Phase II Study of PET-Directed Frontline Therapy With Pembrolizumab and AVD for Patients With Classical Hodgkin Lymphoma
Phase: PHASE2
Conditions: Classical Hodgkin Lymphoma, Lymphocyte-Depleted Classical Hodgkin Lymphoma, Lymphocyte-Rich Classical Hodgkin Lymphoma, Mixed Cellularity Classical Hodgkin Lymphoma, Nodular Sclerosis Classical Hodgkin Lymphoma
Sponsor: Northwestern University

NU Study Number: NU 16H08 
Merck Study Number: 53957 
CONFIDENTIAL 
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Phase II study of PET-directed frontline therapy with pembrolizumab and AVD for patients with 
classical Hodgkin lymphoma 
 
Principal Investigator:  
Jane N. Winter, M.D.  
Northwestern University, Feinberg School of Medicine and the Robert H. 
Lurie Comprehensive Cancer Center, Division of Hematology/Oncology 
 
 
 
 
676 North St. Clair, Suite 850 Chicago, IL 60611 
 
 
 
 
Phone: (312) 695-4538  
Pager: (312) 695-9911 
 
 
 
 
Fax: (312) 695-6189 
 
 
 
 
Email: j-winter@northwestern.edu   
 
  
 
Sub-Investigator(s): 
 
Local Sub-investigators:  
 
 
 
 
Leo Gordon, M.D. 
 
 
 
 
Barbara Pro, M.D. 
Shuo Ma, M.D., Ph.D 
Reem Karmali, M.D. 
 
Andrew Evens, D.O., MSc 
Rutgers Cancer Institute of New Jersey 
195 Little Albany Street 
New Brunswick, NJ 08901  
Phone: (732) 235-5459  
Fax: (732) 448-7894 
Email: andew.evens@rutgers.edu   
Ranjana Advani, M.D. 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA  94305 
Phone: (650) 725-6456 
Email: radvani@stanford.edu 
 
 
Pamela Allen, M.D.  
Emory University School of Medicine   
1365 Clifton Road NE 
Atlanta, GA 30322  
Phone: (404) 718-1900 
 pamela.b.allen@emory.edu 
   
 
 
 
 
 
 
 
Collaborator(s):  
 
Kristy Wolniak, M.D.,Northwestern University, Department of Pathology  
 
 
 
 
Hatice Savas, M.D. Northwestern University, Department of Radiology 
Biostatistician: 
 
Denise Scholtens, Ph.D. Northwestern University, Biostatistics  
 
Study Intervention(s):  
Pembrolizumab, Keytruda  
 
IND Number: 
 
 
132372 
 
IND Holder: 
 
 
Jane Winter, MD 
 
Funding Source:  
Merck Pharmaceuticals 
 
Version Date: 
 
 
March 29, 2019 (Amendment 6) 
 
Coordinating Center:  
Clinical Trials Office 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern University 
676 N. St. Clair, Suite 1200 
Chicago, IL  60611 
Phone: (312) 695-0990 
 
 
 
 
www.cancer.northwestern.edu/research/clinical-trials-office/index.html
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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TABLE OF CONTENTSLIST OF ABBREVIATIONS...................................................................... 5 
STUDY SCHEMA ............................................................................................................................ 7 
STUDY SUMMARY ......................................................................................................................... 9 
1.0 
INTRODUCTION – BACKGROUND & RATIONALE ....................................................... 12 
1.1 
Disease Background...................................................................................................... 12 
1.2 
Intervention Background & Overview ............................................................................ 14 
1.3 
Rationale for the Current Study ..................................................................................... 15 
2.0 
OBJECTIVES & ENDPOINTS ........................................................................................... 18 
2.1 
Primary Objective .......................................................................................................... 18 
2.2 
Secondary Objectives .................................................................................................... 18 
2.3 
Exploratory Objectives ................................................................................................... 18 
3.0 
PATIENT ELIGIBILITY ...................................................................................................... 20 
3.1 
Inclusion Criteria ............................................................................................................ 20 
3.2 
Exclusion Criteria ........................................................................................................... 21 
4.0 
TREATMENT PLAN .......................................................................................................... 23 
4.1 
Overview ........................................................................................................................ 23 
4.2 
Treatment Administration .............................................................................................. 23 
4.2.1 
Pembrolizumab Induction .............................................................................................. 23 
4.2.3 
Pembrolizumab Consolidation ....................................................................................... 25 
4.3 
Toxicity Management & Dose Delays/Modifications ..................................................... 25 
4.4 
Concomitant Medications/Treatments ........................................................................... 30 
4.5 
Rescue/Supportive Care Medications & Lifestyle Guidelines ....................................... 31 
4.6 
Duration of Trial ............................................................................................................. 36 
5.0 
STUDY PROCEDURES ..................................................................................................... 38 
6.0 
RESPONSE ASSESSMENT ............................................................................................. 42 
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NU Study Number: NU 16H08 
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6.1 
Measurability of lesions ................................................................................................. 42 
6.2 
Lymphoma Response Criteria ....................................................................................... 42 
6.3 
FDG-PET/CT Guidelines ............................................................................................... 42 
6.4 
Endpoint assessment .................................................................................................... 43 
7.0 
ADVERSE EVENTS .......................................................................................................... 44 
7.1 
Adverse Event Monitoring ............................................................................................. 44 
7.2 
Definitions & Descriptions .............................................................................................. 45 
7.3 
Adverse Event Reporting ............................................................................................... 47 
7.4 
Other Events Requiring Expedited Reporting ............................................................... 49 
8.0 
DRUG INFORMATION ...................................................................................................... 51 
8.1 
Pembrolizumab .............................................................................................................. 51 
8.2 
Doxorubicin .................................................................................................................... 53 
8.3 
Vinblastine ..................................................................................................................... 54 
8.4 
DACARBAZINE ................................................................................................................. 56 
9.0 
CORRELATIVES/SPECIAL STUDIES .............................................................................. 57 
9.1 
Diagnostic Biopsy – Specimen Procurement & Shipping .............................................. 57 
9.2 
Biopsy Specimen Analysis ............................................................................................ 57 
9.3 
Peripheral Blood Correlatives ........................................................................................ 58 
9.4 
Specimen Banking ......................................................................................................... 58 
10.0 
STATISTICAL CONSIDERATIONS .................................................................................. 59 
10.1 
Evaluability ..................................................................................................................... 59 
10.2 
Sample Size and Accrual .............................................................................................. 59 
10.3 
Data Analyses Plans...................................................................................................... 60 
11.0 
STUDY MANAGEMENT .................................................................................................... 61 
11.1 
Institutional Review Board (IRB) Approval and Consent ............................................... 61 
11.2 
Amendments .................................................................................................................. 61 
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NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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11.3 
Registration Procedures ................................................................................................ 62 
11.4 
Instructions for Participating Sites ................................................................................. 62 
11.5 
Data Management and Monitoring/Auditing .................................................................. 62 
11.6 
Adherence to the Protocol ............................................................................................. 63 
11.7 
Investigator Obligations ................................................................................................. 63 
11.8 
Publication Policy ........................................................................................................... 63 
REFERENCES ............................................................................................................................... 65 
APPENDICES ................................................................................................................................ 69 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
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LIST OF ABBREVIATIONS 
 
AdEERS 
Adverse Event Expedited Reporting System 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
A(B)VD 
Adriamycin, (Bleomycin), Vincristine, Dacarbazine 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
cHL 
Classical Hodgkin Lymphoma 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DV 
Deauville 
EBV 
Epstein Barr Virus 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-Free Survival 
EORTC 
European Organization for Research and Treatment of Cancer 
ESR 
Erythrocyte Sedimentation Rate 
escBEACOPP 
Escalated Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin ®, 
Procarbazine, Prednisone 
FDG 
Fluorodeoxyglucose 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GHSG 
German Hodgkin Study Group 
HbsAg 
Hepatitis B Surface Antigen 
HCV  
Hepatitis C Virus 
HL 
Hodgkin Lymphoma 
H&PE 
History & Physical Exam 
IND 
Investigational New Drug 
INRT 
Involved-node Radiotherapy 
IPS 
International Prognostic Score 
irAE 
Immune-Related Adverse Event 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
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NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
NLPHL 
Nodular Lymphocyte Predominant Hodgkin Lymphoma 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 / PD-L1 
Programmed Death-Ligand 1 
PET-CT 
Positron Emission Tomography and Computed Tomography 
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
RFS 
Relapse-free Survival 
RT  
Radiotherapy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SJS 
Stevens-Johnson Syndrome 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TARC 
Thymus and Activation Related Chemokine 
TB 
Tuberculosis  
TEN 
Toxic Epidermal Necrosis 
TIL’s 
Tumor Infiltrating Lymphocytes 
UPIRSO 
Unanticipated Problems Involving Risks to Subject or Others 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 
 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
STUDY SCHEMA 
escBEACOPP
x2 +/- RTφ
(Follow-Up 
begins)
PET (+)
Pembrolizumab 
Initiation 
q3w x 3 doses
(1 cycle = 21 days)
AVD x2 cycles
(1 cycle = 28 days)
Stage I-II
Stage III/IV
AVD x2ж
cycles
escBEACOPP
x4 +/- RTφ
(Follow-Up 
begins)
Age < 60
Age ≥60
Follow-up*
Stage I-II
Stage III/IV
PET (-)
AVD x4
cycles
PET (+)
PET (-)
Pembrolizumab 
Consolidation₤
q3w x 1 year total
(1 cycle = 21 days)
Follow-up*
Total
<6 cycles ψ
Total 6 
cycles
Follow-up*
PET #2 †‡
PET #1 (Baseline) †‡
PET #3
End of Treatment
PET#4 or CTⱷ
PET (+)
PET (-)
AVD x2
cycles
AVD x2ж
cycles
PET (+)
PET (-)
AVD x4
cycles
AVD x4
cycles
Pembrolizumab Consolidation€
q3w x 2 years total 
(1 cycle = 21 days)
Follow-up*
Follow-up*
 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
†Biopsy in consenting patients and correlative studies to include: chromosome 9p24.1 alterations and PD-1 and PD-L1 
expression  
‡Correlative studies: Including flow cytometry, serum cytokines, and TARC    
*See Study Procedures for follow up. Patients with progressive disease will come off study. 
φ escalated BEACOPP recommended but not required per protocol 
ψ Patients ≥ age 60 unable to complete a total of 6 cycles of AVD chemotherapy due to poor tolerance 
€ Total pembrolizumab treatment: 3 cycles of induction + 32 cycles of consolidation 
₤ Total pembrolizumab treatment: 3 cycles of induction + 14 cycles of consolidation 
ⱷ All patients will have imaging 2-6 weeks after completing chemotherapy and prior to pembrolizumab consolidation (where 
applicable). Imaging will consist of a PET-CT (PET#4) for all patients except those with Stage I/II disease and a negative 
PET#3, who may have a diagnostic CT scan. 
ж Patients with bulky disease (a mass >10 cm) at baseline and a negative PET #3 may receive 4-6 cycles of AVD per investigator 
discretion 
 
 
 
 
 
 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
STUDY SUMMARY 
Title 
Phase II study of PET-directed frontline therapy with pembrolizumab 
and AVD for patients with classical Hodgkin lymphoma 
 
Version 
March 29th, 2019 (Amendment 6) 
Study Design 
This Phase II clinical trial will evaluate the use of pembrolizumab as 
frontline treatment of newly diagnosed Hodgkin lymphoma Stages I-IV 
followed by AVD. 
 
Patients will be treated with pembrolizumab at a flat dose of 200 mg 
every 3 weeks for 3 cycles followed by PET-CT to assess treatment 
response to pembrolizumab alone. Patients will then be treated with AVD 
chemotherapy for 4-6 cycles.  
 
Additional consolidation pembrolizumab will be given in elderly patients 
(≥ 60 years old ) after chemotherapy who either:  
1. Have a Deauville score of 4 or 5 following interim PET-CT (PET #3; 
32 additional doses ), OR  
2. Have a Deauville score of 1-3 following interim PET-CT (PET#3) and 
receive less than the intended 6 cycles of AVD chemotherapy for 
stage III/IV disease because of poor tolerance (14 additional doses). 
Study Center(s) 
Robert H. Lurie Comprehensive Cancer Center 
Rutgers Cancer Institute of New Jersey 
Stanford University Medical Center 
Emory University 
Objectives 
Primary Objective: To assess the rate of complete response (CR) to 
single-agent pembrolizumab induction among patients with cHL  
 
Secondary Objectives: 
1. To evaluate the safety and tolerability of pembrolizumab with 
AVD in the frontline treatment of patients with cHL. 
2. Determine the PFS and OS of the group as a whole. 
3. Determine the predictive value of FDG uptake, using a semi-
quantitative approach (eg, Deauville score), after pembrolizumab 
induction, and after subsequent chemotherapy. 
Exploratory Objectives: 
Assess value of tissue biomarkers and T-cell subsets as 
predictors of response to pembrolizumab. 
 
