
of immune flare or pseudo-progression has been described; patients who experience pseudo-
progression can still derive significant benefit from treatment. This has led to a modification of 
response criteria (the LyRIC criteria) for patients with lymphoma treated with immunotherapy 
(32). The management of patients with apparent progressive disease on this trial should generally 
follow the recommendations of the LyRIC criteria.  Patients with confirmed PD using LyRIC 
criteria who are still felt to derive clinical benefit and have no alternative option for care may 
still continue on therapy past PD, after consultation with the study chair.
Criteria for treatment beyond PD (in addition to discussion with study chair):
•
Absence of signs or symptoms of progressive disease, including laboratory 
abnormalities
•
No decrease in ECOG performance status
•
Absence of rapid PD
•
Absence of PD at an anatomically critical site
6.
DOSING DELAYS/DOSE MODIFICATIONS
There will be no dose modifications on this study. Dose delays will be made as indicated in the 
following table(s). The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays 
and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
If a participant is delayed but is subsequently able to resume treatment, then subsequent 
visits, assessments and treatments will continue every 3 weeks (unless the dosing interval is 
modified per Table 2) from the time treatment has resumed until all cycles of therapy are 
completed. For example, if cycle 4 is delayed 2 weeks and administered on week 12 instead of 
10, cycle 5 and its corresponding assessments should take place on week 15, cycle 6 on week 18, 
etc. 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 2 or 3 (depending on nature of toxicity) including laboratory 
abnormalities, and severe or life-threatening AEs as per Tables 2 and 3 below. If there is a 
question as to whether an AE is or is not immune-related, this should be discussed with the study 
chair.

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26
Table 2. Dose Modification Guidelines for Hematological Drug-Related Adverse Events.
Toxicity
Grade
Hold treatment
Timing for 
restarting treatment
Treatment 
discontinuation
Hematological
1,2,3
No
N/a
N/a
4
Yes
Toxicity resolves to 
grade < 1
Toxicity does not 
resolve within 12 
weeks of last 
infusion
Permanent 
discontinuation 
should be 
considered for any 
life-threatening 
event
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. 

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Table 3. Dose modification guidelines for non-hematological drug related adverse events including immune related adverse 
events (irAEs)
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
AST / ALT 
elevation or 
Increased 
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 

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Protocol Date: April 29, 2022
28
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Intolerable/ 
persistent Grade 2
Withhold
All other 
immune-related 
AEs
Grade 3
Withhold or 
discontinue based 
on the type of 

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
29
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  

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30
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 principal investigator. The reason for 
interruption should be documented in the patient's study record.
Management of suspected immune related AEs should follow the guidelines provided in 
section 5.4.2.
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
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 
pembrolizumab, 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.  An example 
of this may include, but is not limited to, menopause occurring at a physiologically appropriate 
time.
Adverse events may occur during the use of pembrolizumab in clinical trials, or as prescribed in 
clinical practice, from overdose (whether accidental or intentional), from abuse and from 
withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
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. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) if that subject has not undergone any protocol-specified 

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31
procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured per 
guidelines for standard AE reporting.   The following list of reported and/or potential AEs 
(Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the 
event requires expedited reporting in addition to routine reporting.
7.1
Expected Toxicities
Based on the experience with pembrolizumab to date, expected toxicities are listed below.
•
Frequent (>10%): fatigue, rash/pruritus, diarrhea
•
Occasional: nausea/vomiting, arthralgia, anorexia, fever, pneumonitis, hepatotoxicity, 
vitiligo, autoimmune endocrinopathies including hypophysitis/hypopituitarism, 
enterocolitis, edema, weakness, thrombocytopenia, xerophthalmia/xerostomia, 
peripheral neuropathy

Rare (<1%): acute kidney injury, encephalopathy, other cytopenias, pericarditis, 
myositis, myocarditis, Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis.
7.2
Adverse Event Characteristics
•
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
•
For expedited reporting purposes only:

AEs for the agent(s) that are listed above should be reported only if the 
adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.

