Phase II Window Study of Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases
Phase: PHASE2
Conditions: Follicular Lymphoma, Indolent B-Cell Non-Hodgkin Lymphoma, Marginal Zone Lymphoma
Sponsor: University of Washington

 
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UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCHINSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
 
 
TITLE: Phase II window study of pembrolizumab in untreated B-cell non-Hodgkin 
lymphoproliferative diseases 
 
VERSION DATE:  21 July 2021 
 
VERSION NUMBER: 6.0 
 
Investigator and Study Center: 
Sponsor-Investigator  
 
 
 
 
  
Ajay K Gopal, MD 
 
 
 
 
 
 
Professor, UW 
 
 
 
 
 
 
Member, FHCRC 
 
 
 
 
 
 
Seattle Cancer Care Alliance  
 
 
 
 
 
825 Eastlake Ave. E. CE3-300 
 
 
 
 
 
Seattle, WA  98109 
 
 
 
 
 
 
Telephone: (206) 606-2037 
 
 
 
 
This is an investigator-initiated study. The principal investigator Ajay Gopal, MD (who may 
also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor. Therefore, the legal/ethical obligations of the principal investigator include both 
those of a sponsor and those of an investigator. 
 
 
 
 
IRO received 02/23/22
FHCRC IRB Approval  
03 16 2022 
Document Released Date

 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................. 10 
2.0 
TRIAL DESIGN........................................................................................................ 10 
2.1 
Trial Design ........................................................................................................... 10 
2.2 
Trial Diagram ........................................................................................................ 10 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................. 11 
3.1 
Primary Objective & Hypothesis ........................................................................ 11 
3.2 
Secondary Objectives & Hypotheses ................................................................... 11 
3.3 
Exploratory Objectives ......................................................................................... 11 
4.0 
BACKGROUND & RATIONALE .......................................................................... 11 
4.1 
Background ........................................................................................................... 11 
4.1.1 Pembrolizumab: Pharmaceutical and Therapeutic Background ......................... 12 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 13 
4.2 
Rationale ................................................................................................................ 13 
4.2.1 Rationale for pembrolizumab in lymphoma ....................................................... 13 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 13 
4.2.3 Rationale for Endpoints ...................................................................................... 15 
5.0 
METHODOLOGY ................................................................................................... 15 
5.1 
Entry Criteria ........................................................................................................ 15 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 15 
5.1.2 Subject Inclusion Criteria.................................................................................... 15 
5.1.3 Subject Exclusion Criteria .................................................................................. 17 
5.2 
Trial Treatments ................................................................................................... 18 
5.2.1 Dose Selection/Modification .............................................................................. 18 

 
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5.2.2 Timing of Dose Administration .......................................................................... 20 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 20 
5.3.1 Acceptable Concomitant Medications ................................................................ 20 
5.3.2 Prohibited Concomitant Medications.................................................................. 21 
5.4 
Rescue Medications & Supportive Care ............................................................. 21 
5.4.1 Supportive Care Guidelines ................................................................................ 21 
5.5 
Diet/Activity/Other Considerations ..................................................................... 25 
5.5.1 Diet ...................................................................................................................... 25 
5.5.2 Contraception ...................................................................................................... 25 
5.5.3 Use in Pregnancy ................................................................................................ 25 
5.5.4 Use in Nursing Women ....................................................................................... 26 
5.6 
Subject Withdrawal/Discontinuation Criteria ................................................... 26 
5.7 
Subject Replacement Strategy ............................................................................. 27 
5.8 
Clinical Criteria for Early Trial Termination ................................................... 27 
6.0 
TRIAL FLOW CHART ........................................................................................... 28 
6.1 
Study Flow Chart .................................................................................................. 28 
Adverse event assessment1.............................................................................................. 28 
7.0 
TRIAL PROCEDURES ........................................................................................... 29 
7.1 
Trial Procedures ................................................................................................... 29 
7.1.1 Administrative Procedures .................................................................................. 29 
7.1.2 Clinical Procedures/Assessments ........................................................................ 30 
7.1.3 Laboratory Procedures/Assessments .................................................................. 33 
7.1.4 Other Procedures ................................................................................................. 35 
7.1.5 Visit Requirements .............................................................................................. 35 
7.2 
Assessing and Recording Adverse Events .......................................................... 36 

 
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7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
Merck .................................................................................................................. 36 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 37 
7.2.3 Reporting of Adverse Events/Adverse Reactions ............................................... 37 
7.2.4 Evaluating Adverse Events ................................................................................. 39 
7.2.5 Sponsor-Investigator Responsibility for Reporting Adverse Events .................. 42 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 43 
8.1 
Statistical Analysis Plan Summary ..................................................................... 43 
8.2 
Statistical Analysis Plan ....................................................................................... 43 
8.3 
Efficacy Analysis ................................................................................................... 44 
8.3.1 Primary Efficacy Endpoint ................................................................................. 44 
8.3.2 Secondary Efficacy Endpoints ............................................................................ 44 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 45 
9.1 
Investigational Product ........................................................................................ 45 
9.2 
Packaging and Labeling Information ................................................................. 45 
9.3 
Clinical Supplies Disclosure ................................................................................. 46 
9.4 
Storage and Handling Requirements .................................................................. 46 
9.5 
Returns and Reconciliation .................................................................................. 46 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 46 
10.1 
Data and Safety Monitoring Plan ........................................................................ 46 
10.2 
Records .................................................................................................................. 47 
10.3 
Regulatory Responsibilities of Sponsor-Investigator ........................................ 48 
REFERENCES .................................................................................................................. 49 
11.0 
APPENDICES ........................................................................................................... 52 
11.1 
ECOG Performance Status .................................................................................. 52 

 
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11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 52 
11.3 
Response Evaluation ............................................................................................. 52 
11.3.1 The Lugano Response Classification: For FL and MZL (21) ............................. 52 
11.4 
FLIPI Scoring System (26) ................................................................................... 55 
11.5 
Events of Clinical Interest Guidance Document: Version 5 ............................. 56 
11.9.1 OVERVIEW ............................................................................................................... 56 
3.1 
Pneumonitis ........................................................................................................................ 58 
3.2 
Colitis .................................................................................................................................. 60 
3.3 
Endocrine ........................................................................................................................... 61 
3.4 
Hematologic ....................................................................................................................... 64 
3.5 
Hepatic ................................................................................................................................ 65 
3.6 
Neurologic .......................................................................................................................... 67 
3.7 
Ocular ................................................................................................................................. 67 
3.8 
Renal ................................................................................................................................... 68 
3.9 
Skin ..................................................................................................................................... 69 
3.10 
Immediate Evaluation for Potential Skin ECIs ................................................................ 71 
3.11 
Other ................................................................................................................................... 72 
3.12 
Infusion Reactions ............................................................................................................. 73 
3.13 
Follow-up to Resolution ..................................................................................................... 74 
5. Events of Clinical Interest (ECI) – Reference Table ...................................................... 74 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab 
in 
untreated 
indolent 
B-cell 
non-Hodgkin 
lymphoproliferative diseases 
Trial Phase 
II 
Clinical Indication 
Indolent B-cell non-Hodgkin lymphoproliferative diseases without prior 
therapy 
Trial Type 
Nonrandomized, prospective trial 
Type of control 
None 
Route of administration 
Intravenous 
Treatment Groups  
Single group 
Number of trial subjects 
33 
Estimated enrollment period 
18 months 
Estimated duration of trial 
36 months 
Duration of participation 
18 months 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single arm phase II pilot study evaluating the efficacy of single-agent pembrolizumab 
for untreated, indolent B-cell non-Hodgkin lymphoproliferative diseases (iBCL) including 
follicular lymphoma (FL) and marginal zone lymphoma (MZL).  In the window phase, 
treatment will be administered for up to six 3-week cycles and a response assessment 
performed at the conclusion. Patients that tolerate the drug and meet criteria for an objective 
response after 6 cycles may continue to receive pembrolizumab for up to an additional 12 
cycles in the continuation phase. Patients who show progressive disease or stable disease after 
6 cycles may be restaged after 3 additional cycles to assess for pseudoprogression/delayed 
response. Patients who show disease progression after 3 additional cycles will be removed 
from treatment. Patients who do not show evidence of disease progression may continue to 
receive pembrolizumab for up to a total of 18 cycles.   A futility analysis will be performed 
after the first 5 subjects in each of two histologic subgroups (follicular lymphoma, marginal 
zone lymphoma) are treated. We anticipate that subjects will be enrolled over approximately 
18 months and will be followed for outcomes for up to 5 years using standard-of-care 
assessments. 
 