Sample Size 
Up to 30 patients; (for 26 evaluable) enrolling concurrently 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
Diagnosis & Key 
Eligibility Criteria 
Inclusion Criteria 
• 
Histologically confirmed, classical Hodgkin lymphoma (cHL) 
• 
Patients with Stage III and IV disease may have any International 
Prognostic Score (IPS) 
• 
Patients with Stage I and II disease must have at least one 
NCCN unfavorable risk factor (see Appendix D)  
• 
Age ≥18 
• 
Previously untreated disease (except for one week or less of 
corticosteroids). 
• 
ECOG performance status 0, 1. 
• 
Adequate organ and marrow function 
Exclusion Criteria  
• 
Prior chemotherapy for cHL  
• 
Concurrent active malignancy that is life-limiting  
• 
Interstitial lung disease or idiopathic pulmonary fibrosis 
• 
Uncontrolled intercurrent illness  
• 
Active infection or autoimmune disease   
Treatment Plan 
For all patients, PET-CT will be performed prior to treatment (PET#1). 
Treatment will commence with pembrolizumab at 200 mg, flat dosing, 
intravenously, every three weeks for three total doses, followed by re-
staging of disease with PET-CT (PET#2).  All patients will then be treated 
with 2 cycles of AVD followed by PET#3. Subsequent therapy will then be 
based on age, stage, and results of this PET-CT (PET#3). 
 
Younger patients (<60 years old): 
 
• 
Stage I/II:  Those with negative PET#3 (DV Score 1-3) proceed to 
2 additional cycles of AVD (4 cycles permissable for bulky 
masses per investigator discretion) For those with a Deauville 
Score (DV) of 4-5, it is recommended that they receive 2 cycles 
of escBEACOPP +/- RT at investigator discretion. 
 
• 
Stage III/IV: Patients with negative PET#3 (DV Score of 1-3) will 
receive 4 cycles of AVD as tolerated to complete a total of 6 
cycles of AVD. It is recommended that those with a Deauville 
Score (DV) of 4-5 receive 4 cycles of escBEACOPP +/- RT at 
investigator discretion. 
 
 
Elderly patients (≥60 years old): 
 
• 
Stage I/II: Following PET#3, all patients will receive 2 additional 
cycles of AVD (4 total cycles) regardless of Deauville score with 
the option for 4 additional cycles or six total for those with bulky 
disease, per investigator discretion. Those with Deauville 1, 2, or 
3 (PET#3)  will then continue to followup. Those with  Deauville 4 
or 5, should receive consolidation treatment with pembrolizumab 
for 2 years total (3 doses in induction + 32 doses in 
consolidation).  
 
• 
Stage III/IV: Following PET#3, all patients will receive 4 additional 
cycles of AVD (6 total cycles) regardless of Deauville score. 
Those  with  Deauville 4 or 5 (PET#3) should receive 
consolidation treatment with pembrolizumab for 2 years total (3 
doses in induction + 32 doses in consolidation). Those with 
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NU Study Number: NU 16H08 
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Deauville 1, 2, 3 (PET#3) will continue to follow-up if they receive 
all 6 AVD doses successfully. If they were unable to receive the 
full intended 6 cycles of chemotherapy for stage III/IV disease 
because of poor tolerance, they should receive consolidation with 
pembrolizumab for up to 1 year (3 doses in initiation + 14 doses 
in consolidation).  
 
 
Total Study Duration: 9 weeks of initiation therapy with pembrolizumab + 
16-24 weeks of chemotherapy + consolidation for up to 96 weeks (select 
elderly patients) + 2 years of follow-up  
 
Statistical Methodology 
The treatment paradigm of this trial will be considered worthy of further 
evaluation if at least 40% of patients achieve CR at PET#2 (defined as 
Deauville 1-3).  In order to have 84% power to detect an increase from 
the historical control of 20% rates of CR for patients with rel/ref cHL 
treated with pembrolizumab, at a one-tailed alpha of 10%, approximately 
26 evaluable patients will be required total. The accrual goal is 30 
patients to account for possible unevaluable patients.  
 
 
 
 
 
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NU Study Number: NU 16H08 
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1.0 INTRODUCTION – BACKGROUND & RATIONALE 
 
1.1 
Disease Background 
Classical Hodgkin Lymphoma (cHL) has an excellent prognosis with 5-year progression free 
survival exceeding 75-80%1,2. In spite of many advances in the field, elderly patients continue 
to have inferior outcomes compared to their younger counterparts, with 5-year relapse-free-
survival (RFS) estimates ranging from 30-50%3-5. Reasons for the disproportionately inferior 
outcomes have been postulated. Elderly patients tend to have higher risk baseline features6, 
treatment related toxicity, and subsequently significantly fewer elderly patients receive the 
intended full doses of chemotherapy6,7. Young patients, though often cured from their disease, 
may also suffer late effects from therapy reducing their length and quality of life. As such, 
multiple efforts have focused on identifying more tolerable treatment combinations or de-
escalation of therapy, particularly those with favorable disease characteristics. Some 
approaches to limiting toxicity include the elimination of bleomycin from upfront treatment8, 
treatment with an abbreviated course of chemotherapy9, as well as combining novel drugs with 
more tolerable side effects. One such class of drugs that has demonstrated promise and 
tolerability in cHL includes checkpoint inhibitors. The advent of immunotherapy has transformed 
the therapeutic landscape, changing the standard of care across the field and raising questions 
of how best to utilize and assess response to this novel class of drugs. Checkpoint inhibitors, 
such as pembrolizumab, have shown efficacy and tolerability in relapsed Hodgkin lymphoma, 
however their efficacy in the frontline setting combined with chemotherapy has not been 
studied. 
 
1.1.1 
Treatment of Early Stage HL’s 
60% of patients with newly diagnosed HL have early stage disease (stage I/II), and the 
majority are classified as non-bulky disease10. Patients may be further classified as 
“favorable” or “unfavorable” based on additional factors including bulky disease, B 
symptoms, erythrocyte sedimentation rate (ESR), and number of lymph node regions 
involved. There are 4 major prognostic systems, with the German Hodgkin Study 
Group (GHSG) providing the most stringent criteria. Standard treatment for patients 
with early stage favorable disease consists of ABVD (Adriamycin, bleomycin, 
vinblastine, dacarbazine) with or without involved field radiotherapy11,12. Patients with 
favorable disease by the stringent GHSG criteria represent a particularly good 
prognostic group that may be treated with only two cycles of ABVD followed by 20 GY 
of involved field radiotherapy (IFRT).  Additional studies have supported the use of 
radiation free approaches13. In particular, the HD.6 study demonstrated that patients 
with a complete response (CR) by CT scan after 2 cycles of chemotherapy had 
exceptional outcomes with 4 cycles of ABVD alone. Further analysis of individual 
patient data from HD.6, HD10, and HD11 using comparison in the ABVD alone arms 
further supported a chemotherapy alone approach in patients achieving a CR by CT 
after 2 cycles of therapy. Thus the standard of care for non-bulky, early favorable HL 
responding after 2 cycles of therapy is ABVD for 4 cycles without radiation therapy.  
Further radiation-free approaches were assessed in patients with early-stage Hodgkin 
lymphoma, included the RAPID-UK14, and CALGB 5020315 studies. These trials also 
looked at the utility of PET in predicting response to therapy, and PET-adapted 
approaches, further improving the predictive value of interim scans using the more 
sensitive FDG-PET. The need to reduce radiation exposure in those with favorable 
disease was further highlighted by a recent publication in the New England Journal of 
Medicine16 which showed that risks of radiation persisted even 30 years after 
treatment. Of further concern, despite changes in radiation techniques long-term 
radiation toxicity did not decrease in the more contemporary cohort. 
 
1.1.2 
Treatment of elderly HL:  
There are no standard treatment recommendations for elderly HL patients (defined as 
age ≥ 60), and prospective studies assessing novel treatment options in this population 
are limited. Two prospective trials for older HL were recently reported. The first 
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compared VEPEMB (vinblastine, cyclophosphamide, procarbazine, etoposide, 
mitoxantrone and bleomycin) to ABVD17, while the second compared COPP-ABVD and 
BEACOPPbaseline18. Unfortunately, neither trial improved upon ABVD as the standard of 
care, and the results with VEPEMB were overall disappointing. While ABVD remains an 
option, bleomycin lung toxicity is a particular concern in elderly patients3,19,20. Evens 
and colleagues reported the incidence of bleomycin lung toxicity (BLT) in the elderly 
was 32%, with an associated mortality rate of 25%. Similarly, The Mayo Clinic reported 
an incidence of BLT of 33% for patients > age 40 years compared with 11% for 
younger patients21. Efforts aimed at eliminating bleomycin in early-favorable HL22, 
showed decreased local control when bleomycin was omitted, however long term 
survival was not compromised and rates exceeded 98%.   
 
1.1.3 
Role of FDG-PET 
3-Fluorodeoxyglucose-positron emission tomography (PET) has become a standard 
imaging modality complementing CT scans in the management of HL23-26. PET has 
been studied in both early and advanced stage disease, as a prognostic tool, as well as 
a means to direct therapy. CALGB 5020315 enrolled 104 HL patients with stage I/II, 
non-bulky disease. PET-CT was performed after 2 cycles of ABVD. Positivity was 
defined as Deauville score of 4-5. Eighty-one percent of patients were PET negative 
after 2 cycles of chemotherapy, and 2-year PFS for PET-2 negative and positive 
patients was 88 and 54%, respectively. Although PFS was lower than other early stage 
HL trials, this was partially explained by the presence of older and higher risk patients; 
72.1% of patients were unfavorable by the EORTC criteria. The prognostic implications 
of early negative PET were also confirmed in advanced-stage HL27. Moreover, PET-2 
superseded IPS in prognostic importance. Building on this prognostic data, recent 
studies have incorporated PET-directed therapy to identify patients who may be treated 
with a limited number of cycles of chemotherapy. The RAPID-UK study included a total 
of 602 patients with non-bulky early stage HL.  The primary endpoint of the study was 
to assess the non-inferiority of no further treatment, given a negative PET-CT after 
three cycles of ABVD. PET positivity was defined as a Deauville score of 1-2. Patients 
with a positive PET were treated with an additional cycle of chemotherapy and 30 Gy of 
IFRT, while those with a negative PET were randomized to no further treatment or 30 
Gy of IFRT.  Results demonstrated that 75% of patients had negative PET (Deauville 1-
2). The 3-year overall survival rate was exceeded 97% in both groups, with a non- 
significant rate ratio of 0.51 in favor of no further therapy (p = 0.27). Although the study 
did not meet its primary endpoint of non-inferiority, it demonstrated that patients with 
favorable disease and a negative PET after three cycles have excellent short-term 
outcomes with 3 cycles of ABVD alone. However, long-term data is lacking, and the 
majority of patients (65-75%) were favorable by the most stringent GHSG criteria, 
including 75% of the group with a negative PET.  This is a population that otherwise 
would be eligible for treatment with 2 cycles of ABVD and 20Gy of IFRT according to 
HD1011.  
 
The H10 Trial (EORTC/LYSA/FIL)28 assessed PET-intensification in early stage 
disease. Although the initial study was terminated early due to a pre-specified early 
stopping rule, updated results presented at the Lugano meeting29 demonstrated that 
patients with a positive PET2 had improved outcomes (PFS) from intensification to 
escalated BEACOPP chemotherapy followed by involved-node radiotherapy (INRT) 
compared to standard ABVD and INRT, with a 13% overall improvement in 5 year PFS. 
Preliminary reports from studies assessing a PET – adapted approach in advanced 
stage disease are encouraging as well [Johnson et al. RATHL Study CRUK/07/033 
Lugano 2015]30.  Several key issues regarding PET response-adapted therapy need to 
be considered including consistent definitions of PET-negativity versus positivity. 
Studies assessing PET-adapted treatment intensification are encouraging, but more 
data is needed to assess the efficacy of this approach. Furthermore, the implications of 
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a negative PET following novel therapies and in particular immunotherapy are not 
clear.  
 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
 
1.2 
Intervention Background & Overview 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as 
both molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells.  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
 
 
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1.2.1 
Preclinical and Clinical Trial Data 
Please refer to the Investigator’s Brochure for more detailed information regarding 
Preclinical and Clinical data. 
 
PD-1 antibodies have demonstrated clinical activity in HL in the relapsed and refractory 
setting. Dr. Ansell and colleagues demonstrated the single agent activity of nivolumab 
in a group of patients with heavily pre-treated relapsed/refractory HL31. They conducted 
a phase 1 study of hematologic malignancies including 23 patients with cHL treated 
continuously with nivolumab for 2 years or until disease progression.  Results 
demonstrated a high rate of response; 87% objective response, 17% complete 
response, and 86% PFS at 24 weeks. Drug related adverse events were reported in 18 
patients (78%) including: rash (in 22%) and a decreased platelet count (in 17%). Drug-
related grade 3 adverse events, which were reported in 5 patients (22%), included the 
myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal 
inflammation, thrombocytopenia, an increased lipase level, a decreased lymphocyte 
level, and leukopenia. There were no drug-related grade 4 or 5 adverse events.  
 