Other AEs for the protocol that do not require expedited reporting are outlined 
in the next section (Expedited Adverse Event Reporting) under the sub-
heading of Protocol-Specific Expedited Adverse Event Reporting Exclusions.
•
Attribution of the AE:

Definite – 
The AE is clearly related to the study treatment.

Probable – 
The AE is likely related to the study treatment.

Possible – 
The AE may be related to the study treatment.

Unlikely – 
The AE is doubtfully related to the study treatment.

Unrelated – 
The AE is clearly NOT related to the study treatment.
7.3
Expedited Adverse Event Reporting 

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32
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
on the local institutional SAE form. 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) 
regardless of study phase or attribution.
7.3.1
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.  
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 
AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE 
Expected#
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
Not required
10 working 
days
24 hours*
Possible
Probable
Definite
Not required
10 working 
days
Not required
10 working 
days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 1 business day of learning of 
the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
7.3.2
Definition of an Overdose for This Protocol and Reporting of Overdose to the principal 
investigator 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 

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33
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 pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the principal investigator and within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220)
Each participating site is responsible for reporting to the Overall PI and the Overall PI is 
responsible for reporting to Merck Global Safety.
7.3.3
Reporting of Pregnancy and Lactation to the principal investigator 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) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of pembrolizumab, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must 
be reported as serious events (Important Medical Events). If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. Such events must be reported within 24 
hours to the principal investigator and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220)
Each participating site is responsible for reporting the Overall PI and the Overall PI is 
responsible for reporting to Merck Global Safety.
7.3.4
Immediate Reporting of Adverse Events to Merck
7.3.4.1
Serious Adverse Events

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34
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 another important medical event
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these 
events are considered serious by Merck for collection purposes.
•
Is a new cancer (that is not a condition of the study);
•
Is associated with an overdose.
Refer to section 7.3.4.4 and Table 4 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study that occurs to any subject must be reported 
within 24 hours to the principal investigator and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under study 
(reference Section 7.2 for additional details), whether or not related to the Merck product, must 
be reported within 24 hours to the principal investigator and within 2 working days to Merck 
Global Safety.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the principal investigator and to Merck Global Safety.
All subjects with serious adverse events must be followed up for outcome.

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35
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220
7.3.4.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the principal investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the principal investigator and within 2 working days to Merck Global 
Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the principal investigator and within 24 
hours to Merck Global Safety.
Events of clinical interest for this trial include:
1. An overdose of pembrolizumab, as defined in Section 7.3.2 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the principal investigator, 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. 
7.3.4.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.3.4- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless there 
is evidence suggesting a causal relationship between the drug and the event. Any such event will 
be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working days 
either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.

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36
The principal investigator will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study.
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE.
7.3.4.4
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.
Table 4.  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 for an elective procedure to treat a pre-existing condition 
that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that 
is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); 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) (although not serious per ICH definition, is 
reportable to the principal investigator within 24 hours and to Merck within 2 working days to meet 
certain local requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event for collection purposes. 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 
to the principal investigator and to Merck within 2 working days..
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 Merck product to be discontinued?

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Relationship to pembrolizumab
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the 
AE; the greater the correlation with the components and their respective elements (in number and/or 
intensity), the more likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to 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 Merck 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)?
Likely 
Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors

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38
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 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 Sponsor’s product; or (3) the trial is a single-dose drug 
trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 
Merck product relationship).
Yes, there is a reasonable 
possibility of Merck 
product relationship.
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the 
administration of Merck product is reasonable.  The AE is more likely explained by Merck product than 
by another cause.
No, there is not a 
reasonable possibility of 
Merck product relationship
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another cause 
than the Merck product.  (Also entered for a subject with overdose without an associated AE.)
7.4
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting per institutional policy. 
7.5
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8.
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
8.1
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 5.