 

 
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2.2 
Trial Diagram  
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective & Hypothesis 
To gain a preliminary assessment of the efficacy of pembrolizumab as monotherapy for 
patients with untreated iBCL based on ORR measured at the end of a 6-cycle treatment period. 
Hypothesis: Pembrolizumab will have an ORR of ≥ 50% in this untreated population after 6-
cycles.  
3.2 
Secondary Objectives & Hypotheses 
(1) Objective:   
To assess the safety and toxicity profile of pembrolizumab in patients with untreated iBCL. 
Hypothesis: Pembrolizumab will not cause a significant degree of toxicity. 
(2) Objective: 

 
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To measure the efficacy of pembrolizumab used as monotherapy for patients with untreated 
iBCL by assessing clinical outcomes including complete response rate (CR), clinical benefit 
rate (CBR) defined as CR+partial response (PR)+ stable disease (SD) x ≥6 months, time to 
next therapy (TNT), progression-free survival (PFS), and the duration of response (DOR).  
3.3 
Exploratory Objectives 
(1) Objectives:  
To evaluate clinical features including, as applicable, the follicular lymphoma international 
prognostic index (FLIPI) (see appendix 11.5), in addition to standard-of-care biomarkers 
including cytogenetics and Ki67 and correlate with response to pembrolizumab. 
To evaluate baseline expression of proteins in the PD-1 pathway in archived tumor specimens 
and in pretreatment peripheral blood mononuclear cells and correlate with response to 
pembrolizumab.  
To measure peripheral blood T-cell subsets and correlate with response to pembrolizumab.  
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
B-cell non-Hodgkin lymphoproliferative diseases (BCL) are categorized according to how 
aggressively they behave. The indolent BCL subtypes (iBCL) include CLL/SLL, FL, MZL, 
WM/LPL, and, in some circumstances, MCL (1). Owing to immune activation, the early course 
of iBCL often is characterized by minimal progression or even spontaneous remission. The 
contribution of immune modulation in the natural history and treatment of iBCL has been 
borne out in preclinical studies (2) and early phase clinical trials (3-5). 
iBCL inevitably relapse after therapy and typically become increasingly refractory to available 
treatments over time; iBCL are considered incurable short of allogeneic stem cell 
transplantation. Improving on this paradigm is necessary and requires novel strategies that 
minimize toxicity.  
Anti-cancer therapies historically render the greatest benefit in the first-line treatment setting. 
This can be attributed to relatively undeveloped drug-resistance mechanisms in tumors and 
their smaller volume, in addition to the contribution of host immunity (6).  The relatively slow 
early progression of iBCL makes this disease well suited to testing novel, low-toxicity 
treatment approaches in a predefined “window” of time (7).  
4.1.1 Pembrolizumab: Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (8).  Accumulating evidence shows a correlation 

 
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between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies (9).  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (10). The mechanism 
by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-
4 as both molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types. Binding of either PD-1 ligand to PD-1 
inhibits T-cell activation triggered through the T-cell receptor.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T-cell inhibitor.  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.  Pembrolizumab has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for pembrolizumab in lymphoma 
As evidenced by the subset of patients with apparent spontaneous disease regression, the host 
immune system can play a significant role in iBCL (11, 12). Programmed cell death-1 (PD-1) 
is an immune checkpoint receptor expressed on activated T-cells. Tumor cells including 
lymphoid malignancies have been shown to express the ligands of PD-1: PD-L1 and PD-L2 
(13). Engagement of T-cell PD-1 by its ligands downregulates T-cell activity through 
exhaustion. Modulation of the immune checkpoint pathway in iBCL has shown some promise 
in the relapsed and refractory setting in which the monoclonal PD-1 receptor blocking antibody 
nivolumab demonstrated activity as a single agent with an ORR in 4 of 10 patients treated in a 
phase I study (4). In a separate study the monoclonal anti-PD-1 antibody pidilizumab was 
combined with rituximab in patients with relapsed or refractory follicular lymphoma and 

 
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demonstrated an ORR in 19 or 29 patients (66%) with a median time to observed response of 
88 days (range, 53 – 392) (5).  
Pembrolizumab is a humanized monoclonal antibody of PD-1 with high affinity and potency. 
To date, pembrolizumab has shown an excellent safety and toxicity profile (see investigator’s 
brochure), thereby fulfilling an important criterion for its use in the first-line window-of-
opportunity setting (7). Use of immune checkpoint modulating antibodies as mono-therapy in 
the first-line setting has demonstrated efficacy in solid tumors (14, 15). Compared with the 
relapsed and refractory setting, untreated iBCL is accompanied by a relatively intact host 
immune repertoire with a potentially greater capacity to mount an effective anti-tumor immune 
response with immune-checkpoint inhibitor therapy.    
4.2.2 Rationale for Dose Selection/Regimen/Modification  
The choice of the 200 mg Q3W fixed dose 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 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. 
The first evaluation of the safety and pharmacokinetics of pembrolizumab was in an open-label 
Phase I trial (Protocol 001) conducted to evaluate the safety and clinical activity of single agent 
pembrolizumab.  The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 
3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of pembrolizumab showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date. Recent data from other clinical studies 
within the pembrolizumab program has shown that a lower dose of pembrolizumab and a less 
frequent schedule may be sufficient for target engagement and clinical activity.  
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days), 
providing scientific rationale for a Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 

 
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observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well 
within the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma 
indication. The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher 
dose and exposure). The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC 
and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses including the fixed dose 
of 200 mg Q3W is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor 
type. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Assessing the efficacy of pembrolizumab monotherapy in untreated iBCL will be performed 
according to standard response criteria (see section 7.2.1.5).  
Because of the possibility of pseudoprogression(16), asymptomatic patients whose tumors 
demonstrate radiologic progression after initial restaging may receive therapy for 3 additional 
cycles and then will be restaged. Because of possibility of delayed response, patients whose 
tumors demonstrate stable disease may also receive therapy for 3 additional cycles and then 
will be restaged. Patients with tumor burden which doubles in size after initial restaging will 
be considered hyperprogression(17) and will not be eligible for the continuation stage. 
4.2.3.2 Biomarker Research 
Baseline expression by tumor cells and tumor-infiltrating cells of proteins involved in the PD-
1 pathway will be performed on archived samples centrally when tissue is available; expression 
levels will be correlated with response to therapy.   
Enumeration of peripheral blood T-cell subsets will be performed with flow cytometric 
evaluation of peripheral blood mononuclear cells before, during, and after treatment with 
pembrolizumab.  These analyses will identify alterations in T-cell subsets as a possible 
biomarker predicting response to therapy. 

 
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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients must have a confirmed diagnosis of iBCL and not have received prior treatment for it. 
(Prior local radiotherapy is allowed as long as measurable disease is outside prior radiation 
field and all radiation-related adverse events have resolved.). Prior therapy that does not 
include any standard agents used for treatment of FL or MZL is also allowed as long as not in 
the same class of drugs as pembrolizumab.) Criteria for diagnosis include histopathologic 
evidence for FL and MZL. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Must have measurable disease defined by at least one of the following criteria: 
a. Lesions greater than 1.5 cm that can be accurately measured in two dimensions by 
CT (preferred), or MRI. 
 