Pembrolizumab demonstrated equally impressive response rates in the preliminary 
results from the phase 1b study, KEYNOTE-01332, which assessed the single agent 
activity of Pembrolizumab in patients with classical Hodgkin lymphoma after 
brentuximab vedotin failure. Treatment consisted of pembrolizumab 10mg/kg 
administered intravenously every 2 weeks until confirmed tumor progression, excessive 
toxicity, or completion of 2 years of therapy.  The results of 15 patients were reported 
who were evaluable at the 12-week time point. Patients were heavily pre-treated and 
67% had also failed a prior autologous stem cell transplant. There were no serious 
adverse events, and only one patient experienced a grade 3-5 events. 3 patients (20%) 
had a CR at 12 weeks, 5 additional patients had a partial remission (33%), for an 
overall response rate of 53%. 4 patients had progressive disease (27%), however all of 
these actually experienced a decrease in their overall tumor burden. The authors 
concluded that pembrolizumab showed safety and efficacy in a heavily pretreated 
population including patients who progressed after transplantation who generally have 
limited additional treatment options. 
 
1.3 
Rationale for the Current Study 
cHL is unique among lymphoid malignancies in that the malignant RS-cell are relatively rare, 
whereas the bulk of the tumor is composed of an extensive but ineffective inflammatory 
infiltrate33. The low ratio of tumor to immune and inflammatory cells suggests an underlying 
mechanism inducing anti-immunity, and furthermore, that activation of the senescent t-cells 
could represent an effective means of controlling the disease.  
 
The PD-1 PD-L1 ligand system impairs immune response to tumors. PD-1 is up regulated in 
HL, specifically in the malignant RS-cell, and PD-1 is markedly elevated in tumor-infiltrating T 
cells of HL34. Chemitz et al demonstrated that PD-1 signaling has an inhibitory effect on T-cell 
response in HL35.  Epstein Barr Virus (EBV), commonly associated with HL, increases PDL-1 
expression on tumor cells, and increases binding of PD-L-1 to PD-1 on T-cells leading to t-cell 
exhaustion36 . Blockade of the PD-1/PD- ligand pathway restores the cytotoxic function of tumor 
infiltrating T-cells, as assessed by increased IFN-gamma production34. In addition to EBV 
induced amplification of the PDL-1 pathway, Green et al. demonstrated a genetic origin for this 
increased expression in HL. Amplification of 9p24.1 was demonstrated in RS-cell of nodular-
sclerosing HL33. Increased gene expression led to increased expression of PD-1, PDL-1, PD-
L2, and JAK2. Increased activation of the JAK-STAT pathway through JAK2 signaling induced 
further increases in PDL-1 transcription.  
 
The genetic overexpression of markers in the PD pathway suggest tumor dependence on this 
pathway to escape immune surveillance, and that mechanisms aimed at blocking this pathway 
could allow immune activation and control of disease. 
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Amendment 6: March 29th, 2019 
 
 
1.3.1 
Rationale for the Trial and Selected Subject Population 
Based on this accumulated data, we propose a Phase II trial to evaluate the safety and 
efficacy of pembrolizumab followed by PET-directed combination chemotherapy, for 
patients with previously-untreated cHL. We propose evaluation of patients with stage I-
IV disease including elderly patients. 
 
Elderly patients have poor tolerance and outcomes with standard chemotherapy. By 
specifically assessing the elderly cohort, we hope to improve the efficacy and 
tolerability of frontline therapy in a group that otherwise employs a disparate prognosis. 
In this group bleomycin will be omitted, and pembrolizumab will be given both prior to 
AVD, as well as following AVD as consolidation. In the young cohort, we predict that 
the increased efficacy of pembrolizumab added to AVD will improve rates of CR as 
assessed on interim FDG-PET, and thus reduce the total number of patients requiring 
radiation therapy. By avoiding radiation in this cohort we hope to reduce the rates of 
late effects of therapy and second malignancies. Our strategy of administering anti-PD-
1 therapy upfront prior to chemotherapy will allow us to assess the rates of CR on PET-
CT scan which will further increase our understanding of the prognostic significance of 
PET-CT scans with this novel class of agents in HL. 
 
1.3.2 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  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 
MK-3475 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 MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 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).  This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and 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 MK-3475 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 observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 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 MK-3475 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. 
 
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17 
Amendment 6: March 29th, 2019 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors 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. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing 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. 
 
 
1.3.3 
Rationale for Endpoints 
 
 
Efficacy Endpoints 
Our primary endpoint is to assess rate of complete response following pembrolizumab 
alone. Among those patients whose disease has failed frontline treatment, as well as 
treatment with brentuximab vedotin (BV), pembrolizumab has shown dramatic activity, 
with a 53% overall response rate (ORR), 20% rate of CR, and disease regression in 14 
of 15 patients37. We predict an improvement in CR rate of 50% to pembrolizumab alone 
as assessed by PET-CT prior to initiation of chemotherapy among patients treated in 
the frontline setting. 
 
 
 
Exploratory Studies 
The mechanism of suppression of the anti-tumor response is well understood for the 
PD-1 pathway36,38. Utilization of PD-1 blockade in solid malignancies has revealed 
changes in the T-cell lymphocytic subset consistent with on-target effects of anti-PD-1 
agents39. Prior clinical trials for the PD-1 inhibitor, nivolumab, included correlates 
investigating biomarkers of response. Correlative studies in participating patients 
demonstrated copy-number gains in PDL1 and PDL2 and increased expression of 
these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated 
STAT3, indicative of active JAK-STAT signaling. Interestingly, tumor infiltrating T- cells 
expressed low levels of PD-1 on immunohistochemical analysis. Overall, levels of PD-1 
expression were not significantly predictive of response, in contrast to studies in solid 
tumors, where this seems to be more predictive of response. The author’s postulated 
PD-1 blockade may selectively enhance the function of CD8+ T cells with low levels of 
PD-1 expression. 
 
 
In addition to PD-1 and PD-L1 expression, multiple lines of evidence support the 
evaluation of different biomarkers for patients with cHL treated with PD-1 blockade.  
Serum receptors/cytokines CD30, CCL17, and CCL22, may have prognostic value with 
respect to PFS and OS among patients with cHL40.  Moreover, CD8+ T-cell density, 
along with PD-1+ and PD-L1+ tumor/T-cell expression/density, may predict for activity 
of pembrolizumab41,42. And clinical data have shown that PD-1 inhibition yield 
significant increases in number of host PD-L1-bearing activated T-cells43.  These data 
suggest that baseline tumor features, as well as dynamic host features, may be 
important predictors of response to pembrolizumab. Furthermore, a recent abstract by 
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NU Study Number: NU 16H08 
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18 
Amendment 6: March 29th, 2019 
Moscowitz et al44 demonstrated cysteine-cysteine thymus and activation related 
chemokine (TARC) as a biomarker for response and PET normalization in HL after 
treatment with BV. This biomarker warrants additional investigation. 
  
2.0 OBJECTIVES & ENDPOINTS 
 
2.1 
Primary Objective  
Objective: Assess the percent of patients who achieve a complete response (CR) to single-
agent pembrolizumab induction, among patients with cHL using Lugano 2014 criteria, as 
measured at PET#2. 
 
Hypothesis:  We hypothesize that frontline pembrolizumab, followed by FDG-PET-directed 
combination chemotherapy, will produce excellent efficacy.  We predict a CR rate of 50% to 
pembrolizumab alone as assessed by PET-CT prior to initiation of chemotherapy. Furthermore, 
the addition of standard chemotherapy utilizing an age and stage-adjusted approach will result 
in an increased number of patients with PET-negativity at interim PET, and the ability to limit 
the number of cycles of chemotherapy, and further reduce the need for radiation therapy, 
thereby minimizing acute and chronic toxicity.   
 
2.2 
Secondary Objectives  
Objective: Assess the safety and tolerability of pembrolizumab in combination with 
chemotherapy in the frontline setting. 
 
Hypothesis: The combination of pembrolizumab with AVD as frontline treatment will be well 
tolerated. Furthermore, the addition of standard chemotherapy utilizing an age and stage-
adjusted approach will result in an increased number of patients with PET-negativity at interim 
PET, and the ability to limit the number of cycles of chemotherapy, and further reduce the need 
for radiation therapy, thereby minimizing acute and chronic toxicity 
 
 
Objective:  Determine the extent of FDG uptake, using a semi-quantitative approach (eg, 
Deauville score), after pembrolizumab induction, and after subsequent chemotherapy. 
 
Hypothesis:  The percentage of patients with a Deauville score of 1-2 after pembrolizumab 
alone will be 50%. The percentage of patients with a Deauville score of 1-2 following two cycles 
of chemotherapy will exceed 75%. 
 
2.3 
Exploratory Objectives 
Exploratory objectives will assess the value of tissue biomarkers as predictors of response to 
pembrolizumab, including the following: 
 
• 
To characterize PD-1 pathway specific expression and correlate with response 
• 
To characterize serum biomarkers of immune, inflammatory response and other 
biomarkers during treatment 
• 
To characterize levels of soluble PD-L1 related to treatment with pembrolizumab 
• 
To characterize T-lymphocyte subset changes to treatment with pembrolizumab 
• 
To investigate the prevalence and clinical correlation of chromosome 9p24.1 alterations  
for this population 
• 
Assess cysteine-cysteine thymus and activation related chemokine (TARC) as a 
biomarker for response and PET normalization 
 
Each enrolled patient will provide a fresh tissue biopsy sample if available from the biopsy 
performed for diagnosis, or an archived sample as agreed upon by the PI for additional marker 
expression analysis. Peripheral blood will be obtained at specified time points for serum marker 
analysis.  
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PD-1 Pathway Marker Expression 
Tissue sample slides from the baseline biopsy will be evaluated by immunohistochemistry for 
expression of PD-1 and PD-L1 on either malignant cells or within the tumor microenvironment. 
Samples will be deemed either positive or negative for marker expression. Presence/absence 
(binary) of PD-1 and PD-L1 will be correlated with response to pembrolizumab and clinical 
outcomes. 
 
 
Immune and Inflammatory Markers 
Peripheral blood will be tested for serum levels of TNF-α, IFN-γ, IL-2, galectin-1, TGF-β, IL-10, 
IL-13, and indoleamine 2 3-dioxygenase (IDO). Testing will be performed using commercially 
available kits. Levels will be compared from specified time points through treatment. 
 
 
Soluble PD-L1 
Peripheral blood obtained at day 1 of cycle #1 then at the off-treatment visit will be analyzed by 
a commercially available ELISA assay (USCN Life Sciences – product number SEA788Hu). 
Levels will be compared to evaluate for a change (increase/decrease) following treatment with 
pembrolizumab. 
 
 
Lymphocyte Subset Changes 
The endpoint is whether or not a patient is a lymphocyte subset responder. Responders are 
defined as either a) a 50% increase or b) a half standard deviation increase in lymphocyte 
subsets. Lymphocyte subsets will be evaluated by flow cytometry on peripheral blood obtained 
at specified time points through the treatment period41-43. Flow cytometry analysis will include 
the following surface markers: CCR7, CD3, CD4, CD8, CD14, CD16, CD20, CD25, CD45RO, 
CD56, CD57, CD62L, CD107a, CD127, FoxP3, B7-H1 (PD-L1), B7-DC (PD-L2), HLADR, and 
PD-1. The following intracellular markers will be evaluated: TIA1, granzyme, perforin. We will 
complete an 8-10 color flow cytometry analysis to properly group biomarkers for determination 
of specific lymphocyte populations. Two specific lymphocyte populations will be evaluated: 
CD4+CD25+PD-L1+ T lymphocytes and CD4+CD62L+CD127+ T lymphocytes. Lymphocyte 
subsets are continuous measurements in cells/μL. 
 
 
Chromosome 9p24.1 Alterations 
Tissue sample slides from the baseline biopsy will be evaluated by FISH break-apart probes for 
mutations at chromosome 9p24.1. Presence of amplifications. Frequency and magnitude 
of 9p24.1 alterations-polysomy, copy gain, and amplification will be determined. We will also 
assess the association of 9p24.1 alterations with clinical parameters, including stage (early 
stage I/II favorable risk, early stage unfavorable risk, advanced stage (AS, III/IV) and 
progression-free survival (PFS), as well as age. 
 
 
TARC Thymus and Activation-Regulated Chemokine/CCL17 (TARC) 
Patients will have TARC assessed prior to therapy utilizing patient’s serum. TARC will be 
measured using a commercially available double antibody sandwich ELISA. Elevation of TARC 
has been associated with decreased response to chemotherapy and an increased inflammatory 
environment. We will correlate pre-treatment TARC levels with PET responses and assess for 
changes in TARC levels after treatment with immunotherapy. 
 
 
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20 
Amendment 6: March 29th, 2019 
3.0  
PATIENT ELIGIBILITY 
The target population for this study is patients with Hodgkin lymphoma. This will be a multicenter trial 
conducted at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 
Northwestern University will serve as the lead site and coordinating center for this study. Participating 
sites will include Rutgers Cancer Institute, Memorial Sloan Kettering Comprehensive Cancer Center, 
and Emory University. 
 
A total of 26 evaluable subjects will be needed for this trial (therefore up to 30 may be enrolled in order 
to achieve this goal). Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Jane Winter at (312) 695-4538, or to the local PI at each participating site. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers are 
not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be registered 
to the study. Study treatment may not begin until a subject is registered. Please refer to Section 11.3 for 
complete instructions regarding registration procedures. 
 