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Table 5. Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
8.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
8.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the principal investigator 
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.
8.4
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.
8.5
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 after 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.
A list of the adverse events and potential risks associated with pembrolizumab can be found in 
Section 7.1.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Correlative Studies
We will analyze tumors from pre-and on-treatment time points, when available.  We plan to 

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analyze EBV expression, PD-L1 and PD-L2 expression, as well as PD-1 expression in the 
microenvironment.  We will also perform FISH to assess the integrity of the PD-L1/2 locus.  We 
will perform multi-parameter analyses of the tumor micro-environment.  In addition, peripheral 
blood samples will be analyzed for absolute and relative amounts of various lymphocyte 
subsets.  Those results will be correlated with responses, in an exploratory fashion.  Those 
studies are subject to sample and funding availability.
10. STUDY CALENDAR
Baseline evaluations are to be conducted within 28 days of the start of protocol therapy with the 
exception of the bone marrow biopsy and lymph node biopsy which should be performed within 
90 days of cycle 1, day 1. Assessments must be performed prior to the administration of any 
study agent. Study assessments and agents should be administered within + 3 days of the 
protocol-specified date, unless otherwise noted.

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Trial period
Screening
Treatment Cycles
EOT
Post-treatment
To be repeated beyond 9 
cycles until EOT unless 
otherwise noted
Treatment cycle/name
1
2
3
4
5
6
7
8
9l
30 days 
after 
last 
dose
60 days 
post-
EOT
Follow-upd
Survival 
follow-upe
Scheduling window
-28 to -1
+3
+3
+3
+3
+3
+3
+3
+3
(+10 
days)
(+10 
days)
Q12 weeks
(+14 days) 
from last post-
treatment visit
Q12 weeks 
(+14 days)
Informed consent
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Medical history
X
Concurrent meds
X
X--------------------------------------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs including 
pulse oximetry
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Height
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Lymph node biopsy 
(archival or newly 
obtained biopsy)
Xg
Xg
Xg
Pembrolizumab
X
X
X
X
X
X
X
X
X
CBC w/diff (auto or 
manual)
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistrya
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, HCV, HBVm
X
EKG 
X
Adverse event 
evaluation
 X------------------------------------------------------------------------------------------------------X
Blood for correlative 
studies n
X
X
X
X
PET/CT and EBV viral 
load h
X
X
X
Xf
     X  
         
B-HCG
Xb
T3, Free T4, TSHo
X
X
X
X
X
X
X
Urinalysis
X
PT/INR and PTT
X
Pulmonary function 
tests c
X