4. Must have indication for treatment (Adapted from NCCN 2015 Guidelines) 
Any of the following constitute an indication for treatment: 
a. Significant symptoms due to any iBCL: Which may include pain/discomfort, limitation 
of function, fatigue/malaise/constitutional symptoms, B-symptoms (fever, weight 
loss, night sweats), pruritus; 
b. Threatened end-organ function due to any iBCL; 
c. Progressive cytopenia secondary to any iBCL; 
d. Steady progression of FL and MZL 
 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1. 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥500/µL a, b 
Platelets 
≥25 000/µL a, b 
Hemoglobin 
≥8 g/dL a, b 
Renal 
 

 
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Creatinine 
OR 
Measured or calculated 
c creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 
× 
ULN 
OR 
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN  
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN 
unless 
participant 
is 
receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
aGrowth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if 
needed. 
bNo lower limit if cytopenia is related to bone marrow involvement. 
cCreatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 
 
7. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
8. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year.  
9. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
 
 

 
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3. Has a known history of active TB (Bacillus Tuberculosis). 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had prior chemotherapy, radiation therapy, or immunotherapy for the diagnosis of 
iBCL. 
6. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
9. Has known history of, or any evidence of active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Be in urgent need of therapy for lymphoma related complications (such as hyperviscosity 
syndrome) and those with bulky disease. 
18. Has received a live vaccine within 30 days of planned start of study therapy. 

 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of the dose to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.   
5.2.1.2 Dose Modification  
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. See Section 5.6.1 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including 
use of corticosteroids.

 
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Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
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  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 

 
Protocol v6.0 dated 21 July 2021 
 
 
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Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2a 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3b or 4c  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withholdd 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinued  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
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.  
 

 
Protocol v6.0 dated 21 July 2021 
 
 
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Nephritis grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 3 or 4 
Permanently 
discontinue 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Myocarditis 
Grade 1  
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other irAEs 
Persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
evente.   
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x 
baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 

 
Protocol v6.0 dated 21 July 2021 
 
 
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e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (e.g., vasculitis and sclerosing cholangitis). 
 
 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., 
elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be placed back on study therapy within 
3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor-Investigator or lead sub-investigator. The reason 
for interruption should be documented in the patient's study record.

 
Protocol v6.0 dated 21 July 2021 
 
 
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5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The sponsor-investigator should discuss any questions regarding 
this with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post response/stable disease relapse) of this trial: 

 
Protocol v6.0 dated 21 July 2021 
 
 
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• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor-investigator. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. 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 is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 

 
Protocol v6.0 dated 21 July 2021 
 
 
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• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o 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 that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, 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. 
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 

 
Protocol v6.0 dated 21 July 2021 
 
 
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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.  
 
• 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 4 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab. 
Table 4 Infusion Reaction Treatment Guidelines 

 
Protocol v6.0 dated 21 July 2021 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the participant 
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 
(PEMBROLIZUMAB) 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. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
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. 
 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 

 
Protocol v6.0 dated 21 July 2021 
 
 
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5.5.2 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.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study, they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor-Investigator and to Merck.  If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to to Merck without delay and 
within 24 hours to the Sponsor-Investigator and within 2 business days of investigator 
knowledge 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 Merck and followed as described above and in Section 7.2.2. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 

 
Protocol v6.0 dated 21 July 2021 
 
 
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5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.  Subjects who require cessation of 
study therapy but do not withdraw consent may remain in standard follow-up for up to 5 years. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• Confirmed radiographic disease progression 
• Unacceptable adverse experiences as described in Section 5 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events may be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Patients may have post-
treatment follow-up for disease status up to 5 years at longest, or until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. 
5.7 
Subject Replacement Strategy 
Subjects who fail to complete study therapy will not be replaced. 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 

 
Protocol v6.0 dated 21 July 2021 
 
 
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3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
 
Screening 
Period 
 
Treatment Phase 
End of 
treatment6 
Long-term 
 Follow-up7 
Window 
Cycles (1-6) 
Response 
assessment8 
Continuation Cycles 
(7-18)9 
 
 
Scheduling and Timing 
-42 to -1d 
+/- 3d 
 
+/- 3d 
 
 
Informed consent 
X 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Medication review (prior and 
concomitant) 
X 
X 
 
X 
 
 
Trial treatment administration 
 
X 
 
X 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
X 
Survival status 
 
 
 
 
 
X 
Vital signs 
X 
X 
 
X 
X 
 
Physical exam 
X 
X 
 
X 
X 
 
ECOG performance status 
X 
X 
 
X 
X 
 
Adverse event assessment1 
X 
X 
 
X 
X 
 
CBC and differential 
X 
X 
X 
X 
X 
 
Comprehensive metabolic panel 
and LDH  
X 
X 
X 
X 
X 
 
HepB SAg, Hep B Core Ab, 
HepC Antibody and HIV screen 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
T3, FT4, and TSH 
X 
X 
 
X 
X 
 
PT/INR and aPTT 
X 
 
 
 
 
 
Correlative studies blood draw 
X 
 
X 
 
X 
 
Bone marrow studies2 
X 
 
 
 
X 
 
Pregnancy test3 
X 
 
 
 
 
 
Tumor assessment5 
X 
X 
X 
X 
X 
 
Archival Tissue collection4 
X 
 
 
 
 
 
 
1Adverse events will be recorded from the time of a subject signing consent up until 30 days after the last dose of pembrolizumab, or 90 days 
after the last dose of pembrolizumab in the case of serious adverse events. 
2If bone marrow involvement by iBCL was previously shown then repeat bone marrow exam at screening is not required as it is assumed 
positive. Otherwise, bone marrow studies include aspirate and unilateral biopsy and should be performed at screening unless a waiver is 
approved by the study Sponsor-Investigator or sub-Investigator.  If all bone marrow studies are negative at screening, these do not need to be 
repeated.  If bone marrow status is unknown or positive at screening, patients will need to a have bone marrow study for confirmation of a 
CR. 
3 Pregnancy test is only required in women of childbearing potential. 
4Archived tumor samples are requested for pathologic confirmation and biomarker analysis. If an archived specimen is not available or 
contains insufficient material, a fresh tumor biopsy (if clinically feasible) will be requested. Correlative studies may be performed on any 
available tissue.  
5Tumor assessment labs and/or imaging (see section 7.1.2.5) will be performed prior to cycle 4 (within 7 days of scheduled treatment dose) 
during the window phase. Tumor assessment will be performed prior to cycle 7 (within 7 days of scheduled treatment dose) to determine 
eligibility for continuation on study in continuation phase. Tumor assessment labs and/or imaging will be performed prior to cycles 11 and 
15 (within 7 days of scheduled treatment dose) during the continuation phase, as applicable. Tumor assessment labs and/or imaging will be 
performed at end-of-treatment evaluation only for subjects who did not have tumor assessment labs and/or imaging performed within 60 days 
of end-of-treatment. Tumor assessment labs and/or imaging will also be performed as indicated per clinical standard of care (e.g. as appropriate 
for disease, to evaluate clinical suspicion of disease progression). Patients who have stable disease or asymptomatic radiologic disease 
progression prior to cycle 7 will remain in the window phase with restaging prior to cycle 10 to evaluate for pseudoprogression or delayed 
response. Patients who have restaging prior to cycle 10 are not required to have tumor assessments prior to cycle 11. Patients who have 
radiologic disease progression with doubling of tumor size prior to cycle 7 will be categorized as hyperprogression and will not proceed to 
the continuation phase. 
6End-of-treatment evaluations should be done within 30 days (+/- 14 days) of the last dose of pembrolizumab or prior to the start of a new 
anti-cancer drug, whichever is first.  
7Long-term follow-up should be done according to the patient’s physician standard of care. This may be performed at patients’ local 
physician’s offices. Long-term follow-up will assess survival and disease progression; for clarification, subjects may be contacted by the 
study team until death, subject withdrawal of consent, lost to follow-up, or study termination, whichever occurs first. 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
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8Response assessment will be performed prior to cycle 7 (within 7 days of scheduled treatment dose) only for those subjects that complete 6 
cycles of treatment in the window phase.  
9During treatment in the continuation phase, clinical assessment (physical exam including performance status, adverse event and medication 
review) will be performed on day 1 (+/- 3 days) of each odd-numbered cycle only, or as clinically indicated. Studies performed for response 
assessment9 do not need to be repeated prior to cycle 7.  
 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart in Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements and applicable laws and 
regulations. 
 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  The subject will not have received prior treatment for 
the disease. 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.    
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
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characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs); see the separate ECI guidance document in Appendix 11.3.10 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A physical exam should be performed during screening.  
7.1.2.3 Vital Signs 
Vital signs will be taken at screening, prior to the administration of each dose of trial treatment 
and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0).  Vital signs 
should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be 
measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of trial treatment, and after discontinuation of trial treatment as 
specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
Tumor imaging and assessment of disease will be performed according to each disease 
subtype: 
7.1.2.5.1 Follicular lymphoma  
FDG-PET imaging will be required during study screening and prior to treatment on cycle 7 
to determine candidacy for continuation on study. Contrast-enhanced computed tomography 
(CT) of the chest, abdomen, and pelvis alone will be performed at each tumor assessment. For 
measurement of response, 2014 criteria as described in “Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification” will be used (see Appendix 11.3.1) (18). CT imaging of the neck 
will be performed as indicated for standard of care. 
All CT scans should be performed with IV contrast unless contraindicated, and abdominal and 
pelvis scans should be performed with oral contrast.   