3.1 
Inclusion Criteria 
3.1.1 
Patients must have a histologically confirmed diagnosis of classical Hodgkin lymphoma 
including nodular sclerosis, mixed cellularity, lymphocytic-rich, and lymphocyte 
depleted subtypes by the 4th edition of the WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues published in 2008 (NLPHL excluded).45 
 
3.1.2 
Patients must have measurable disease by the Lugano Criteria (Appendix C). 
 
3.1.3 
Patients must have previously untreated disease (except for one week or less of 
corticosteroids). 
 
3.1.4 
Patients must be age ≥ 18 years. 
 
3.1.5 
Patients must exhibit a/an ECOG performance status of 0-1. 
 
3.1.6 
Stage III and IV patients may any International Prognostic Score (IPS). 
 
3.1.7 
 Stage I and II patients must have at least one NCCN unfavorable risk factor (see 
Appendix D). 
 
3.1.8 
Patients must have adequate organ and bone marrow function within 14 days prior to 
registration, as defined below:  
• 
leukocytes  
 
≥ 3,000/mcL 
• 
absolute neutrophil count 
≥ 1,500/mcL 
• 
platelets 
 
 
≥ 100,000/mcl 
• 
total bilirubin 
 
within normal institutional limits 
• 
AST(SGOT)/ALT(SPGT) 
≤ 2.5 X institutional upper limit of normal (ULN) 
• 
creatinine  
 
within normal institutional limits 
 
Platelet transfusions are acceptable prior to treatment to achieve the above numbers, 
however growth factors are not allowed within 14 days of registration. 
 
3.1.9 
Females of child-bearing potential (FOCBP) and males must agree to avoid becoming 
pregnant, or impregnating a partner, respectively, by complying with any of the 
approved contraception techniques (see section 4.5.2) prior to registration, for the 
duration of study participation, and for 120 days following completion of therapy. 
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. Should a female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
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NOTE: Male patients will be considered of non-reproductive potential if they have 
azoospermia. Female patients will be considered of non-reproductive potential if they 
are either: 
(1) post-menopausal (defined as at least 12 months with no menses without  
an alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
 
3.1.10 FOCBP must have a negative pregnancy test within 7 days prior to registration on 
study. NOTE: a negative pregnancy test is also required within 3 days prior to first dose 
of pembrolizumab and therefore may need to be repeated if screening test is more than 
3 days prior to first dose. 
 
3.1.11 Patients must have the ability to understand and the willingness to sign a     written 
informed consent prior to registration on study. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients are not eligible who have had prior chemotherapy, targeted small molecule 
therapy, or radiation therapy prior to registration. 
NOTE:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
3.2.2 
Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days prior to 
registration are not eligible. 
 
3.2.3 
Patients who have a known history of active TB   (Bacillus Tuberculosis) are not 
eligible. 
 
3.2.4 
Patients must not have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to pembrolizumab. 
 
3.2.5 
Patients who have an uncontrolled intercurrent illness including, but not limited to any 
of the following, are not eligible:  
• 
Symptomatic congestive heart failure (ejection fraction lower than institutional lower 
limit of normal [LLN] 
• 
Unstable angina pectoris 
• 
Cardiac arrhythmia 
 
3.2.6 
Patients who have a known additional malignancy that is progressing or requires active 
treatment are not eligible.  NOTE: Exceptions include basal cell carcinoma of the skin 
or squamous cell carcinoma of the skin that has undergone potentially curative therapy 
or in situ cervical cancer. 
 
3.2.7 
Patients who have known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis are not eligible.  
 
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Amendment 6: March 29th, 2019 
NOTE: Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to registration.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
 
3.2.8 
Patients who have active autoimmune disease that has required systemic treatment in 
the past 2 years are not eligible (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).  
NOTE: Replacement therapy (e.g. Thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
 
3.2.9 
Patients who have a history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis are not eligible. 
 
3.2.10 Patients who have an active infection requiring systemic therapy are not eligible, except 
for uncomplicated urinary tract infections. 
 
3.2.11 Patients are not eligible who have 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.   
 
3.2.12 Patients who have known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial are not eligible. 
 
3.2.13 Patients may not be pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, from registration through 120 days 
after the last dose of trial treatment. 
 
3.2.14 Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent are not eligible. 
 
3.2.15 Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) are not eligible. 
 
3.2.16 Patients who have active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected) are not eligible. 
 
3.2.17 Patients who received a live vaccine within 30 days of planned start of study therapy 
are not eligible. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine. 
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. 
 
 
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NU Study Number: NU 16H08 
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23 
Amendment 6: March 29th, 2019 
4.0 TREATMENT PLAN 
 
4.1 
Overview 
Patients with de novo classical Hodgkin lymphoma with any stage disease will be 
eligible for participation. All patients must have a baseline PET-CT prior to treatment 
(PET#1). Treatment will be divided into three phases: 
• 
Pembrolizumab “lead in” for 3 cycles (21-days each) followed by PET-
CT (PET#2) 
• 
Standard chemotherapy: 
AVD for 2 cycles (28 days each) followed by interim PET-CT (PET#3) 
followed by AVD for an additional 2-4 cycles (depending on age, stage, 
and PET-CT results: 2 cycles** for Stage I/II and 4 cycles for Stage 
III/IV). Patients <60 years old with positive PET-CT (PET #3, Deauville 4, 
5) will NOT receive additional AVD, and may receive escBEACOPP at 
investigator’s discretion (x2 cycles for Stage I/II and x4 cycles for Stage 
III/IV) with an option for consolidative radiotherapy. 
**Patients with bulky disease (>10 cm) at baseline and a negative PET 
#3 may receive a total of 4-6 cycles of AVD per investigator  discretion 
• 
Pembrolizumab consolidation for up to 2 years total treatment (3 
doses in induction + 32 or 14 doses in consolidation) in select patients 
≥60 years old who have either positive PET#3 or advanced stage 
disease and receive less than the intended 6 cycles of AVD because of 
poor tolerance. 
PET/CT completed at the timepoints outlined above will be reviewed centrally. See 
Section 6.3.1 for central review requirements.  
 
4.2 
Treatment Administration 
 
4.2.1 
Pembrolizumab Induction  
All patients will receive 3 cycles of pembrolizumab starting cycle 1 day 1. 
Pembrolizumab should be administered on Day 1 of each 21-day cycle after 
all procedures/assessments have been completed as detailed on the Study 
Procedures Table (Section 5.0).  Pembrolizumab 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. This treatment will be followed by an investigational PET/CT 
(PET#2), 3 weeks after completion of cycle 3 (+/- 3 days). 
 
Pembrolizumab 200 mg will be administered as an approximately 30 minute 
IV infusion on day 1 of each 21-day cycle.  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. 
 
Patients will receive pre-treatment acetaminophen 650 mg po and 
diphenhydramine 50 mg po given 30 minutes prior to the pembrolizumab 
infusion. Pembrolizumab 200 mg IV in 50 mL of 0.9% NaCl will be infused 
over 30 minutes on day 1 of each 21 day cycle. 
 
4.2.2 
Standard Chemotherapy 
 
 
4.2.2.1 Cycle 1 & 2: AVD chemotherapy post pembrolizumab “lead in”  
Treatment should be administered on day 1 of each 28 day cycle 
after all procedures/assessments have been completed as detailed 
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on the Study Procedures Table (Section 5.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
 
Doxorubicin (Adriamycin) 25 mg/m2, vinblastine 6 mg/ m2, and 
dacarbazine 375mg/ m2 will be on day 1 and 15 of a four week cycle. 
 
• 
All patients will receive treatment with 2 cycles of AVD.  
• 
Treatment will commence 21 days after final dose of induction 
pembrolizumab, but not prior to PET #2 (+/- 3 days). Treatments 
will be on days 1 and 15 of a 28-day cycle.  
• 
PET-CT (PET#3) should occur on day 117-120, or day 26-29 of 
AVD cycle 2 as listed in section 5.0.  
 
AVD supportive care measures 
Pre-medications: 
We recommend patients receive pre-treatment with acetaminophen 
650 mg po and diphenhydramine 50 mg po given 30 minutes prior to 
AVD as per institutional protocol. 
 
 
 
Prophylactic antibiotics: 
Prophylactic antibiotic use (e.g., Levaquin, nystatin) is at the 
discretion of the treating physician.  
 
Growth factor protocol: 
In elderly patients granulocyte colony stimulating factor (e.g., G-CSF) 
is recommended and in accordance with ASCO guidelines. Please 
record all granulocyte (or erythrocyte) colony stimulating factors on 
the treatment forms. 
 
4.2.2.2 Cycle 3-6: AVD (or escBEACOPP) 
4.2.2.2.1 For those with a negative PET #3 
For all patients with a negative PET #3, additional AVD 
should commence 4 weeks after day 1 cycle 2 of AVD (after 
PET#3). Patients will receive a total of 4-6 cycles 
depending on stage and tolerability. 
a. Patients with stage I/II disease should receive two 
additional cycles of AVD for a total of 4 cycles of AVD. 
Patients with bulky disease (>10 cm mass) at baseline 
and a negative PET #3 may receive 4-6 cycles of AVD 
per investigator discretion. 
b. Patients with stage III/IV disease should receive four 
additional cycles of AVD for a total of 6 cycles of AVD  
 
4.2.2.2.2 For those with a positive PET #3 (Deauville 4,5) 
 
PET- Adapted Treatment for patients <60 with positive 
PET#3: 
Patients age <60 with Deauville score of 4-5 on PET#3 may 
transition to escBEACOPP  (escalated bleomycin, 
etoposide, doxorubicin, cyclophosphamide, vincristine) +/- 
radiation therapy (RT) at the investigators’ discretion 
a. Patients with stage I/II disease may transition to 2 
cycles of escBEACOPP +/- RT 
b. Patients with stage III/IV disease may transition to 4 
cycles of escBEACOPP +/- RT 
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Amendment 6: March 29th, 2019 
c. Patients with progressive/relapsed disease as defined 
in section 6.1.2.1 will be taken off study. 
 
Patients 60 or older with a Deauville score of 4, 5 positive 
PET #3 will continue on AVD for a total of four- six cycles of 
AVD, depending on stage and tolerability.  
 
  
4.2.2.2.3 Repeat Imaging (PET#4 or CT Scan) 
All patients will have repeat imaging 2-6 weeks after 
completing chemotherapy and prior to pembrolizumab 
consolidation (where applicable). Imaging will consist of a 
PET-CT (PET#4) for all patients except those with Stage I/II 
disease and a negative PET#3, who may have a diagnostic 
CT scan. 
 
 
4.2.3 
Pembrolizumab Consolidation 
Patients who are ≥60 may receive pembrolizumab consolidation (either 14  
or 32 additional doses) if they fall into the categories below: 
• 
Elderly patients with any stage disease with a positive PET #3 (Deauville 
4, 5) will proceed to pembrolizumab consolidation at a dose of 200mg IV 
flat dose every 21 days for 2 years total treatment (3 induction doses + 
32 consolidation doses). 
• 
Patients with stage III/IV disease with a negative PET #3 who  receive < 
the planned 6 cycles of AVD therapy will proceed to pembrolizumab 
consolidation at a dose of 200mg IV flat dose every 21 days for up to 1 
year total treatment (3 induction doses + 14 consolidation doses). 
• 
In patients receiving consolidation therapy, pembrolizumab should 
commence 4 weeks after day 1 of the final cycle of AVD. For patients in 
remission having received fewer than six full cycles of AVD, patients may 
be followed with CT scans every three months during consolidation.  For 
other patients receiving consolidation, PET/CT is recommended every 3 
months during consolidation therapy until negative. Once PET-CT is 
negative, CT’s should be obtained every three months during 
consolidation. 
4.3 
Toxicity Management & Dose Delays/Modifications 
Any patient who receives at least one dose of study therapy will be evaluable for 
toxicity endpoints. Each patient will be assessed for the development of toxicity 
according to the timeframe referenced in the Schedule of Events table. Toxicity will 
be assessed according to the CTCAE (version 4.03)  
 
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 PI 
and approved by DSMC. The reason for interruption should be documented in the 
appropriate eCRF. Once subjects resume treatment, they will continue with the full 
number of planned cycles of therapy (i.e. treatments will be delayed not skipped). 
 
4.3.1 
Pembrolizumab Dose Modifications 
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 4.1 below. See 
Section 4.5.3 for supportive care guidelines, including use of corticosteroids. 
 
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Table 4.1: Dose Modification Guidelines for Pembrolizumab-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. 
4. 
For signs or symptoms of Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), withhold 
pembrolizumab and refer the patient for specialized care for assessment and treatment. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.03) 
Action taken 
to pembro 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs 
and symptoms of pneumonitis 
• Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid treatment 
• Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
• Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
• Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
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Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin replacement 
therapy for participants 
with T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
• Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• Monitor for signs and 
symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per standard 
of care 
• Monitor for signs and 
symptoms of thyroid disorders.  
 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• Monitor changes of renal 
function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE administer 
corticosteroids  
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuatio
n include and 
not limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy 
or achieved metabolic control (in case of T1DM).   
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4.3.2 
AVD Dose Modifications 
Dose delays and reductions of AVD chemotherapy only are to be done at the 
discretion of the treating physician and must be clearly documented on the 
Treatment eCRF in NOTIS along with the CTCAE (version 4.03) grade. 
Delays of greater than 5 weeks from the last dose due to AVD toxicity must 
be approved by the PI, and the QAM must be included on this 
correspondence. The following are only recommendations (are not 
mandatory) for modifications for AVD; pembrolizumab modifications are 
mandatory and are described above in Table 4.2.  
 