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Bone marrow biopsy 
and aspirate
Xj
Xk
Xk
Xk
Xk
Survival status
X
a:
Comprehensive metabolic profile, LDH, phosphorus
b:
Female subjects of childbearing potential should have a negative urine or serum pregnancy test 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.  
c:
FVC; FEF25-75; FEV1; DLCO; pulse oximetry; hemoglobin should be obtained within 3 days prior to PFTs; repeat PFTs are at 
investigator discretion
d:      In subjects who discontinue therapy without documented disease progression every effort should be made to continue monitoring disease 
by radiographic imaging every 12 weeks (+ 14 days) until one of the following occurs: star t of new anti-cancer therapy; documented 
disease progression by investigator assessment; end of study; or death, whichever occurs first
e:      After the start of new anti-cancer treatment or documented disease progression by investigator assessment, the subject will transition to 
the Survival Follow-up and the patient or their primary physician should be contacted by telephone or email every 12 weeks (+/- 14 days) 
to assess survival status
f:      Patients who achieve a metabolic complete remission (defined as Deauville 1-3) may be followed subsequently with CT of the chest, 
abdomen, and pelvis rather than PET/CT at the discretion of the treating investigator; after cycle 9 radiology restaging will occur every 4 
cycles (e.g, on cycles 13, 17, 21, etc) until cycle 33. There is a + 3-day window for radiology tests but radiographic restaging should 
occur prior to drug administration for a cycle on which restaging is due though this could include a scan the same day as but prior to 
dosing of study drug.
g:      At screening, fresh biopsy (1 core) or archival tissue within 90 days of C1D1 (5 unstained slides, 5µm) is required, unless an exception is 
given by the study chair. Fresh biopsy samples at week 6 (+ 7 days) and at the time of discontinuation due to disease progression are 
optional but highly recommended unless the tumors are considered inaccessible by the treating physician or concerns that a biopsy is 
contraindicated due to safety concerns. 
h:      In subjects with an unconfirmed PD assessment who continue study therapy a radiology assessment should be performed 12 weeks (+ 7 
days) from the time of unconfirmed PD assessment or at the time of treatment discontinuation.  If a scan was previously obtained within 
30 days of the time of treatment discontinuation then a repeat radiology examination is not required.  Imaging should occur at any time 
that disease progression is suspected. Those who have EBV positive lymphoma will have EBV viral load assessed at screening. If 
positive, it will be subsequently checked at every disease assessment. 
i:       Pulse oximetry recommended but not required.  Study drug should be held for pulse oximetry recording less than 94% when pulse 
oximetry is obtained during treatment.
j:       Must be performed within 90 days of day 1 of therapy. Patients only require a bone marrow biopsy at screening if they have unexplained 
cytopenias of grade 2 or greater at baseline or if PET/CT is suggestive of bone marrow involvement.
k:      Bone marrow biopsy only needs to be repeated to confirm CR 
l:       Up to 35 cycles
m:     HIV 1/2 antibody, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis C antibody
n:      Please refer to section 9.1 for more details
o:      T3, Free T4 and TSH to be drawn every 3 cycles after cycle 9.

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11. MEASUREMENT OF EFFECT
11.1
Response Criteria
The primary objective of this study is overall response rate (ORR). Response and progression 
will be evaluated following the 2014 Lugano criteria for the primary endpoint and LyRIC for 
secondary endpoint. Patients will undergo tumor restaging, using the appropriate combination of 
imaging and bone marrow biopsies, after cycles 2 and 5 and 8 and then every 4 cycles thereafter 
until cycle 32.  Radiographic restaging will also be performed at the 60-day post-treatment 
follow-up visit and at pre-specified intervals thereafter (see Study Calendar, section 10).  
Imaging will consist of PET/CT scans until the patient has achieved a metabolic CR (defined as 
Deauville score 1-3) at which juncture transition to CT of the chest, abdomen and pelvis will be 
acceptable at the discretion of the treating physician.  Response assessment will follow standard 
criteria (Lugano criteria) for lymphoma.  Bone marrow biopsy will be required within 30 days of 
radiology testing to confirm CR for patients with marrow involvement at baseline.  A repeat 
bone marrow biopsy is not necessary to confirm CR if there was no marrow involvement at 
baseline. 
11.2
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
11.2.1 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started, or death due to any 
cause. Participants without events reported are censored at the last disease evaluation).
Duration of complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation.
11.2.2 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease evaluation.

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For patients with progression of disease on imaging, it is strongly recommended that   a 
confirmatory biopsy be obtained whenever possible.
11.2.3 Response Review
The tumor imaging metrics core (TIMC) at Dana-Farber Cancer Institute or an analogous facility 
at collaborating sites will assess radiographic response
12. DATA REPORTING/REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality in accordance with DF/HCC SOPs.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 

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12.3
Multicenter Guidelines
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix C.

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.

Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This study is an open-label phase II clinical trial. The primary endpoint is overall response rate. 
Secondary end points include examining the overall and complete response rates of 
pembrolizumab in the subgroup of patients with biologically selected subtypes of relapsed and 
refractory diffuse large B-cell lymphoma. We will also describe the safety and toxicity of 
pembrolizumab in patients with biologically selected subsets of relapsed and refractory diffuse 
large B-cell lymphoma. We will also report the complete response rate, duration of response, 
duration of complete response, progression free survival, and overall survival.
13.2
Sample Size, Accrual Rate and Study Duration
13.2.1 Sample size
The study will be powered based on the number of patients with EBV+ DLBCL enrolled.  
Patients with other allowed lymphoma histologies will be enrolled until the accrual goal of 20 
patients with EBV+ DLBCL/TCHRLCL/plasmablastic lymphoma is met (with a maximum of 10 
patients in any given lymphoma histology) at which time accrual to all lymphoma cohorts will 
close.  The exact number of patients enrolled depends on the accrual of non-EBV+ DLBCL 
patients, but is expected to be 24-30 patients.  If by the time 20 patients with EBV+ DLBCL are 
accrued, the total accrual is <24, accrual will continue to all 3 cohorts (including EBV+ DLBCL) 
until the total accrual reaches 24.
Six patients with histiocytic sarcoma, follicular dendritic cell sarcoma, and/or interdigitating 
dendritic cell sarcoma will be included in the trial and accrual to this subgroup can continue 
independent of closure of the study to accrual of lymphoma patients.  Given the extremely rare 

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nature of these diseases, these patients are being included for exploratory purposes only and the 
statistics of the trial will not be powered based upon this patient population.
13.2.2 Statistical considerations
The hypothesis of this trial is that the response rate of pembrolizumab in this patient population 
will be 40% or higher.  Assuming at least 20 patients are enrolled, we would consider the 
treatment promising if at least 6 patients respond.  With this design, the study would have 
approximately 87% power to detect a difference in the response rate between 15% (the null 
hypothesis) and 40% (the alternative hypothesis), at a significance level of 0.07 (based on the 
exact binomial distribution).  The maximal 90% confidence interval around the estimates for 
response and toxicity will be approximately +/-20%.  
We anticipate accrual of 1 patient per month yielding an accrual period of 24 months.  We 
anticipate following the last patient accrued for 6 months before being able to determine best 
overall response (the primary endpoint).  Patients will be followed for 2 years after accrual for 
secondary endpoints such as PFS, OS, and duration of response for total study duration of 
approximately 4 years.
13.3
Stratification Factors
Response rates, PFS and DOR will also be reported for each histology (EBV+ DLBCL, PMBL, 
TCHRLCL).
13.4
Interim Monitoring Plan
The trial will be monitored by a DSMC and will be stopped at the judgment of the DSMC should 
excessive toxicity be observed.  There are no stopping rules for futility.
13.5
Analysis of Primary Endpoints
Primary and secondary analyses will be performed on all patients who had measurable disease 
present at baseline, received at least one cycle of study drug, and had their disease re-evaluated 
for response. Response rates will be tabulated and reported as proportions with 90% exact 
binomial confidence intervals for each point estimate.
See Section 11 for additional details and definitions.
13.6
Analysis of Secondary Endpoints
Complete response rate, duration of response, duration of complete response, progression free 
survival, and overall survival will be reported for the entire cohort. 
Response rates will be tabulated and reported as proportions with 90% exact binomial 
confidence intervals for each point estimate. Time-to-event endpoints will be assessed using the 
method of Kaplan and Meier; follow-up time will be estimated using the reverse Kaplan-Meier 

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method; estimates will be reported along with 90% confidence intervals where estimable using 
Greenwood's formula to calculate variance.
As secondary analyses, additional response criteria may be used to estimate response rates, and 
these rates will be assessed and reported as described above.
Sub-populations of patients may also be analyzed for by histology for response and time-to-event 
endpoints if sample sizes are sufficient. The methods described above will be used to report 
corresponding endpoints.
Abnormal laboratory test results and attributions to study drug will be summarized.
13.6.1 Safety analyses
Safety evaluations will be performed for the total cohort of patients including all who received at 
least one dose of study treatment. Incidence, severity, and type of adverse events (AEs) will be 
tabulated and reported as proportions.
SAEs, deaths, and other safety-related events resulting in discontinuation from study will be 
reported separately.
Safety analyses may also be performed by sub-populations of patients depending on the size of 
each.
13.6.2 Correlative analyses
Correlative studies examining the relationship between PD-1/PD-L1/PD-L2 expression, immune 
microenvironment, and circulating lymphocyte with outcome will be performed where samples 
are available. The exact studies to be performed are subject to sample and funding availability. In 
the case of insufficient sample size for meaningful statistical analyses, correlative data will be 
reported with descriptive statistics.
13.7
Reporting and Exclusions
The primary analyses will be on an intent-to-treat basis, considering all patients who are enrolled 
on study. Secondary analyses and toxicity analyses will be performed on the subset of eligible 
patients who received at least 1 dose of study drug.
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 