 
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7.1.2.5.2 Marginal Zone Lymphoma in which Nodal Disease is Known or Suspected 
CT of the chest, abdomen, and pelvis will be performed at each tumor assessment. For 
measurement of response, 2014 criteria as described in “Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification” will be used (see Appendix 11.3.2) (18). CT imaging of the neck 
will be performed as indicated for standard of care. 
All CT scans should be performed with IV contrast unless contraindicated, and abdominal and 
pelvis scans should be performed with oral contrast.   
7.1.2.6 Bone marrow aspirate and biopsy 
A bone marrow aspirate and biopsy will be obtained before the first dose of study drug, and 
for confirmation of CR when indicated.  Bone marrow aspirate and biopsy requirements may 
be waived by the Sponsor-Investigator or lead sub-Investigator.  These samples will be 
evaluated locally.   
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Assessment of available archived tumor tissue for correlative study analysis will be performed 
during the screening period. Available pretreatment biopsy tissue will be provided for 
correlative study analysis. Peripheral blood correlative study samples will be collected during 
screening, at response assessment, and at end-of-treatment (see Section 6.1). 
Specimen Requirements 
• A 5-10 mL specimen of peripheral blood in a lavender- (EDTA) or green- (sodium heparin) 
tube is acceptable for each draw. 
• Storage/Transport Temperature: Specimens can be transported with a cold pack or wet ice, 
but do not fix or freeze specimens. 
• Unacceptable Conditions: Frozen specimens, specimens greater than 48 hours old, specimens 
fixed in formalin for flow cytometry. 
Address for shipping specimens:  
Seattle Cancer Care Alliance 
Hematopathology Laboratory G7800 
825 Eastlake Ave E. 
Seattle, WA  98109 
 

 
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7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below and in Section 6.1. All chemistry and hematology studies may be performed 
within 3 days of pembrolizumab dosing prior to day 1 of each cycle. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   

 
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Table 5 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
Hepatitis B Surface Antigen (HBsAg) 
 
Calcium 
 
Hepatitis B Core Antibody (HBcAb) 
 
Chloride 
 
Hepatitis C Antibody 
 
Glucose 
 
 HIV Screening 
 
Phosphorus 
 
 PK 
 
Potassium   
 
 Blood for correlative studies 
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

 
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Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
The screening period begins upon signing consent and includes evaluations as described in 
Section 6.1. The screening period may last up to 42 days. 
7.1.5.2 Treatment Period 
The treatment period includes the window phase during which pembrolizumab is administered 
every 21 (+/- 3) days for 6 cycles. Subjects that are determined to have an objective response 
or stable disease at the point of response assessment prior to cycle 7 (or cycle 10 if 
pseudoprogression/delayed response) may continue on study in the continuation phase. During 
the continuation phase pembrolizumab is administered every 21 (+/- 3) days for up to 12 
additional cycles to complete a total of up to 18 cycles.  
7.1.5.3 End-of-treatment Visit 
Thirty days (+/- 14 d) after the last dose of pembrolizumab, irrespective of cause of cessation, 
an end-of-treatment visit should be performed. However, if a subject requires additional anti-
cancer therapy, the off-study visit may occur earlier.   
The off-study visit will include laboratory studies, medical history, physical exam, remission 
status, concomitant medications, adverse events, and documentation of any ECI and 
subsequent management, as in Section 6.0. All AEs that occur prior to the end-of-treatment 
visit should be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded.   

 
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After the end-of-study visit, additional follow-up will be conducted as per routine standard of 
care for up to 5 years unless other criteria for withdrawal are met (see Section 5.6). Long-term 
follow-up may be performed at patients’ local physician’s offices. Long-term follow-up will 
assess survival and disease progression; for clarification, subjects may be contacted by the 
study team until death, subject withdrawal of consent, lost to follow-up, or study termination, 
whichever occurs first. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
Adverse events grade 3 and higher, as well as AEs requiring clinical intervention/dose 
modification, ECIs and SAEs of any grade, will be recorded from the time the consent form is 
signed up until 90 days following the last dose of pembrolizumab and at each examination on 
the Adverse Event case report forms/worksheets. The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 

 
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If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 2 working 
days of investigator knowledge to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 2 working days of investigator knowledge to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Reporting of Adverse Events/Adverse Reactions 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 

 
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Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 2 business days of investigator knowledge to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators 
will cross reference this submission according to local regulations to the Merck Investigational 
Compound Number (IND, CSA, etc.) at the time of submission.  Additionally, investigators 
will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI). See appendix 11.10, ECI Guidance Document, for management and reporting of ECI. 
ECI and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 2 business days of investigator knowledge to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to Merck, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. * 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 

 
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1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest Guidance 
Document” (previously entitled, “Event of Clinical Interest and Immune-Related Adverse 
Event Guidance Document”).  This document can be found in Appendix 4 and provides 
guidance regarding identification, evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document from 
the date of first dose through 90 days following cessation of treatment, or 30 days after the 
initiation of a new anticancer therapy, whichever is earlier, need to be reported within 2 
business days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220), 
regardless of attribution to study treatment, consistent with standard SAE reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
 
 
 
 
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Table 6 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 

 
 
 
 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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7.2.5 Sponsor-Investigator Responsibility for Reporting Adverse Events  
The sponsor-investigator is required to report all problems, events and information that require 
prompt reporting to the IRB within ten (10) calendar days of learning of the problem. The 
sponsor-investigator will also report serious, unexpected, suspected adverse reactions and 
other significant safety information to FDA as required under 21 CFR 312.32.  
 
Adverse events grade 3 and higher, as well as AEs requiring clinical intervention/dose 
modification, ECIs, and SAEs of any grade, will be reported from the time of signing of 
consent up until 90 days following the last dose of pembrolizumab. 
 
If a problem, event or information is determined to be an unanticipated problem involving risks 
to participants or others, it will be reviewed by the convened IRB, appropriate steps will be 
taken and it will be reported to appropriate institutional and governmental officials as provided 
under applicable law. 
 
For the purposes of this protocol, the terms Adverse Event, Serious Adverse Event (Related, 
Possibly Related or Unexpected) and Unanticipated Problem are defined in accordance with 
the most current Fred Hutchinson Cancer Research Center Institutional Review Board Policy 
2.6. 
 
Routine Reporting 
Routine reporting is required for all grade 3, 4 and 5 adverse events.  Routine reporting will 
be conducted in accordance with applicable FDA regulations, and agreements with Merck. 
Expedited Reporting  
With respect to each research study he or she is conducting, the principal investigator must 
ensure that the following problems, events, and information involving risks to research 
participants or others are reported to the IRB not later than ten (10) calendar days after he or 
she first becomes aware of the problem, event, or information. 
 
 
 
 
Adverse Events Requiring Expedited Reporting 
Adverse events require expedited reporting if they meet all three of the following criteria: 
(1)  unexpected, and  
(2)  related or possibly related to the research and   
(3) serious or suggest that the research places research participants or others at a greater 
risk of physical or psychological harm than was previously known or recognized. 
 