Table 4.2: AVD Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Grade/Description 
Doxorubicin 
Vinblastine 
Dacarbazine 
Hematologic Toxicities 
Thrombocytopenia 
Grade 1 or 2 
Maintain dose 
level. 
Maintain dose 
level 
Maintain dose level. 
Grade 3 or 4 
Transfuse to 
maintain platelets 
>20 
Transfuse to 
maintain platelets 
>20 
Transfuse to 
maintain platelets 
>20 
Neutropenia* 
Grade 1-3 
(without fever) 
Maintain dose 
level. 
Maintain dose 
level 
Maintain dose level. 
Grade 3  (ANC 
500-1000) w/ fever 
or Grade 4 (ANC 
<500) 
Patients with 
severe persistent 
neutropenia, 
especially despite 
use of granulocyte 
growth factor, 
could have a 
reduction of 
doxorubicin and 
vinblastine by 
25%. 
Patients with 
severe persistent 
neutropenia, 
especially 
despite use of 
granulocyte 
growth factor, 
could have a 
reduction of 
doxorubicin and 
vinblastine by 
25%. 
Maintain dose level 
Non-hematologic Toxicities 
Allergic reaction or 
hypersensitivity 
≤ Grade 3 
Hold dose until 
resolved to ≤ 
Grade 1 & then 
resume at same 
dose level. 
Hold dose until 
resolved to ≤ 
Grade 1 & then 
resume at same 
dose level. 
Hold dose until 
resolved to ≤ Grade 
1 & then resume at 
same dose level. 
Grade 4 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Gastrointestinal 
Grade 3-4 oral 
ulceration or 
diarrhea 
 
 
 
Hold 
chemotherapy 
until symptoms 
clear, then may 
reinstate at 75% 
full dose. Doses 
may be re-
escalated as 
tolerated. 
Hold 
chemotherapy 
until symptoms 
clear, then may 
reinstate at 75% 
full dose. Doses 
may be re-
escalated as 
tolerated. 
Hold chemotherapy 
until symptoms 
clear, then may 
reinstate at 75% full 
dose. Doses may be 
re-escalated as 
tolerated. 
Grade 4 
constipation 
N/a 
Decrease dose 
by 50%, then re-
escalate on a 
vigorous bowel 
regimenϕ 
N/a 
Hepatotoxicity+ 
Bilirubin > 1.5 <3.0 
50% dose 
reduction 
50% dose 
reduction 
Maintain dose level 
Bilirubin ≥ 3.0<5.0 
75% dose 
reduction 
75% dose 
reduction 
Bilirubin > 5 
 
Omit doxorubicin, 
may consider 
substituting 
cyclophosphamide 
Hold therapy and 
investigate cause 
Hold therapy and 
investigate cause 
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Transaminases 
2-3x ULN 
25% dose 
reduction 
Maintain dose 
level 
No dose adjustment 
specified, follow 
institutional 
guidelines 
Transaminases  
> 2-3x ULN 
50% dose 
reduction 
Maintain dose 
level 
Hold and investigate 
the cause 
Infection 
≥ Grade 3 
Hold dose until systemic treatment for infection is complete. If 
no neutropenia, resume at same dose level.  If neutropenic, 
follow instructions above (hematologic section). 
Hepatitis B** 
reactivation 
Any grade 
If the hepatitis B virus DNA level rises during this monitoring, 
management should be reviewed with an appropriate specialist 
with experience managing hepatitis and consideration given to 
halting chemotherapy. 
Neuropathy 
Grade 2 w/ pain or 
Grade 3 
Maintain dose 
level 
Consideration for 
50% dose 
reduction 
Maintain dose level 
Grade 4 (severe 
motor neuropathy) 
N/a 
Permanently 
discontinue 
vinblastine 
n/a 
Renal dysfunction 
CrClcr 46-60 
mL/minute 
Maintain dose 
level 
Maintain dose 
level 
Administer 80% of 
dose 
CrCLcr 31-45 
mL/minute 
Maintain dose 
level 
Maintain dose 
level 
Administer 75% of 
dose 
CrClcr  <30 
mL/minute 
No dose 
adjustment per 
protocol, consult 
with a pharmacist 
No dose 
adjustment per 
protocol, consult 
with a pharmacist 
Administer 70% of 
dose 
Cardiac toxicity¥ 
If LVEF below the 
institutional lower 
limit of normal and 
at least a 5% 
absolute decrease 
from the baseline 
LVEF value 
OR 
Any absolute 
decrease of ≥15% 
from the patient’s 
baseline value 
Hold drug: If LVEF 
improves back to 
baseline prior to 
the next 
doxorubicin and/or 
if an arrhythmia 
has been 
controlled, 
doxorubicin may 
be administered if 
it is felt by the 
managing 
physician to be in 
the best interest of 
the patient. 
n/a 
n/a 
Pulmonary 
Any Grade 
n/a 
n/a 
n/a 
* Routine use of growth factors is not recommended in patients receiving bleomycin. Leukopenia is not a factor for delay of 
treatment or reduction of dose intensity in patients receiving bleomycin. Also, if drug dose is reduced due to hematologic 
toxicity, full dose should be resumed when blood counts return to normal. 
** All lymphoma patients should be tested for both HbsAg and HbcoreAb. If either test is positive, such patients should be 
treated with lamiVUDine during chemotherapy and for six months afterwards. Such patients should also be monitored with 
frequent liver function tests and hepatitis B virus DNA at least every two months.  
+ May give full dose with recovery of bilirubin < 1.5, Gilberts disease is not included. 
Φ Vinblastine may cause severe hypomotility with constipation or ileus. Inform patients prior to administration and advise the 
patient to maintain regular bowel function. 
¥  Doxorubicin may result in congestive heart failure. MUGA scans (or echocardiogram) should be repeated routinely s/p cycle 
4 of AVD as described in the Schedule of Activities, or earlier and more frequently, if clinically indicated.  
 
 
 
 
Hematologic Toxicity 
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For absolute neutrophil count of <500 on the day of treatment, addition of G-
CSF (filgrastin) therapy should be considered. This is strongly preferred due 
to the long half-life of pegfilgrastim. 
 
Growth factors may be used prophylactically. Additionally, patients with 
severe persistent neutropenia, especially despite use of granulocyte growth 
factor, could have a reduction of doxorubicin and vinblastine by 25%. 
 
 
 
Other Considerations: 
There may be other toxicities whereby the treating physician believes it 
would be ‘best medical practice’ to dose reduce a particular chemotherapy 
agent. This should be discussed with the study PI on a case-by-case basis 
and the QAM should be included on all such correspondence. 
 
 
 
Chemotherapy intolerance 
If any of the above grade 3 or 4 non-hematologic toxicities or grade 4 
hematologic toxicities last > 2 weeks or if the severe toxicity is ‘recurrent’, the 
patient may be deemed “chemotherapy intolerable” and stop further 
chemotherapy. This designation should be discussed with the study PI. In 
addition, this designation may be applicable for any other grade 3 or 4 non-
hematologic toxicities not listed above and it is deemed by the treating 
physician that the patient should not continue further chemotherapy. 
Chemotherapy intolerable patients may still proceed with consolidation 
pembrolizumab therapy if they have achieved either a PR or CR at time of 
chemotherapy intolerable designation. These patients should have repeat 
staging CT scans performed prior to initiation of pembrolizumab 
consolidation therapy. 
 
4.4 
Concomitant Medications/Treatments 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial and are listed in section 4.5.2.  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 final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject’s primary physician.  
 
4.4.1 
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 appropriate eCRF 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 eCRF. 
 
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 for the purpose of toxicity 
management beyond 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7. 
 
4.4.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
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• 
Investigational agents other than pembrolizumab 
• 
Patients requiring radiation therapy (except as specified in the protocol 
for those age < 60 with a Deauville score of 4-5 on interim PET/CT 
(PET#3)) will be taken off study.   
• 
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 during and within 1 week of treatment for any 
purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.   
NOTE: The use of physiologic doses of corticosteroids may be approved 
after consultation with the PI. 
NOTE: Dexamethasone is permitted as a pre-medication only during 
AVD chemotherapy.  
 
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. 
 
4.5 
Rescue/Supportive Care Medications & Lifestyle Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating investigator. Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined 
below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be 
applied when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 
4.4 for dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 
 
Pneumonitis:  
• 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
• 
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 
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Amendment 6: March 29th, 2019 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
• 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
• 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.   
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
• 
For T1DM or Grade 3-4 Hyperglycemia 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
Hypophysitis: 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
• 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
• 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
• 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
• 
Grade 3-4 hyperthyroidism, treat with an initial dose of IV corticosteroid followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
• 
Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
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33 
Amendment 6: March 29th, 2019 
 
 
4.5.1 
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 (MK-
3475). 
 
Table 4.3 Pembrolizumab Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 33rticarial 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
 
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34 
Amendment 6: March 29th, 2019 
 
 
4.5.2 
Management of Cardiac Toxicities  
During treatment with pembrolizumab, patients will be closely monitored for 
cardiac toxicities. For patients with evidence of congestive heart failure, 
myocardial infarction, cardiomyopathy, or myositis, cardiac evaluation should 
take place including lab tests and cardiology consultations as clinically 
indicated including ECG, CPK, troponin, and ECHO. 
 
Pembrolizumab dosing should be modified according to Table 4.5.  
Table 4.4 – Management of Cardiac Toxicities 
Cardiac *  
Management/Next Dose for Pembrolizumab Cardiac 
Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.** 
Evaluate for signs and symptoms of CHF, ischemia, 
arrhythmia or myositis. Obtain history EKG, CK (for 
concomitant myositis), CK-MB. Repeat troponin, CK 
and EKG 2-3 days. If troponin and labs normalize may 
resume therapy. If labs worsen or symptoms develop 
then treat as below. Hold pending evaluation  
Grade >2 with 
suspected 
myocarditis 
Hold dose.** Admit to hospital. Cardiology consult. 
Rule out MI and other causes of cardiac disease. 
Cardiac Monitoring. Cardiac Echo. Consider cardiac 
MRI and cardiac biopsy. Initiate high dose 
methylprednisolone. If no improvement within 24 hours, 
add either infliximab, ATG or tacrolimus. Consult 
algorithm for more details. Resume therapy if there is a 
return to baseline and myocarditis is excluded or 
considered unlikely. 
Grade >2 with  
confirmed  
myocarditis 
Off protocol therapy. Admit to CCU (consider transfer 
to nearest Cardiac Transplant Unit). Treat as above. 
Consider high dose methylprednisolone  
Add ATG or tacrolimus if no improvement. Off 
treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”  
Note: The optimal treatment regimen for immune mediated myocarditis has not 
been established. Since this toxicity has caused patient deaths, an aggressive 
approach is recommended.  
 
 
4.5.3 
Diet/Activity/Contraception/Other Considerations 
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab has transient adverse effects on the 
composition of sperm.  For this trial, male subjects will be considered to be of 
non-reproductive potential if they have azoospermia (whether due to having 
had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are 
either:  
(1) post-menopausal (defined as at least 12 months with no menses 
without  
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an alternative medical cause; in women < 45 years of age a high 
follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 
weeks prior to screening;  
OR 
(3) has a congenital or acquired condition that prevents 
childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid 
becoming pregnant or impregnating a partner, respectively, while receiving 
study drug and for 120 days after the last dose of study drug by complying 
with one of the following:   
 
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during 
heterosexual activity.   
 
Acceptable methods of contraception are‡:  
• 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
• 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in 
conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used 
together) 
• 
hormonal contraceptive: oral contraceptive pill 
(estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory 
agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, 
35rticar-thermal, post-ovulation methods, etc.) and withdrawal are not 
acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during 
the study.  In order to participate in the study subjects of childbearing 
potential must adhere to the contraception requirement (described above) 
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36 
Amendment 6: March 29th, 2019 
from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 
120 days after the last dose of trial therapy.  If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements 
for contraception, that subject should not be entered into the study. 
 
4.5.4 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with 
pembrolizumab, the subject will immediately be removed from the study. The 
site will contact the subject at least monthly and document the subject’s 
status until the pregnancy has been completed or terminated. The outcome 
of the pregnancy will be reported to the PI and to Merck without delay, and 
within 24 hours to the PI and within 2 working days to Merck if the outcome is 
a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn).   
 
The treating investigator will make every effort to obtain permission to follow 
the outcome of the pregnancy and report the condition of the fetus or 
newborn to the PI.   If a male subject impregnates his female partner the 
study personnel at the site must be informed immediately and the pregnancy 
reported to the PI and to Merck and followed as described above and in 
Section 7.3.5.2 
 
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. 
 
4.6 
Duration of Trial 
4.6.1 
Duration of Therapy 
Patients will be treated with 3 cycles of pembrolizumab (9 weeks) followed by 
AVD for 4-6 cycles (4-6 months) followed by pembrolizumab consolidation 
(selected patients) for up to 2 total years of pembrolizumab.  
 
4.6.2 
Duration of Follow Up 
Once patients are off treatment for any reason, they will have a final off-
treatment visit approximately 30 days post-last dose of study therapy. 
Thereafter, they will be followed with at least one clinic visit every 3 months 
for up to 2 years from end of treatment. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event.  
 