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Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 
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T-cell LYMPHOMA after first relapse or progression: spectrum of disease and rare long-
term survivors.J CLIN ONCOL. 2013;31(16):1970-6. 
Vranic S, Ghosh N, Kimbrough J, Bilalovic N, Bender R, ET AL. PD-L1 Status in Refractory 
Lymphomas.PLOS ONE. 2016 Nov 18;11(11):e0166266.
Nicolae A, Pittaluga S, Venkataraman G, Vijnovich-Baron A, Xi L, Raffeld M, Jaffe 
ES.Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-
Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist. AM J 
SURG PATHOL. 2013;37(6):816-26. 
Jo JC, Kim M, Choi Y, Kim HJ, Kim JE, Chae SW, Kim H, Cha HJ.Expression of programmed 

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cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal 
type. ANN HEMATOL. 2016 Oct 3. [Epub ahead of print].
Khodadoust M, Rook AH, Porcu PL, Foss FM, Moskowitz AJ, et al. Pembrolizumab for 
treatment of relapsed/refractory mycosis fungoides and sezary syndrome:clinical efficacy in a 
citn multicenter phase 2 Study, Blood 2016; 128(22): abst181.

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B 
LUGANO AND LYRIC RESPONSE CRITERIA (31, 32)
Criteria
CR
PR
PD
PET-CT score 4 or 5 with an increase in intensity of uptake 
from baseline and/or new FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment assessment. OR 
On CT, an individual node/lesion must be abnormal with: 
LDi >1.5 cm and increase by ≥50% from PPD nadir and an 
increase in LDi or SDi from nadir 0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm
In the setting of splenomegaly, the splenic length must 
increase by >50% of the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must increase to >16 cm). If no 
prior splenomegaly, must increase by ≥2 cm from baseline. 
New or recurrent splenomegaly
New or clear progression of preexisiting nonmeasured 
lesions
Regrowth of previously resolved lesions
A new node >1.5 cm in any axis or a new extranodal site 
>1.0 cm in any axis; if <1.0 cm in any axis, its presence 
must be unequivocal and must be attributable to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
AND/OR new or recurrent involvement of the bone marrow
Lugano
PET-CT, 
score 1, 2, or 
3*with or 
without a 
residual mass 
on 5PS† OR 
on CT, target 
nodes/nodal 
masses must 
regress to 
≤1.5 cm in 
LDi
PET-CT 
score 4 or 5 
with reduced 
uptake 
compared 
with baseline 
and residual 
mass(es) of 
any size. OR 
On CT ≥50% 
decrease in 
SPD of up to 
6 target 
measurable 
nodes and 
extranodal 
sites
As with Lugano with the following exceptions:
IR
IR(1): ≥50% increase in SPD in first 12 weeks
IR(2): <50% increase in SPD with
a. New lesion(s), or
b. ≥50% increase in PPD of a lesion or set of lesions at any 
time during treatment
LYRIC
Same as 
Lugano
Same as 
Lugano
IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size meeting criteria for PD

IR, immune response; LDi, longest diameter; PPD, product of the perpendicular diameters; SDi, short diameter; 5PS, 5-point scale.

↵* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. 
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment).

↵† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake greater than 
liver; 5, uptake markedly higher than liver (2-3 times SUVmax in normal liver) and/or new lesions; X, new areas of uptake unlikely to 
be related to lymphoma.