Unless otherwise specified in the Protocol, therapeutic oncology protocols are not required to 
specify monitoring parameters for Grade I or II toxicities as described in the Common 
Terminology Criteria for Adverse Events published by the National Cancer Institute.  These 
adverse events are expected and occur routinely in the subject population being studied.  They 
should be monitored and treated in the practice of routine clinical care.  
 
 
 

 
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8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
This is a single-arm phase II study designed to show a statistically significantly improved 
overall response rate (ORR) from the fixed benchmark of 25%. This rate is based on early data 
of efficacy of immune checkpoint modulating antibodies used in treating FL in the relapsed 
and refractory setting (4). Though representing a lower ORR than has been shown for other 
first-line therapeutic strategies in iBCL (19) this threshold was chosen with consideration for 
pembrolizumab’s novel mechanism of action compared with standard iBCL treatments and the 
potential for achieving long-term remissions with low toxicity (20).  
8.2 
Statistical Analysis Plan 
We shall use the backbone of a Simon two-stage minimax design for this trial with an 
additional look to potentially stop for futility based on outcomes observed in two specific 
histology subgroups (follicular lymphoma, marginal-zone lymphoma). With 33 patients, a 
Simon two-stage minimax design yields 90% to observe an ORR that is statistically 
significantly higher (at the one-sided significance level of .05) than the fixed ORR rate of 25% 
if the assumed-true ORR with the regimen currently proposed is 50%.  In the first stage, if we 
observe 4 or fewer responses among 16 patients (25% or less), consideration will be given to 
terminating the study due to lack of sufficient efficacy. On the other hand, if 5 or more 
responses are seen among the first 16 patients (and observed ORR of at least 31%), an 
additional 17 patients will be enrolled. At this point, if 13 or more responses are seen among 
the 33 patients (an observed rate of at least 39%), the study will conclude that the proposed 
treatment is potentially efficacious and worthy of further study.   
The modification to the above Simon two-stage design will include an interim look within the 
first stage, with this interim look consisting of subtype-specific analyses.  If there are 0 
responses among the first 6 patients with follicular lymphoma, accrual of such patients will be 
stopped.  The same rule will be applied to patients with marginal-zone lymphoma.  If the true 
probability of response is 50%, the probability of seeing 0 responses among 6 patients 
is .016.  This additional look has a small impact on the power of the Simon design (since, under 
the alternative hypothesis, we may incorrectly stop at least one group for futility, hence 
decreasing the power (i.e., increasing the Type II error or false negative rate).  In particular, if 
one assumes a 50% ORR (consistent with the alternative hypothesis in the Simon design) in 
both subtypes with an equal probability of enrollment to each subtype, the addition of the 
subtype-specific 
rules 
from 
above 
decreases 
the 
power 
from 
90% 
to 
approximately 87% (estimated from 5,000 simulations).  Note that if in each subtype there are 
0 responses in the first 6 patients, for a total of 0/12, these results would lead to stopping the 
trial per the Simon two-stage rules as it would not be possible to achieve at least 5 responses 
in the first 16 patients. 
If the study is stopped due to lack of efficacy in a histologic subgroup, the study may only be 
reopened to accrual for patients with that histology with modifications (e.g. addition of a 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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second agent, change in dosing, etc) that have been reviewed and approved where appropriate 
by the sponsor, scientific review, and relevant regulatory bodies.  
Suspension rules for toxicity: 
Prior studies treating patients that have not received prior chemotherapy suggest that the rates 
of grade ≥3 immune-related AEs occur in approximately 10% of patients (Reck et al, NEJM 
2016). Infusion reactions of ≥grade 3 are less common and less consistently reported in 
publications. For this reason, we will initiate a suspension rule for infusion- or immune-related 
AEs of ≥grade 3 of up to 12%. This will be deemed to occur if the lower level of a one-sided 
80% confidence interval for immune-related or infusional AEs of ≥grade 3 exceeds 12%. 
Operationally, the study will be suspended and referred to the DSMC for consideration of 
results and appropriate modification or termination of the study if 
•  3 out of the first 11 or fewer, 5 out of the first 22 or fewer, 6 out of the first 33 or fewer 
have ≥ grade 3 immune related or infusional AEs  
If the true probability of ≥grade 3 AEs is 5%, the probability of suspending the trial due to 
excess AEs after 11, 22, and 33 patients is approximately <0.02, 0.02, and 0.02, 
respectively.  If the true probability of ≥grade 3 AEs is 30%, the probability of suspension 
due to excess AE is approximately 0.80, 0.94, and 0.99, respectively.   (Probabilities of 
suspension estimated from 5,000 simulations).  
8.3 
Efficacy Analysis 
Response assessments will be performed as described in Section 7.1.2.5. 
8.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall response rate (CR + PR for FL and MZL) and will 
be calculated for all treated patients. The corresponding 95% two-sided confidence interval 
will be derived. 
8.3.2 Secondary Efficacy Endpoints 
8.3.2.1 Duration of response 
Duration of response will be measured from the time by which the measurement criteria are 
met for CR or PR, whichever is recorded first, until death or the first date by which recurrent 
or progressive disease is objectively documented. Subjects who are progression-free and alive 
at the time of clinical cut-off or have unknown status will be censored at the last tumor 
assessment. 
Non-responders will be excluded from the analysis of DOR. Kaplan Meier methodology will 
be used to estimate event-free curves. 

 
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8.3.2.2 Progression-free survival 
PFS will be measured for each disease cohort as time from the first study drug administration 
to the first occurrence of lymphoma progression or death from any cause. 
Data for subjects without disease progression or death will be censored at the date of the last 
tumor assessment. Kaplan-Meier methodology will be used to estimate the event-free curves. 
8.3.2.3 Time to next therapy 
Time to additional anti-neoplastic treatment will be measured from the time of first study drug 
administration until the date of the first subsequent therapy given to treat the iBCL. Data for 
subjects that have not received additional anti-neoplastic therapy will be censored at the date 
of last known contact. 
8.3.2.4 Safety Analysis 
Adverse events and serious adverse events will be reviewed internally on an ongoing basis to 
identify safety concerns. Safety summaries will include tabulations in the form of tables. The 
frequency of treatment-emergent AE’s will be summarized. Additional AE summaries will 
include AE frequency by AE severity and relationship to the study drug. 
AE’s requiring discontinuation of the study drug will be summarized separately, both overall 
and by AE severity and by relationship to the study drug. Clinically significant abnormal 
laboratory values will be summarized over study visits. 
8.3.2.5 Biomarkers 
Biomarker data will be collected on all subjects enrolled on study and examined for correlation 
of response to pembrolizumab in aggregate and within disease subtypes cohorts. Descriptive 
statistics will be used for hypothesis-generating endpoints.  
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 

 
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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-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. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Data and Safety Monitoring Plan 
Ongoing trial oversight is carried out by the Principal Investigator and study staff. These 
individuals will communicate on a regular basis to review recently acquired data and adverse 
events. The data recorded within the research charts and protocol database is compared with 
the actual data that is available from the medical record and/or clinical histories.  Data detailed 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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in the research case report forms includes the nature and severity of all toxicities, which are 
also reported as described above.   
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University 
of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, Fred Hutch Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or Fred Hutch 
employees unaffiliated with the conduct of the study.  Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data 
and Safety Monitoring Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) 
and the Fred Hutch/University of Washington Cancer Consortium Institutional Review Board 
(IRB).  The review committees evaluate accrual, adverse events, stopping rules, and adherence 
to the applicable data and safety monitoring plan for studies actively enrolling or treating 
patients.  The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects.  Approval of committees as 
applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state, and federal guidelines. 
10.2 Records 
Research staff under the supervision of the investigators will maintain case report forms and 
secured databases on the relevant clinical and laboratory data.  Records maintained in 
investigators' offices will be secured with access limited to study personnel. Authorization for 
access to medical records will be obtained from all patients in accordance with provisions of 
the Health Insurance Portability and Accountability Act (HIPAA). 
10.3 Regulatory Responsibilities of Sponsor-Investigator 
The Sponsor-Investigator will ensure that the study is conducted in accordance with all 
applicable institutional, state, and federal regulatory requirements, including, but not limited 
to: compliance with requirements for IRB and other regulatory approvals, monitoring 
responsibilities, reporting obligations, and compliance with standards for written informed 
consent from all patients entering the study. In addition, the investigator will ensure oversight 
of the study via data and safety monitoring as described above. 
 