For patients who undergo allogeneic stem cell transplant (SCT) within 2 
years of study treatment, transplant parameters and adverse events will be 
recorded as detailed in section 4.6.3. 
 
4.6.3 
Subject Withdrawal/Discontinuation Criteria from Treatment and/or  
 
Overall Study 
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 if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other 
safety reasons. Specific details regarding discontinuation or withdrawal are 
provided in Table 4.1. 
 
A subject must be discontinued from the trial for any of the following reasons: 
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37 
Amendment 6: March 29th, 2019 
• 
Patient voluntarily withdraws from treatment (follow-up permitted) 
• 
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent (no follow-up permitted). 
• 
Confirmed radiographic disease progression 
• 
Note: For unconfirmed radiographic disease progression, please see 
Section 5.1.6 
• 
Unacceptable toxicity/adverse experiences as described in Section 4.4 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject (i.e. continuation not in the 
patient’s best interest) 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Patient develops a second malignancy that requires treatment which 
would interfere with this study 
• 
Noncompliance or inability to comply 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 5 
(Protocol Flow Chart). After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment as. Subjects who 
discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a 
non-study cancer treatment, withdrawing consent or becoming lost to follow-
up.  After documented disease progression each subject will be followed by 
telephone for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
 
Patients who undergo allogeneic transplant will be monitored for adverse 
events. For subjects who have an allogeneic SCT within 24 months of last 
study treatment, transplant parameters will be collected and specific events 
will be collected for 18 months from the date of the allogeneic transplant to 
include graft-versus-host-disease (acute and/or chronic), veno-occlusive 
disease, febrile syndrome (a steroid-requiring febrile illness without an 
infectious cause), and encephalitis, for all grades, and regardless of 
relationship to study drug.   Additional medically important adverse events 
post-allogeneic SCT may be submitted at the Investigator’s discretion. 
If available and relevant to an event post-allogeneic SCT, concomitant 
medications and/or laboratory results may also be reported. 
 
4.6.4 
Patient Replacement 
Any patient who is registered to the study and then withdrawn without 
receiving any study treatment may be replaced. Any patient who completes 
fewer than 2 total cycles of therapy and is withdrawn for any reason except 
PD or toxicity will still be considered evaluable for toxicity endpoints; 
however, for the purpose of efficacy endpoints, another patient may be 
added; if the maximum accrual of 30 is reached without achieving the 26 
evaluable necessary for evaluation of efficacy, an increase to the accrual 
goal may be requested with the approval of the Data and Safety Monitoring 
Committee (DSMC) at Northwestern University. No follow-up is required for 
patients that withdrew and did not receive any study treatment. 
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38 
Amendment 6: March 29th, 2019 
5.0  STUDY PROCEDURES 
 
Trial Period: 
Screening Phase 
Treatment Cycles1 
Off Rx 
Surveillance 
Treatment Cycle/Title: 
Main Study 
Screening  
Pembrolizumab 
PET #2 
AVD2,3 
PET #3 
 
AVD3,4 
Post-Chemo Assessment 
Pembrolizumab5 
Discont 
Survival Follow-Up 
1 
2 
3 
1-2 
 
4-35 
 
 
3-66 
Scheduling Window (Days): 
Within 28 days of 
registration 
1 
± 3 
22 
± 3 
43 
± 3 
64 ± 3 
120 ± 3 
2-4 weeks after last 
dose of 
chemotherapy ± 3 
 30 days after last 
dose (pembro or 
AVD, ±5 days) 
Every 12 weeks  
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
Trial Treatment Administration 
 
x 
x 
x 
 
x 
 
x 
 
x 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
x  
x 
Survival Status7 
 
 
 
 
 
 
 
 
 
 
 
x 
Clinical Procedures/Assessments 
Review Adverse Events 
 
x 
x 
x 
 
x 
 
x 
 
x 
X20 
X20 
Physical Examination 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
Vital Signs8 Weight and Height24 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
ECOG Status9 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
Echocardiogram/MUGA  
x 
 
 
 
 
 
 
X21 
 
 
 
 
Unfavorable risk factors/IPS10 
x 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum 
β-HCG 
x22 
x22 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
x 
 
 
 
 
 
 
 
 
 
 
 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
39 
Amendment 6: March 29th, 2019 
Trial Period: 
Screening Phase 
Treatment Cycles1 
Off Rx 
Surveillance 
Treatment Cycle/Title: 
Main Study 
Screening  
Pembrolizumab 
PET #2 
AVD2,3 
PET #3 
 
AVD3,4 
Post-Chemo Assessment 
Pembrolizumab5 
Discont 
Survival Follow-Up 
1 
2 
3 
1-2 
 
4-35 
 
 
3-66 
Scheduling Window (Days): 
Within 28 days of 
registration 
1 
± 3 
22 
± 3 
43 
± 3 
64 ± 3 
120 ± 3 
2-4 weeks after last 
dose of 
chemotherapy ± 3 
 30 days after last 
dose (pembro or 
AVD, ±5 days) 
Every 12 weeks  
CBC with ANC11 
x11 
x 
x 
x 
 
x3 
 
x3 
 
x 
x 
 
Comprehensive Serum Chemistry 
Panel11 
x11 
x 
x 
x 
 
x3 
 
x3 
 
x 
x 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH12 
x 
 
 
x 
 
 
 
 
 
x 
 
 
ESR 
x 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B, Hepatitis C13 
x 
 
 
 
 
 
 
 
 
 
 
 
Quantiferon-gold TB blood test25 
x25 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
PET-CT14 
x14 
 
 
 
x14 
 
x14 
 
X15 
x16 
x15 
 
CT scan17 
x 
 
 
 
 
 
 
 
 
x23 
x 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood performed by CENTRAL laboratory  
Archival or Newly Obtained 
Tissue Collection18 
x 
x18 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection19 
 
x 
 
 
 
x 
 
 
 
 
x 
 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
40 
Amendment 6: March 29th, 2019 
1 Treatment cycle of pembrolizumab defined as 21 days, Treatment cycle of AVD defined as 28 days with treatment on days 1 and 15 
2 Interim assessment by FDG-PET #2 for primary endpoint assessment on day 64 +/- 3 days 
3Labs including CBC w/ANC and comprehensive chemistry panel, physician visit with physical examination and vital signs to be performed on day 1 of each cycle of AVD. 
4 Interim assessment by FDG-PET #3 for PET-directed therapy on day 117-120 prior to AVD cycle 3  
5 Elderly patients may receive consolidation for a total of up to 1 or 2 years pembrolizumab treatment. Elderly patients who do not achieve CR after additional AVD will have pembrolizumab 
consolidation for up to 32 additional doses. Elderly patients with Stage III/IV disease who achieve CR after <6 cycles AVD will receive pembrolizumab consolidation for up to 14 
additional doses. See section 4.2.3 for details.    
6 See study schema in 1.2 
7 Patients will be followed (either by routine clinic visit or by phone call) for survival every 12 weeks (±7 days) for 2 years from the last dose of study drug. Patients should also be monitored 
for occurrence of an allogeneic stem cell transplant within 24 months from the last study treatment. If patient undergoes an allo-SCT in this timeframe, transplant parameters and adverse 
events must be reported as specified in section 4.6.3 (up to 18 months from the time of SCT).  
8 Vital Signs include: Blood pressure, pulse, respiratory rate, and oxygen saturation  
9 See Appendix A 
10 See Appendix D 
11 Comprehensive chemistry panel and CBC with differential are required within 14 days of study registration. Chemistry panel will include glucose, calcium, albumin, ALT, AST, sodium, 
potassium, total bilirubin, alk phose, and creatinine. CBC with differential must include Absolute Neutrophil Count.  
12 At baseline and every 6 weeks while on therapy with pembrolizumab. 
13Patients must have HIV Ab screen; and Hepatitis B Sag, Sab, and core; and Hepatitis C Ab testing within 6 weeks of registration. 
14 PET/CT is required for eligibility within 6 weeks prior to registration (standard of care) and at specified time points for tumor assessment for the primary endpoint analysis. PET#2 should 
take place prior to starting AVD (research procedure). PET#3 should take place at the end of AVD Cycle 2 (standard of care) . Copies of PET/CT scans should be de-identified and CD 
disks with DICOM files shipped within 30 days for central review as outlined in section 6.3.1. 
15  All patients will have a PET/CT 2-6 weeks after the completion of chemotherapy (or diagnostic CT’s for patients with Stage I/II disease and a negative PET#3) (standard of care). This 
will be prior to starting consolidation treatment (when applicable) or as part of the procedures for study discontinuation. Patients receiving consolidation will also have a final PET/CT 
as part of study discontinuation. 
16  For patients who receive pembrolizumab consolidation, imaging is recommended every 3 months. Once a PET-CT is negative, patients may undergo CT’s every three months during 
consolidation.   
17 Diagnostic quality CT scan of the chest/abdomen/pelvis is required within 6 weeks prior to registration. If there is involvement of the neck then a diagnostic quality CT Neck is required.  
18 Correlative studies on tissue specimens are recommended if there is adequate tissue on the baseline sample acquired for diagnosis. Patients who agree to undergo a repeat biopsy (optional: 
done as a research procedure) for the interim assessment will provide tissue 2-4 weeks after the first dose of pembrolizumab as specified in the lab manual, however repeat biopsy is not 
required. 
19 See separate lab manual for details of correlative studies (research procedures). Study labs include:  
       (1) sodium heparin tube for FlowCore,  
       (2)  SST tube for Inflammatory and Immune Markers, 
       (3) SST tube for Soluble PD-L1 
     (4) SST for CCL17 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
41 
Amendment 6: March 29th, 2019 
Trial Period: 
Screening Phase 
Treatment Cycles1 
Off Rx 
Surveillance 
Treatment Cycle/Title: 
Main Study 
Screening  
Pembrolizumab 
PET #2 
AVD2,3 
PET #3 
 
AVD3,4 
Post-Chemo Assessment 
Pembrolizumab5 
Discont 
Survival Follow-Up 
1 
2 
3 
1-2 
 
4-35 
 
 
3-66 
Scheduling Window (Days): 
Within 28 days of 
registration 
1 
± 3 
22 
± 3 
43 
± 3 
64 ± 3 
120 ± 3 
2-4 weeks after last 
dose of 
chemotherapy ± 3 
 30 days after last 
dose (pembro or 
AVD, ±5 days) 
Every 12 weeks  
20 Adverse events will be followed for the first 30 days after treatment discontinuation. SAE’s will be recorded for 90 days after treatment discontinuation. For patients who undergo allogeneic 
stem cell transplant (SCT) within 24 months of last study treatment, transplant parameters and adverse events will be recorded according to section 4.6.3 (up to 18 months from the time 
of SCT). 
21 Echo or MUGA to be repeated after 4 cycles of doxorubicin 
22 Pregnancy test (serum or urine) is required within 7 days of registration. Pregnancy test should also be repeated C1D1 if not done within 72 hours of study treatment. 
23 CT scans to be performed at baseline and every three months during pembrolizumab consolidation after PET-CT is negative (see footnote 14) 
24 Height required at baseline but not at subsequent visits 
25 Within 6 weeks prior to registration. 
 
 

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
42 
Amendment 6: March 29th, 2019 
6.0  
RESPONSE ASSESSMENT 
6.1 
Measurability of lesions 
6.1.1 
Measurable disease  
Lesions that may be accurately measured in two dimensions by CT, MRI, plain x-
ray, or other conventional technique and have a greatest transverse diameter of 
1 cm or greater; or palpable lesions with both diameters 2 cm or greater. 
Splenomegaly alone is not sufficient to qualify as measurable disease. NOTE: 
PET scans are insufficient for evaluation of measurable disease.  
 
6.1.2 
Non-measurable disease  
All other lesions including unidimensional lesions, lesions too small to be 
considered measurable, pleural or pericardial effusion, ascites, bone disease, 
leptomeningeal disease, lymphangitis, pulmonitis, abdominal masses not 
confirmed or followed by CT or disease documented only by PET imaging or 
indirect evidence (e.g., lab values).  
 
6.2 
Lymphoma Response Criteria  
NOTE: These criteria are based upon the criteria for the LUGANO 2014 Response 
Criteria (Appendix C). Patients who receive consolidation with pembrolizumab will also 
have disease assessed by the Immune Response Criteria (Appendix F) as an exploratory 
assessment. 
 
The criteria use the following categories of response: Complete Response (CR), 
Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). In the 
case of stable disease, follow-up assessments must have met the SD criteria at 
least once after study entry at a minimum interval of six weeks. 
 
6.3 
FDG-PET/CT Guidelines 
All patients should have a pre-treatment FDG-PET/CT scan as a baseline to compare 
with subsequent scans to assess response. This should be performed no more than 35 
days (5 weeks) before registration, as is consistent with standard of care.  
 
Investigational FDG-PET/CT (PET #2) will be performed to assess the response to the 
first three (3) cycles of pembrolizumab lead-in, our primary endpoint, 
 
Subsequent FDG-PET/CT (PET #3) will be completed after the 2nd cycle of AVD.  
 
A fourth FDG-PET/CT (PET#4) will be performed after completion of chemotherapy, prior 
to starting pembrolizumab consolidation (if applicable), unless patient is Stage I/II and 
has a negative PET#3; these patients can have a diagnostic CT scan. 
 