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APPENDIX C
DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN
1
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the pocedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that will be 
participating in the research protocol.
1.1 Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.
1.2 Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead 
Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves 
as the Coordinating Center for the DF/HCC Multi-Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at 
DF/HCC and all Participating Institutions. In most cases the DF/HCC Sponsor is the same person 
as the DF/HCC Overall Principal Investigator; however, both roles can be filled by two different 
people.
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.   

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Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related 
to multi-center clinical research.
DF/HCC Research Informatics for Operations (RIO): A group within DF/HCC responsible for 
providing a comprehensive data management platform for managing clinical trial data.
2
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
2.1 DF/HCC Sponsor
The DF/HCC Sponsor, Dr. Eric Jacobsen, will accept responsibility for all aspects of conducting 
a DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed.

Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language. 

Monitor progress and overall conduct of the study at all Participating Institutions. 

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with FDA (investigator-held IND trials), as applicable.

Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol.

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
Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements. 
2.2 Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain FDA correspondence, as applicable.

Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS).

Distribute protocol and informed consent document updates to Participating 
Institutions as needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review and submission to the DFCI IRB, as 
necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring. 

Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites

Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications.
2.3 Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements. 
The general responsibilities for each Participating Institution may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB.

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
Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research 
related activities. 

Submit Serious Adverse Event (SAE) reports to local IRB per institutional 
requirements and to the Coordinating Center, in accordance with DF/HCC 
requirements. 

Submit protocol deviations and violations to local IRB per institutional requirements 
and to the DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings.
3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
3.1 Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.   
3.2 Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB 
of these revisions.

Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 

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required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures.
3.3 Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols.  This 
document will be provided separately to each Participating Institution.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician members 
of the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. Participating institutions must follow the DF/HCC requirement that only attending 
physicians obtain informed consent and re-consent for all interventional drug, biologic, or device 
research.  
3.4 IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB. 

Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB. 

Participating Institution’s IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.
3.5 IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to continue 
research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.  

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3.6 Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, with 
the approval from the DFCI IRB, will provide a consent template, with information regarding 
authorization for the disclosure of protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 
collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements.
3.6.1
 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned protocol case number (as described below) be 
used for all participant specific documents. Participant initials may be included or retained for 
cross verification of identification. 
3.7 DF/HCC Multi-Center Protocol Registration Policy
3.7.1
Participant Registration and Randomization
To register a participant, the following documents should be completed by the Participating 
Institution 
and 
e-mailed 
to 
the 
Coordinating 
Center: 
Megan Forsyth
Dana-Farber Cancer Institute
450 Brookline Ave
Boston, MA 02215
Megan_Forsyth@DFCI.HARVARD.EDU
Phone: 857-215-1405
Fax: 617-632-6625

Copy of required laboratory tests including: All screening evaluations.

Signed informed consent document

Signed DFCI eligibility checklist

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
HIPAA authorization form (if separate from the informed consent document)

Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration 
form)
The Coordinating Center will review the submitted documents in order to verify eligibility and 
consent. To complete the registration process, the Coordinating Center will:

Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS).

Upon receiving confirmation of registration, the Coordinating Center will inform 
the Participating Institution and provide the study specific participant case number, 
and, if applicable, assigned treatment and/or dose level. 
Treatment or other protocol-specific interventions may not begin without confirmation 
from the Coordinating Center that the participant has been registered.
Registration can only occur during normal business hours, Monday through Friday from 8:00 AM 
to 5:00 PM Eastern Standard Time. 
3.7.2
 Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other 
protocol-specific interventions. Treatment and other protocol-specific interventions may not be 
initiated until the Participating Institution receives confirmation of the participant’s registration 
from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any 
violations to this policy.
3.7.3
 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be 
permitted. All Participating Institutions are required to fully comply with this requirement. 
3.8 DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number.  Participating 
Institutions should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.  
3.8.1
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB.