 

 
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REFERENCES 
 
1. 
Martin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, et al. Outcome of 
deferred initial therapy in mantle-cell lymphoma. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2009;27(8):1209-13. 
2. 
Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al. Prediction 
of survival in follicular lymphoma based on molecular features of tumor-infiltrating 
immune cells. The New England journal of medicine. 2004;351(21):2159-69. 
3. 
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I 
safety and pharmacokinetic study of CT-011, a humanized antibody interacting with 
PD-1, in patients with advanced hematologic malignancies. Clinical cancer research : 
an official journal of the American Association for Cancer Research. 
2008;14(10):3044-51. 
4. 
Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. ASH 
Conference; 2014:291-. 
5. 
Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, et al. Safety and activity 
of PD1 blockade by pidilizumab in combination with rituximab in patients with 
relapsed follicular lymphoma: a single group, open-label, phase 2 trial. The lancet 
oncology. 2014;15(1):69-77. 
6. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
reviews Cancer. 2012;12(4):252-64. 
7. 
Glimelius B, and Lahn M. Window-of-opportunity trials to evaluate clinical activity of 
new molecular entities in oncology. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO. 2011;22(8):1717-25. 
8. 
Disis ML. Immune regulation of cancer. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2010;28(29):4531-8. 
9. 
Francisco LM, Sage PT, and Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunological reviews. 2010;236:219-42. 
10. 
Talmadge JE, Donkor M, and Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer metastasis reviews. 2007;26(3-4):373-400. 
11. 
Horning SJ, and Rosenberg SA. The natural history of initially untreated low-grade 
non-Hodgkin's 
lymphomas. 
The 
New 
England 
journal 
of 
medicine. 
1984;311(23):1471-5. 
12. 
Drobyski WR, and Qazi R. Spontaneous regression in non-Hodgkin's lymphoma: 
clinical and pathogenetic considerations. American journal of hematology. 
1989;31(2):138-41. 
13. 
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, 
PD-1 ligands, and other features of the tumor immune microenvironment with response 
to anti-PD-1 therapy. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2014;20(19):5064-74. 
14. 
Carbone DP, Socinski MA, Chen AC, Bhagavatheeswaran P, Reck M, and Paz-Ares 
L. A phase III, randomized, open-label trial of nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) versus investigator's choice chemotherapy (ICC) as first-line therapy for 
stage IV or recurrent PD-L1+ non-small cell lung cancer (NSCLC). ASCO Meeting 
Abstracts. 2014;32(15_suppl):TPS8128. 

 
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15. 
Gettinger SN, Shepherd FA, Antonia SJ, Brahmer JR, Chow LQM, Juergens RA, et al. 
First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced 
NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status. ASCO 
Meeting Abstracts. 2014;32(15_suppl):8024. 
16. 
Wang Q, Gao J, and Wu X. Pseudoprogression and hyperprogression after checkpoint 
blockade. International immunopharmacology. 2018;58:125-35. 
17. 
Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. 
Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated 
by Anti-PD-1/PD-L1. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2017;23(8):1920-8. 
18. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and non-Hodgkin lymphoma: the Lugano classification. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2014;32(27):3059-68. 
19. 
Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, et al. Rituximab 
extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: 
eastern cooperative oncology group protocol e4402. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2014;32(28):3096-102. 
20. 
Moreno BH, and Ribas A. Anti-programmed cell death protein-1/ligand-1 therapy in 
different cancers. British journal of cancer. 2015. 
21. 
Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. 
Follicular lymphoma international prognostic index. Blood. 2004;104(5):1258-65. 
 

 
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11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation  
11.3.1 The Lugano Response Classification: For FL and MZL (18) 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of 
the following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3* with or without a residual mass on 
5PS† 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
No extralymphatic sites of disease 

 
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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake 
    
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
 New lesions 
None 
None 
 Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial remission (all of the 
following) 
    Lymph 
nodes 
and 
extralymphatic 
sites 
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
 
At interim, these findings suggest responding disease 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 
 
At end of treatment, these findings indicate residual 
disease 
When no longer visible, 0 × 0 mm 
 
 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
    
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 
 New lesions 
None 
None 
 Bone marrow 
Residual uptake higher than uptake in normal marrow 
but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further evaluation with 
MRI or biopsy or an interval scan 
Not applicable 
No response or 
stable disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, 
extranodal lesions 
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met 

 
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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
    
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease requires at least 
1 of the following 
    
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
PPD progression: 
    
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
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 at 
least 2 cm from baseline 
New or recurrent splenomegaly 
    
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (eg, infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
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 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 

 
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• Abbreviations: 
5PS, 
5-point 
scale; 
CT, 
computed 
tomography; 
FDG, 
fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of 
a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, 
cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular 
to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
• 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). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable 
in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal 
lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be 
considered not measured. These sites include any nodes, nodal masses, and extranodal 
sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response, 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow 
activation as a result of chemotherapy or myeloid growth factors). 
† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > 
mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than  
11.4 FLIPI Scoring System (21) 
Patients diagnosed with FL are assigned points according to the following system; the sum of 
the points constitutes the FLIPI score: 
1. Age greater than 60 years 
2. Stage III or IV disease 
3. Greater than 4 lymph node groups involved 
4. Serum hemoglobin less than 12 g/dL 
5. Elevated serum LDH 
 
 
 

 
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11.5 Events of Clinical Interest Guidance Document: Version 5 
11.9.1 OVERVIEW 
The purpose of this appendix is to provide study sites with guidance on the identification and 
management of Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) 
program. 
Based on literature review, and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are the primary Event of Clinical Interest 
(ECI). Immune-related AEs are adverse events associated with the treatment of patients with 
immunotherapy treatments that appear to be associated with the immune therapy’s mechanism 
of action. Based on these potential irAEs, the sponsor has defined a list of specific adverse 
event terms (ECIs) that are selected adverse experiences that must be reported to Merck within 
2 business days from the time the Investigator/physician is aware of such an occurrence, 
regardless of whether or not the investigator/physician considers the event to be related to study 
drug(s). In addition, these ECIs require additional detailed information to be collected and 
entered in the study database. ECIs may be identified through spontaneous patient report and / 
or upon review of subject data. Table 1 provides the list of terms and reporting requirements 
for AEs that must be reported as ECIs for MK-3475 protocols. Of note, the requirement for 
reporting of ECIs applies to all arms, including comparators, of MK- 3475 clinical trials 
Given that our current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab. Therefore, any Grade 3 or higher event that the 
investigator/physician considers to be immune-related should be reported as an ECI regardless 
of whether the specific event term is in Table 1 and reported to Merck within 2 business days 
from the time the Investigator/physician is aware of such an occurrence. Adverse events that 
are both an SAE and an ECI should be reported one time as an SAE only, however the event 
must be appropriately identified as an ECI as well in in the database. 
Table 1: Events of Clinical Interest 
 Pneumonitis (reported as ECI if ≥ Grade 2)  
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
 Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic 
steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis
 Endocrine (reported as ECI)  
Type 1 diabetes mellitus (if new onset) 

 
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Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to
treat the AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP)
Idiopathic 
(or 
immune) 
Thrombocytopenia Purpura (ITP)
Disseminated 
Intravascular
Coagulation (DIC)
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
 Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or
 Infusion Reactions (reported as ECI for any grade)  
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 Neurologic (reported as ECI for any grade)  
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the
Uveitis 
Iritis 
 Renal (reported as ECI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose
modification or use of systemic steroids to treat the AE) 
 Skin (reported as ECI for any grade)  
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 Skin (reported as ECI if ≥ Grade 3)  
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Any rash considered clinically significant in the physician’s judgment 
 Other (reported as ECI for any grade)  
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor. The information collected should be 
entered into the narrative field(s) of the Adverse Event module in the database (please note, if 
narrative entry into the database is not available, please use the narrative text box on the 
1727/AER Form). If additional Medical History or Concomitant Medications are reported, the 
Medical History and Concomitant Medication modules in the database must be updated. 
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the 
physician is instructed to follow the ECI reporting guidance but does not need to follow the 
treatment guidance (below). Therefore, these recommendations should be seen as guidelines 
and the treating physician should exercise individual clinical judgment based on the patient. 
For any question of dose modification or other treatment options, the specific language in the 

 
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protocol should be followed. Any questions pertaining to the collection of this information or 
management of ECIs should be directed to your local Sponsor contact. 
 