Subsequent FDG-PET/CT scans are recommended every 3 months during consolidation 
until a patient achieves PET-negativity, then only CTs will be obtained. See Section 5- 
Schedule of Activities for other times of response assessments.  
 
Only full-ring integrated FDG-PET/CT scanners are acceptable 
(coincidence cameras are not acceptable). The CT of the FDG- PET/CT 
is used for attenuation correction of PET data and anatomic localization. 
CT settings and patient preparation should follow institutional guidelines.  
 
6.3.1 
Central Review of PET/CT 
All patients will have a retrospective central review PET/CT (PET#1, PET#2, 
PET#3, and PET#4) for research purposes. As scans are performed in real time, 
a de-identified image of the PET should be sent for reviewed at the Northwestern 
University by Dr. Savas  
 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
43 
Amendment 6: March 29th, 2019 
Results of central reads will not be reported in real time and will therefore not be 
the determinant for patient care. Findings will be communicated to participating 
sites retrospectively, including any discrepancies between the central research 
read and local radiology read.  
 
PET/CT scans should be de-identified and put on CD disks as DICOM files to be 
shipped to Northwestern QAM (See address below). Disks should be shipped 
with a completed Imaging Shipping Form (See NOTIS for Imaging Shipping 
Form). At the time of shipping, QAM should be notified 
(croqualityassurance@northwestern.edu), and can provide any specific shipping 
instructions. Scans will be stored electronically at Northwestern. 
 
Shipping address: 
 
 
 
 
Clinical Trials Office – Quality Assurance 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern University 
676 N. St. Clair, Suite 1200 
 
Chicago, IL  60611 
 
6.1.1.1 Analysis Using Total Metabolic Volume 
We will measure the total metabolic tumor volume, TMTV, to estimate 
the total tumor burden and correlate with outcome. We will utilize 
methodology recommended by the European Association of Nuclear 
Medicine for solid tumors and widely used for Hodgkin lymphoma. 41  
 
6.4 
Endpoint assessment 
 
 
6.4.1 
Primary Endpoint 
Our primary endpoint is to assess rate of complete response following 
pembrolizumab alone on FDG-PET (PET#2). This will be performed following 
three cycles of pembrolizumab on week 10. The scheduling window is day 64 +/- 
3 days. Negative PET is defined as Deauville score of 1-3 as assessed by central 
review.  Patients will be considered evaluable for this endpoint if they have 
received at least one dose of pembrolizumab. 
 
6.4.2 
Secondary Endpoints 
 
 
Toxicity Endpoints 
The frequency and severity of adverse events by type, severity (grade), timing, 
and attribution to pembrolizumab will be assessed once per cycle according the 
NCI-CTCAE version 4.03. All patients who receive at least one dose of 
pembrolizumab will be evaluable for toxicity endpoints. 
 
 
 
Efficacy Endpoints 
Response and progression will be evaluated using the LUGANO 2014 Response 
Criteria46.  
 
Patients treated with pembrolizumab consolidation will also have disease 
assessed by the updated immune response criteria47 in addition to LUGANO 
response criteria as an exploratory assessment. 
 
6.4.3 
Relapsed Disease (RD) 
RD includes the following:  
• 
Lymph nodes should be considered abnormal if the long axis is more 
than 1.5 cm regardless of the short axis. If a lymph node has a long axis 
of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
44 
Amendment 6: March 29th, 2019 
more than 1.0. Lymph nodes ≤ 1.0 x ≤ 1.0 cm will not be considered as 
abnormal for relapse or progressive disease; 
• 
Appearance of any new lesion more than 1.5 cm in any axis during or at 
the end of therapy, even if other lesions are decreasing in size. 
Increased FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new 
lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without 
histologic confirmation; 
• 
At least a 50% increase from nadir in the sum of the product of the 
diameter (SPD) of any previously involved nodes, or in a single involved 
node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the 
short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 
1.5 x 1.5 cm or more than 1.5 cm in the long axis; 
• 
At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis; 
• 
Lymphoma confirmed by repeat biopsy. 
 
6.4.4 
Progression Free Survival (PFS) 
PFS will be defined as the length of time from treatment on protocol until the first 
occurrence of disease relapse, progression, re-initiation of cytotoxic 
chemotherapy, or death due to disease, or until last contact if the patient did not 
experience any of these from the end of treatment through two years of follow up. 
 
6.4.5 
Overall Survival (OS) 
OS will be defined as time from study enrollment until death, or until last contact 
if the patient did not die from the end of treatment through two years of follow up. 
 
7.0  
ADVERSE EVENTS 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires a high 
level of monitoring, as outlined in the DSMP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations and as required by the NCI 
AdEERS Reporting Guidelines.   
 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for timepoints). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• 
any abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• 
death. 
 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
7.2 
Definitions & Descriptions 
7.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
 
Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of 
the Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary 
significantly in frequency or severity from expected levels are not to be 
considered adverse events.  Examples of this may include, but are not limited to, 
teething, typical crying in infants and children and onset of menses or 
menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational 
(including placebo or active comparator medication) or marketed, manufactured 
by, licensed by, provided by or distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in 
clinical trials, or as prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event.  
 
All adverse events that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. 
Such events will be recorded at each examination on the Adverse Event eCRFs.  
The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.3. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
46 
Amendment 6: March 29th, 2019 
 
7.2.2 
Severity of AE’s 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
• 
Fatal (grade 5): the event caused death. 
 
7.2.3 
Serious Adverse Events (SAEs) 
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 90 days after the last administration of study drug, must be 
reported upon discovery or occurrence. 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
• 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
• 
Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
47 
Amendment 6: March 29th, 2019 
7.2.4 
Unanticipated Problems Involving Risks to Subject or Others 
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria: 
• 
Is unanticipated in terms of nature, severity, or frequency 
• 
Places the research subject or others at a different or greater risk of harm 
• 
Is deemed to be at least possibly related to participation in the study.    
 
7.3 
Adverse Event Reporting 
7.3.1 
Routine Reporting 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine Aes will 
be reviewed by the Data and Safety Monitoring Committee (DSMC) according to 
the study’s phase and risk level, as outlined in the DSMP.  
 
7.3.2 
Determining if Expedited Reporting is Required 
This includes all events that occur within 90 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
 
1) 
Identify the type of adverse event using the NCI CTCAE v 4.03. 
 
 
2) 
Grade the adverse event using the NCI CTCAE v 4.03. 
 
 
3) 
Determine whether the adverse event is related to the protocol therapy.   
 
 
 
Attribution categories are as follows: 
• 
Definite: AE is clearly related to the study treatment. 
• 
Probable: AE is likely related to the study treatment. 
• 
Possible: AE may be related to the study treatment. 
• 
Unlikely: AE not likely to be related to the study treatment. 
• 
Unrelated: AE is clearly NOT related to the study treatment. 
 
 
4) 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current protocol 
• 
the drug package insert 
• 
the current Investigator’s Brochure 
 
 
7.3.3 
Expedited Reporting to the Northwestern University QAM/DSMC 
All SAEs must be reported to the assigned QAM within 24 hours of becoming 
aware of the event. Completion of the NU CTO SAE Form is required. 
 
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include: 
• 
Protocol description and number(s) 
• 
The patient’s identification number 
• 
A description of the event, severity, treatment, and outcome (if known) 
• 
Supportive laboratory results and diagnostics 
• 
The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the DSMC at their next meeting. 
 
7.3.4 
Expedited Reporting to the Northwestern University IRB 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
48 
Amendment 6: March 29th, 2019 
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their local 
IRB guidelines for reporting to their local IRBs. 
• 
Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU IRB 
within 24 hours of notification.  
• 
Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to the NU IRB within 5 
working days of notification. 
• 
All other deaths of NU subjects not previously reported, other non-NU subject 
deaths that were unanticipated and unrelated, and any other SAEs that were 
not previously reported as UPIRSOs will be reported to the NU IRB at the 
time of annual continuing review. 
 
7.3.5 
Reporting to the FDA  
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening. 
 
The FDA will be notified within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life-threatening. 
This includes any previous SAEs that were not initially deemed reportable, but 
are later determined to meet the criteria for reporting (i.e. by the DSMC). 
 
All other SAEs will be reported on an annual basis as part of the annual FDA 
report. 
 
7.3.6 
Expedited Reporting to Merck 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.5 for additional details) that occurs 
to any subject must be reported within 24 hours to the NU QA and/or IRB (see 
section 7.3.3.1 and 7.3.3..2) and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. The NU CTO SAE form 
will be used. 
 
For the time period beginning at treatment allocation/randomization through 90 
days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, any serious 
adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study (reference Section 
7.2.3.5 for additional details whether or not related to the Merck product, must be 
reported within 24 hours to the S and within 2 working days to Merck Global 
Safety. The NU CTO SAE form will be used. 
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside 
of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
49 
Amendment 6: March 29th, 2019 
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, European Union (EU), Pharmaceutical and Medical Devices 
agency (PMDA) or other local regulators. Investigators will cross reference this 
submission according to local regulations to the Merck Investigational Compound 
Number (IND, CSA, etc.) at the time of submission. Additionally investigators will 
submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
7.4 
 
Other Events Requiring Expedited Reporting 
 
7.4.1 
Overdose  
For purposes of reporting to Merck, an overdose of pembrolizumab will be 
defined as any dose of 1,000 mg or greater (≥5 times the indicated dose). NOTE: 
the Northwestern University IRB requires reporting of any overdose according to 
their Reportable New Information criteria. No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment 
should be provided if clinically indicated. In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported using 
the NU CTO SAE form within 24 hours to the PI and within 2 working days hours 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
7.4.2 
Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them) that occurs during the 
trial. 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s 
product, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.  All 
reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
50 
Amendment 6: March 29th, 2019 
Events). If the pregnancy continues to term, the outcome (health of infant) must 
also be reported. 
Such events must be reported using the NU CTO SAE form within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
7.4.3 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220). 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 
days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, any ECI, or 
follow up to an ECI, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.4.1 that is not 
associated with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  
 
7.4.4 
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck unless 
there is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the PI within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study. 
The Northwestern University DSMC will monitor 50rticaria aggregated efficacy 
endpoint events and safety data to ensure the safety of the subjects in the trial. 
Any suspected endpoint which upon review is not progression of the cancer 
under study will be forwarded to Merck Global Safety as a SAE within 2 working 
days of determination that the event is not progression of the cancer under study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be 
considered a SAE. 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
51 
Amendment 6: March 29th, 2019 
 
8.0 DRUG INFORMATION 
 
8.1 
Pembrolizumab 
8.1.1 
Other names:  
 
MK-3475; Keytruda® 
 
8.1.2 
Classification – type of agent  
Immunotherapy (Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody) 
 
8.1.3 
Mode of action 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute 
to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a 
monoclonal antibody that binds to the PD-1 receptor and blocks its interaction 
with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the 
immune response, including the anti-tumor immune response. In syngeneic 
mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 
 
8.1.4 
Storage and stability 
Clinical supplies must be stored in a secure, limited-access location. Store 
pembrolizumab vials under refrigeration at 2 to 8 degrees Celsius I or 36 to 46 
degrees Fahrenheit (F). Do not freeze; do not shake. Storage following dilution: 
Store at room temperature for up to 4 hours (the 4 hour countdown begins when 
the vial is pierced, and includes room temperature storage of admixture solutions 
in the IV bags and the duration of infusion) or refrigerated at 2—8 degrees C 
(36—46 degrees F) for up to 20 hours. If refrigerated, allow the IV bags to come 
to room temperature prior to use. Do not freeze.  Receipt and dispensing of trial 
medication must be recorded by an authorized person at the trial site. Clinical 
supplies may not be used for any purpose other than that stated in the protocol.  
 
 
8.1.5 
Protocol dose specifics 
Pembrolizumab 200 mg will be administered as a set dose of 200 mg IV for all 
cycles regardless of weight. There are no dose modifications for toxicity. 
 
8.1.6 
Preparation 
Preparation for Intravenous Infusion 
• 
Visually inspect the solution for particulate matter and discoloration prior 
to administration. The solution is clear to slightly opalescent, colorless to 
slightly yellow. Discard the vial if visible particles are observed.  
• 
Dilute pembrolizumab injection (solution) to intravenous administration.  
• 
Withdraw the required volume from the vial(s) of pembrolizumab and 
transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by 
gentle inversion. The final concentration of the diluted solution should be 
between 1 mg/mL to 10 mg/mL. 
• 
Discard any unused portion left in the vial. 
 
8.1.7 
Route of administration for this study 
Administer infusion solution intravenously over 30 minutes through an 
intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter.  
 
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8.1.8 
Incompatibilities 
No specific incompatibilities are listed. Do not co-administer other drugs through 
the same infusion line. 
 
8.1.9 
Availability & Supply  
Merck will supply pembrolizumab (investigational / clinical supply) directly to the 
NU Investigational Pharmacy at no charge to subjects participating in this clinical 
trial. The Merck Drug Request Form, provided by Merck and available in NOTIS, 
should be completed and emailed to the contacts listed on the form. 
 
The treating investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
8.1.10 Side effects 
The following are some of the adverse events that have occurred in prior clinical 
trials. Please refer to the current investigator’s brochure for a complete listing of 
all adverse events. 
 