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For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB.
3.8.2
 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. enrollment 
of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation. 
3.8.3
 Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical 
record and/or regulatory documents to describe all protocol exceptions, deviations and violations. 
The DF/HCC Sponsor will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is 
submitted to the Participating Institution IRB, per institutional policy. A copy of the Participating 
Institution’s IRB report and determination will be forwarded to the Coordinating Center within 10 
business days after the original submission. The deviation may not be implemented without all 
required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations.
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation 
reports to CTEP via an internal DF/HCC process, as applicable.
3.9 Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants. 

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All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center. 
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.9.1
Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol section 7.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB Adverse Event Reporting Policy. 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.  Participating Institutions 
will review and submit to their IRB according to their institutional policies and procedures
3.9.2
Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports 
are distributed to the Participating Institutions. Participating Institutions will review and submit 
to their IRB according to their institutional policies and procedures.
3.10
Data Management
 
DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC RIO provides a web based training for all 
eCRF users.
  
3.10.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study forms are 
received with missing or questionable data, the submitting institution will receive a written or 
electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
Responses may be returned on the written query or on an amended paper case report form, or in 
the case of electronic queries, within the electronic data capture (eDC) system. In the case of a 

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written query for data submitted on a paper case report form, the query must be attached to the 
specific data being re-submitted in response.  
If study forms are not submitted on schedule, the Participating Institution will periodically receive 
a Missing Form Report from the Coordinating Center noting the missing forms. 
4
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol section 8.1. 
Participating Institutions should order their own agent regardless of the supplier.
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock.  If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB.
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent 
according to state and federal requirements. The local IRB should be kept informed of who will 
supply the agent so that any regulatory responsibilities can be met in a timely fashion. 
5
MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol.
5.1 Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring will occur before the clinical phase of the protocol begins, continue during 
protocol performance and through study completion. Additional monitoring practices may include 
but are not limited to; source verification, review and analysis of the following: eligibility 
requirements of all participants, informed consent procedures, adverse events and all associated 
documentation, study drug administration/treatment, regulatory files, protocol departures, 
pharmacy records, response assessments, and data management. 
Participating institutions will be required to participate in monthly Coordinating Center initiated 
teleconferences. E-mails highlighting overall protocol progress and important announcements will 
be distributed regularly.

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On-Site Monitoring: Participating institutions will be required to participate in monitoring one on-
site visit. At this time, source documentation verification (SDV) will be conducted by having 
access to participants’ complete medical record and source documents.  Access to the site 
regulatory binder and site’s pharmacy records will also be required.
Remote Monitoring: Participating Institutions will be required to forward de-identified copies of 
participants’ eligibility packetsand informed consent documents to the Coordinating Center to aid 
in source data verification within 30 days of subject enrollment. Source verification of all case 
report form data will occur remotely once per patient. At the time of visit, participating institutions 
will be required to forward de-identified copies of the participant’s medical record to the 
Coordinating center for review.
5.2 Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring of 
Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the protocol, 
DF/HCC Sponsor requirements or federal and local regulations. Participating Institutions may also 
be subject to an audit as determined by the DF/HCC Sponsor.
5.3 Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
It is expected that a minimum accrual of at least 2 patients per site annually will occur. 
6
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated activities 
were appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, applicable Standard Operating Procedures (SOPs), and the 
Code of Federal Regulations (CFR).
6.1 DF/HCC Internal Audits
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. If 
violations which impact participant safety or the integrity of the study are found, more participant 
records may be audited. 

DF/HCC Protocol #: 17-448
Protocol Date: April 29, 2022
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6.2 Audit Notification
It is the Participating Institution’s responsibility to notify the Coordinating Center of all external 
audits or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to 
the Coordinating Center, within 12 weeks after the audit date. 
6.3 Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. 
The Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee 
would forward the final audit report and corrective action plan to the DFCI IRB as applicable.
6.4 Participating Institution Performance
The DF/HCC Sponsor and the DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its responsibilities 
as described above.