Dose Modification/Discontinuation 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event. Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of 
treatment may be considered assuming the patient meets the criteria for resumption of 
treatment. 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to 
Merck within 2 business days regardless of attribution to study treatment. The AEs listed 
in this document and any event that meets the ECI criteria (as noted) in Table 1 or in the 
respective protocol (event term and Grade) must be reported regardless of physician-
determined causality with study medication and whether or not considered immune-related 
by the physician (unless otherwise specified). 
Physicians/study coordinators/designated site personnel are required to record these 
experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or 
on paper) and to provide supplemental information (such as medical history, concomitant 
medications, investigations, etc.) about the event. 
– Please refer to the Data Entry Guidelines (DEGs) for your protocol. 
– Please refer to protocol for details on reporting timelines and reporting of Overdose 
and Drug Induced Liver Injury (DILI). 
 
3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guidelines when 
an ECI is reported. 
 
3.1 Pneumonitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported 
to the Sponsor within 2 business days of the event: 
– Pneumonitis 
– Interstitial lung disease 

 
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– Acute interstitial pneumonitis 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered. 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection.  It is important that patients with a suspected diagnosis of pneumonitis 
be managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid 
treatment should not be delayed for a therapeutic trial of antibiotics. If an alternative 
diagnosis is established, the patient does not require management as below; however the AE 
should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider ID consult 
– Conduct an in-person evaluation approximately twice per week 
– Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge 
the patient develops a second episode of Grade 2 or higher pneumonitis. 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Hospitalize patient 
– Bronchoscopy with biopsy and/or BAL is recommended. 
– Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 
mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue 
additional anti-inflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, 
initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by 
a more prolonged taper and administer additional anti-inflammatory measures, as 

 
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needed 
– Add prophylactic antibiotics for opportunistic infections. 
 
3.2 Colitis 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor 
within 2 business days of the event: 
– Colitis 
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic 
– Gastrointestinal perforation 
– Intestinal obstruction 
– Necrotizing colitis 
– Diarrhea 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 2 
business days, abdominal pain, mucus or blood in stool): 
– Report as ECI 
– Hold pembrolizumab. 
– Symptomatic Treatment 
– For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with 
blood and/or mucus, 
– Consider GI consultation and endoscopy to confirm or rule out colitis 
– Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
– If symptoms worsen or persist > 3 days treat as Grade 3 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– Report as ECI 

 
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– Hold pembrolizumab. 
– Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 
hours) When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with 
diffuse and severe ulceration and/or bleeding. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory 
measures as described in the literature [5]. Discontinue additional anti-inflammatory 
measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 
days. If symptoms worsen during steroid reduction, initiate a retapering of steroids 
starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and 
administer additional anti-inflammatory measures as needed. 
Grade 4 events: 
– Report as ECI 
– Permanently discontinue pembrolizumab. 
– Manage as per Grade 3. 
 
3.3 Endocrine 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and 
should be reported to the Sponsor within 2 business days of the event: 
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism 
– Hypothyroidism 
– Thyroid disorder 
– Thyroiditis 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However, the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or 

 
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hyperthyroidism 
Grade 2-4 events: 
– Report as ECI if appropriate 
– Hold pembrolizumab 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Pituitary gland imaging should be considered (MRIs with gadolinium and selective 
cuts of the pituitary can show enlargement or heterogeneity and confirm the 
diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day. 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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
– Consultation with an endocrinologist may be considered. 
 
Hyperthyroidism and Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– Report as ECI if appropriate (see Table 1) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal 
insufficiency. 
– Therapy with pembrolizumab can be continued while treatment for the thyroid 
disorder is instituted. 
– 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. 
– Consultation with an endocrinologist may be considered. 
 

 
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Grade 3 hyperthyroidism events: 
– Report as ECI 
– Hold pembrolizumab. 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously 
followed by oral prednisone 1 to 2 mg/kg per day. 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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Manage as per Grade 3 
 
Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
The following AE terms are considered ECIs and should be reported to the Sponsor within 2 
business days of the event: 
– Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis 
(DKA) 
– Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA). 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt 
worsening of pre- existing diabetes associated with laboratorial evidence of beta cell failure. 
All attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), 
T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or 
poorly controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above 
criteria should be reported as ECIs regardless of etiology. The patients may present with 
hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic 
ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory 
evidence of metabolic acidosis, or low or undetected c-peptide. 
 
Course of Action 
T1DM should be immediately treated with insulin. 
T1DM or Grade 3-4 Hyperglycemia events: 

 
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– Report as ECI if appropriate (see Table 1) 
– Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of beta cell failure, and resume 
pembrolizumab when patients are clinically and metabolically stable. 
– 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. 
– Consultation with an Endocrinologist is recommended. 
– Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, 
and insulin may be obtained. 
 
3.4 Hematologic 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of 
systemic steroids to treat the AE, are considered an ECI and should be reported to the Sponsor 
within 2 business days of the event: 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 
– Haemolytic Uraemic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. 
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, 
haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to confirm the 
diagnosis. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab 
– Prednisone 1-2 mg/kg daily may be indicated 
– Consider Hematology consultation. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 

 
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Grade 3 events: 
– Report as ECI 
– Hematology consultation. 
– Hold pembrolizumab Discontinuation should be considered as per specific protocol 
guidance. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI 
– Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
 
3.5 Hepatic 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose 
modification or use of systemic steroids to treat the AE), are considered ECIs and should be 
reported to the Sponsor within 2 business days of the event: 
– Autoimmune hepatitis 
– Hepatitis 
– Transaminase elevations 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other hepatic diseases. However, the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient 
meets the laboratory criteria for potential DILI defined as: 
• 
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value 
that is greater than or equal to three times (3X) the upper limit of normal (ULN) and 
• 
An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
ULN and 
• 
At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
• 
As a result of within-protocol-specific testing or unscheduled testing. 

 
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Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a 
DILI event. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total 
bilirubin >1.5 to 3.0 times ULN. In the case of Gilbert’s syndrome where baseline 
bilirubin > 1.5 ULN, hold pembrolizumab when bilirubin > 1.5 to 3.0 times baseline 
level 
– Monitor liver function tests more frequently until returned to baseline values 
(consider weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns 
to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics 
for opportunistic infections, and resume pembrolizumab per protocol 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
– Permanently discontinue pembrolizumab for patients with liver metastasis who 
begin treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases 
≥50% relative to baseline and lasts ≥1 week. 
 
Grade 3 events: 
– Report as ECI 
– Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total 
bilirubin >3.0 times ULN. 
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic 
injury, if necessary 
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When 
symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg 
every 4 hours or prednisone at 1 to 2 mg/kg should be started and continued over no 
less than 4 weeks. 
– If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. 
Infliximab is not recommended due to its potential for hepatotoxicity. 
– Several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI 

 
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– Permanently discontinue pembrolizumab 
– Manage patient as per Grade 3 above 
 
3.6 Neurologic 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 2 business days of the event: 
– Autoimmune neuropathy 
– Demyelinating polyneuropathy 
– Guillain-Barre syndrome 
– Myasthenic syndrome 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However, the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Moderate (Grade 2) – consider withholding pembrolizumab. 
– Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab 
– Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or 
equivalent once per day. If condition worsens consider IVIG or other 
immunosuppressive therapies as per local guidelines 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
3.7 Ocular 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor 
within 2 business days of the event: 
– Uveitis 

 
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– Iritis 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported 
regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
– Discontinue pembrolizumab as per protocol if symptoms persist despite treatment 
with topical immunosuppressive therapy. 
 
Grade 3 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Hold pembrolizumab and consider permanent discontinuation as per specific 
protocol guidance. 
– Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Permanently discontinue pembrolizumab. 
– Treat with corticosteroids as per Grade 3 above 
 
3.8 Renal 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor 
within 2 business days of the event: 
– Nephritis 
– Nephritis autoimmune 
– Renal failure 
– Renal failure acute 

 
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Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids 
to treat the AE. 
All attempts should be made to rule out other causes such as obstructive uropathy, progression 
of disease, or injury due to other chemotherapy agents. A renal consultation is recommended. 
However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Hold pembrolizumab 
– Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
– Discontinue pembrolizumab 
– Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or 
equivalent once per day. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 
3.9 Skin 
Rash and Pruritus 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor within 2 business days of the event: 
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically 
significant, in the physician's judgment, should be treated as an ECI. Clinical 
significance is left to the physician to determine, and could possibly include rashes 

 
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such as the following: 
– rash with a duration >2 weeks; OR 
– rash that is >10% body surface area; OR 
– rash that causes significant discomfort not relieved by topical medication or 
temporary cessation of study drug. 
 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the Sponsor within 2 business days of the event: 
– Dermatitis exfoliative 
– Erythema multiforme 
– Steven’s Johnson syndrome 
– Toxic epidermal necrolysis 
Please note, the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine 
HCl). 
– Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– Hold pembrolizumab. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Permanently discontinue pembrolizumab. 
– Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 

 
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3.10 Immediate Evaluation for Potential Skin ECIs 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon 
as possible. Obtain appropriate consent for subject photographs if a consent form 
addendum is required by your IRB/ERC. 
– Take digital photographs of: 
o the head (to assess mucosal or eye involvement), 
o the trunk and extremities, and 
o a close-up of the skin lesion/rash. 
 
– If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
– The time/date stamp should be set in the 'ON' position for documentation purposes. 
– Photographs should be stored with the subject’s study records. 
– The Sponsor may request copies of photographs. The local study contact (e.g., CRA) 
will provide guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past 
Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the Medical History eCRF. 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the 
questions in Appendix 3 (Presentation of the Dermatologic Event) as a guide. This information 
should be summarized and entered in narrative format in the AE eCRF. Please use the available 
free-text fields, such as Signs and Symptoms. Note pertinent negatives where applicable to 
reflect that the information was collected. Any treatments administered should be entered on 
the Concomitant Medication eCRF. 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the 
Vital Signs eCRF. Perform standard laboratory tests (CBC with manual differential and serum 
chemistry panel, including LFTs). 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the Adverse 
Experience eCRF as part of the narrative. 
 

 
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F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
– For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
– For clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory 
or to a pathologist experienced in reviewing skin specimens. 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results. 
3.11 Other 
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 2 business days of the event: 
– Myocarditis 
– Pericarditis 
– Pancreatitis 
– Any additional Grade 3 or higher event which the physician considers to be immune 
related 
All attempts should be made to rule out other causes.  Therapeutic specialists should be 
consulted as appropriate. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– Withhold pembrolizumab. 
– Systemic corticosteroids may be indicated. 
– Consider biopsy for confirmation of diagnosis. 
– If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– Hold pembrolizumab 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or 
equivalent once per day. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab 
treatment may be restarted and the dose modified as specified in the protocol 

 
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Grade 4 events: 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or 
equivalent once per day. 
– Discontinue pembrolizumab 
 
3.12 Infusion Reactions 
The following AE terms, regardless of grade, are considered ECIs and should be reported to 
the Sponsor within 2 business days of the event: 
– Allergic reaction 
– Anaphylaxis 
– Cytokine release syndrome 
– Serum sickness 
– Infusion reactions 
– Infusion-like reactions 
 
Course of Action 
Refer to infusion reaction table in the protocol and below. 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 

 
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Infusion Reactions 
 
3.13 Follow-up to Resolution 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated 
with information regarding duration and clinical course of the event. Information obtained 
from the consulting specialist, including diagnosis, should be recorded in the appropriate AE 
fields. Free-text fields should be used to record narrative information: 
– Clinical course of the event 
– Course of treatment 
– Evidence supporting recovery 
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. 
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 with: 
Diphenhydramine 50 mg p.o. (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg p.o. 
(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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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– Follow-up to the clinical course 
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF. 
 
5.Events of Clinical Interest (ECI) – Reference Table 
 Pneumonitis (reported as ECI if ≥ Grade 2)  
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
 Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids 
to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis
 Endocrine (reported as ECI)  
Type 1 diabetes mellitus (if new onset) 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to
treat the AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP)
Idiopathic 
(or 
immune) 
Thrombocytopenia Purpura (ITP)
Disseminated 
Intravascular
Coagulation (DIC)
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
 Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or
 Infusion Reactions (reported as ECI for any grade)  
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 Neurologic (reported as ECI for any grade)  
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the
Uveitis 
Iritis 
 Renal (reported as ECI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose
modification or use of systemic steroids to treat the AE) 
 Skin (reported as ECI for any grade)  
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 Skin (reported as ECI if ≥ Grade 3)  

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Any rash considered clinically significant in the physician’s judgment 
 Other (reported as ECI for any grade)  
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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6. Past Medical History Related to Dermatologic Event 
 
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into 
the Medical History eCRF. 
 
1. Does the subject have any allergies? 
□ Yes □ No 
If yes, please obtain the following information: 
a. Any allergy to drugs (including topical or ophthalmic drugs)?  
□ Yes □ No 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, 
etc): 
_____________________________________________________________________
_________________________________________________________________ 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, 
etc.?  
□Yes □ No 
Describe the agent and type of allergic response: 
_____________________________________________________________________
_____________________________________________________________________ 
c. Any allergy to food? □ Yes □ No 
Describe the food and type of allergic response:  
_____________________________________________________________________
_____________________________________________________________________ 
Any allergy to animals, insects? □ Yes □ No 
Describe the allergen and type of allergic response:  
_____________________________________________________________________
___________________________________________________________________ 
Any other allergy? □ Yes □ No 
Describe the allergen and type of allergic response: 
_____________________________________________________________________
_____________________________________________________________________ 
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? 
□ Yes □ No 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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If so what kind?   
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No 
If so what kind?   
 
4. Is the current finding similar to a past experience? □ Yes □ No 
 
7. Presentation of the Dermatologic Event 
 
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key 
information should be summarized and entered on the Adverse Experience eCRF. Any 
treatments administered should be entered on the Concomitant Medication eCRF. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study 
drug? 
___________________________________________________________________________
___________________________________________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind?   
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry 
detergents, soap, personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind?   
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? 
□ Yes □ No 
If so what kind?   
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind?   
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind?   
 
7. Has the subject come into contact with any family or house members who are ill? 
□ Yes □ No 
If so what kind?   
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or 
rash (e.g. Molluscum Contagiosum)? □ Yes □ No 
9. Has the subject had recent sun exposure? □ Yes □ No 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 

 
Protocol v6.0 dated 21 July 2021 
 
 
 
 
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If so what kind?   
 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No 
iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No 
If so what kind?   
 
12. For the current rash, has the subject used any other medication, such as inhaled 
bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic 
corticosteroid? □ Yes □ No 
List medication(s) and dose(s)   
_____________________________________________________________________
_____________________________________________________________________ 
13. Is the rash pruritic (itchy)? □ Yes □ No 
 
8. Focused Skin Examination 
 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
Primary Skin Lesions Description 
Color:   
 
General description: 
_____________________________________________________________________
_____________________________________________________________________ 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
_____________________________________________________________________
_____________________________________________________________________ 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
_____________________________________________________________________
_____________________________________________________________________ 
Any associated signs on physical examination? 
_____________________________________________________________________
_____________________________________________________________________