 
 
Most common (seen in >10% of patients): 
• 
Fatigue 
• 
Headache 
• 
Chills 
• 
Difficulty sleeping 
• 
Dizziness 
• 
Leg swelling 
• 
Itching and/or rash 
• 
Elevated blood sugar level 
• 
High triglycerides (type of cholesterol) 
• 
Lower levels of calcium or sodium in the blood 
• 
Nausea and/or vomiting 
• 
Decreased appetite 
• 
Diarrhea or constipation 
• 
Pain in the abdomen 
• 
Cough 
• 
Shortness of breath 
• 
Fever 
 
Less common (seen in 1 to 10% of patients): 
• 
Skin infection 
• 
Abnormal thyroid function (decreased or increased) 
• 
Colitis (inflammation or infection of the colon [large intestine] 
• 
Sepsis (infection in the bloodstream) 
• 
Kidney failure 
• 
Pneumonitis (inflammation of the lung) or pneumonia (infection in the lung) 
  
Rare but serious or life-threatening (seen in <1% of patients) 
Immune system attacking adrenal gland (adrenocortical insufficiency), joints 
(arthritis), liver (hepatitis), kidneys (nephritis), skin (dermatitis) muscles 
(myositis), eyes (optic neuritis or uveitis), pancreas (pancreatitis), brain (partial 
epilepsy), or other organs causing possibly irreversible damage to these organs 
 
8.1.11 Nursing implications 
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Administer pre-treatment medications per protocol. Advise patients on the 
possible side effect profile. Follow infusion rate protocol with vigilant monitoring 
for possible infusion-related effects. 
 
Pembrolizumab will be administered as an IV infusion ((dilution as stated above) 
over approximately 30 minutes  Every effort should be made to target infusion 
timing to be as close to 30 minutes as possible.  However, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
 
 
When an IV bag is used for the infusion, the IV line will be flushed with a volume 
of normal saline equal to the priming volume of the infusion set used after the 
contents of the IV bag are fully administered 
 
Since the compatibility of   with other IV medications and solutions, other than 
normal saline (0.9% [w/v] sodium chloride for injection) and D5W , is not known, 
the Pembrolizumab solution should not be infused through an IV line in which 
other solutions or medications are being administered. The date, start time, 
interruption, and completion time of Pembrolizumab administration must be 
recorded in the source documents.  
 
8.1.12 Return and Retention of Study Drug 
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. 
 
8.2 
Doxorubicin  
8.2.1 
Other names.  
Adriamycin, Rubex, Adriamycin RDF, Adriamycin PFS, hydroxydaunorubicin, 
hydroxydaunomycin, ADR.  
 
8.2.2 
Classification 
Anthracycline antibiotic.  
 
8.2.3 
Mode of Action.  
Intercalation between adjoining nucleotide pairs in the DNA helix causes 
inhibition of DNA and DNA-dependent RNA synthesis. Free radical generation is 
responsible for cardiac toxicity. Doxorubicin also inhibits topoisomerase II.  
8.2.4 
Storage and stability.  
Rubex or Adriamycin RDF intact vials are stable protected from light at room 
temperature. Adriamycin PFS vials must be refrigerated. Reconstituted solutions 
are stable for 24 hours at room temperature and 48 hours under refrigeration. 
The Adriamycin RDF 150 mg multidose vial is stable after reconstitution for 7 
days at room temperature or 15 days if refrigerated and protected from sunlight.  
8.2.5 
Dose specifics.  
Doxorubicin will be given intravenously at a dose of 25 mg/m2 on days 1 and 15 
of each AVD chemotherapy cycle. A cycle will be repeated every 28 days. Use 
actual weight to calculate body surface area and doses. See section 4.4 
regarding dose modifications (toxicity-related). 
 
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8.2.6 
Preparation.  
Add 5, 10, 25, 50, or 75 ml of preservative-free normal saline to the 10, 20, 50, 
100, or 150 mg vial to produce a solution containing 2 mg/ml. 
 
8.2.7 
Administration.  
Intravenously as a bolus injection. Peripheral vein administration is allowed.  
 
8.2.8 
Incompatibilities.  
Physically incompatible with heparin, fluorouracil, aminophylline, cephalothin, 
dexamethasone, diazepam, hydrocortisone, and furosemide. 
 
Stable with vincristine in normal saline for 5 days at room temperature protected 
from light. Also compatible in solution with cyclophosphamide.  
 
8.2.9 
Availability.  
Commercially available as powder for injection in 10, 20, 50, 100, 150 mg vials, 
and as 2 mg/ml solution for injection in 10, 20, 50, and 200 mg vials.  
 
8.2.10 Side effects.  
Hematologic: Leukopenia (dose-limiting), also thrombocytopenia and anemia. 
Nadir 10-14 days, recovery in 21 days. Dermatologic: Alopecia, usually complete; 
hyperpigmentation of nail beds and dermal creases; radiation recall. 
Gastrointestinal: Nausea and vomiting, sometimes severe; anorexia, diarrhea; 
mucositis, especially with daily x 3 schedule. Cardiovascular: Arrhythmias, ECG 
changes; rarely sudden death. Congestive heart failure due to cardiomyopathy 
related to total cumulative dose; risk is greater with total doses > 550 mg/m2, 
mediastinal irradiation pre-existing cardiac disease, advanced age; risk is 
reduced with weekly or continuous infusion regimens. Other: Red discoloration of 
urine; fever; anaphylactoid reaction; may enhance cyclophosphamide cystitis or 
mercaptopurine hepatotoxicity. Local effects: Vesicant if extravasated; flush 
along vein, facial flush.  
 
8.2.11 Nursing/patient implications.  
Monitor CBC, platelet counts. Vesica–t - do not extravasate. Refer to 
extravasation protocol if inadvertent infiltration occurs. Advise patient of alopecia. 
Instruct on how to obtain wig, hairpiece, etc. Hair loss generally occurs 2-4 
weeks after injection and is usually complete. Advise patient of red discoloration 
of urine for 24 hours after administration of the drug. Administer antiemetics as 
indicated. Assess for stomatitis and treat symptomatically. Generally occurs 7-10 
days after injection. Be aware “f "Ad”ia" fla–e - most common reaction consists of 
an erythematous streak up the vein. It is associated wi54rticarialria and pruritus. 
Occasionally the use of corticosteroids and/or antihistamines has been useful. 
Monitor for signs and symptoms of cardiomyopathy. Calculate total cumulative 
dose with each administration.  
 
 8.3 
Vinblastine  
8.3.1 
Other names.  
Velban, vinblastine sulfate, vincaleukoblastine, VLB, Velsar, Alkaban AQ.  
 
8.3.2 
Classification 
Vinca alkaloid (tubulin inhibitor).  
 
8.3.3 
Mode of Action.  
Vinblastine binds to tubulin, a protein that forms microtubules, thus interfering 
with spindle formation during metaphase and causing cessation of cellular 
mitosis.  
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8.3.4 
Storage and stability.  
Drug vials are stored in the refrigerator. Reconstituted vinblastine, 1 mg/ml, is 
stable for 30 days in the refrigerator. Further diluted to a concentration of 0.01 
mg/ml in normal saline or 5% dextrose, vinblastine is stable for 24 and 72 hours, 
respectively, at room temperature.  
 
8.3.5 
Dose specifics 
Patients will receive Velban intravenously at a dose of 6 mg/m2 on days 1 and 15 
of each AVD chemotherapy cycle. A cycle will be repeated every 28 days. Use 
actual weight to calculate body surface area and doses. See section 5.3.3 
regarding dose modifications (toxicity-related).  
 
8.3.6 
Preparation.  
The 10 mg vial is reconstituted with 10 ml of bacteriostatic normal saline, yielding 
a concentration of 1 mg/ml. Doses for continuous infusion may be further diluted 
with 50 ml or more of normal saline or 5% dextrose in water.  
 
8.3.7 
Administration.  
Intravenously as a bolus injection.  
 
 
8.3.8 
Incompatibilities.  
Furosemide, heparin; Infusaid pumps.  
 
Compatibilities. Vinblastine is physically stable in normal saline solutions for at 
least 5 days, alone or mixed with doxorubicin, at 8, 25, and 32°C. Vinblastine is 
also compatible in solution with metoclopramide and bleomycin.  
 
 
8.3.9 
Availability.  
Vinblastine is commercially available in 10 mg vials, as a lyophilized powder and 
as a 1 mg/ml solution.  
 
8.3.10 Side effects.  
Hematologic: Leukopenia, thrombocytopenia, anemia. Dermatologic: Alopecia, 
epilation; skin and soft tissue damage if extravasated (the manufacturer 
recommends subcutaneous injection of hyaluronidase and application of heat to 
help disperse the drug); rash, photosensitivity. Gastrointestinal: Nausea, vomiting 
(preventable); constipation (see neurological side effects); abdominal pain 
(cramps), anorexia, diarrhea, mucositis, gastrointestinal hemorrhage. Neurologic: 
Peripheral neuropathy (loss of deep tendon reflexes, paresthesias, paralysis); 
autonomic neuropathy (constipation, paralytic ileus, urinary retention, 
orthostasis); vocal cord paralysis; myalgias; Raynaud's phenomenon; headache, 
seizures, depression, dizziness, malaise; may be enhanced by concomitant use 
of interferon. Pulmonary; Bronchospasm (acute shortness of breath), more 
common when administered with mitomycin; pulmonary edema. Other: Severe 
pain in the jaw, pharynx, bones, back or limbs following injection; syndrome of 
inappropriate antidiuretic hormone (SIADH); fever; ischemic cardiotoxicity; 
enhanced interferon toxicity.  
 
8.3.11 Nursing/patient implications.  
Premedicate with antiemetics as needed. Administer by slow IV push. Vesica–t - 
do not extravasate. Refer to extravasation protocol if inadvertent infiltration 
occurs. Assess for neurotoxicity. Assess for constipation. Monitor CBC and 
platelet count.  
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8.4   
Dacarbazine 
8.4.1 
Other names 
DTIC, DTIC-D’me‚, DIC, imidazole carboxamide, dimethyl triazeno imidazole 
carboxamide.  
 
8.4.2 
Classification.  
Alkylating agent.  
 
8.4.3 
Mode of Action.  
Activity may be the result of at least 3 mechanisms: 1) alkylation; 2) 
antimetabolite activity as a purine precursor; and 3) interaction with sulfhydryl 
(SH) groups in proteins. Dacarbazine appears to be more active in G2 phase but 
is not particularly cell cycle phase specific.  
 
8.4.4 
Storage and stability.  
Store vials under refrigeration and protected from light. In solution, dacarbazine 
is stable for 96 hours if refrigerated and protected from light, 24 hours if not 
refrigerated but protected from light. When further diluted in 500 ml D5W or NS, it 
is stable for 24 hours if refrigerated, and 8 hours at room temperature and 
protected from light. Photodegradation: The manufacturer of dacarbazine states 
that the drug does not decompose when left at room temperature under normal 
lighting conditions for eight hours.  
 
NOTE: A change in color of solution from pale yellow to pink is indicative of 
decomposition of the drug.  
 
8.4.5 
Dose specifics.  
Patients will receive Dacarbazine intravenously at a dose of 375 mg/m2 on days 
1 and 15 of each cycle of AVD chemotherapy. Cycles will be repeated every 28 
days. Use actual weight to calculate body surface area and doses. See section 
5.3.3 regarding dose modifications (toxicity- related).  
 
8.4.6 
Preparation.  
Dilute the 100, 200, and 500 mg vials with 9.9, 19.7, and 49.5 ml of sterile water, 
respectively, resulting in a concentration of 10 mg/ml. Protect the drug from direct 
light. Do not freeze. Discard if solution turns pink/red. The drug can be further 
diluted in 50-500 ml of 5% dextrose or normal saline.  
 
8.4.7 
Administration.  
Usually administered by intravenous infusion over 30 minutes or longer; has also 
been given IV push.  
 
8.4.8 
Incompatibilities.  
Metabolism of dacarbazine may be induced by phenytoin or phenobarbital. 
Toxicity may be enhanced if given concomitantly with allopurinol, azathioprine, or 
mercaptopurine. Dacarbazine is physically incompatible with hydrocortisone 
sodium succinate and heparin.  
 
8.4.9 
Side effects.  
Central nervous system: Infusion-site pain; Dermatologic: Alopecia 
Gastrointestinal: Nausea and vomiting (>90%), anorexia; Hematologic & 
oncologic: Bone marrow depression (onset: 5 to 7 days; nadir: 7 to 10 days; 
recovery: 21 to 28 days), leukopenia, thrombocytopenia <1% (Limited to 
important or life-threatening): Anaphylaxis, anemia, diarrhea, dysgeusia, 
eosinophilia, erythema, facial flushing, facial paresthesia, flu-like symptoms 
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(fever, myalgia, malaise), hepatic necrosis, increased liver enzymes (transient), 
paresthesia, renal function test abnormality, skin photosensitivity, skin rash, 
urticaria, venous obstruction (hepatic vein) 
 
8.4.10 Nursing implications 
Premedicate with antiemetics as agent is highly emetogenic. Infuse over 15-60 
minutes. Irritant- rapid infusion may cause severe venous irritation. Assess for 
allergic reactions. Monitor CBC and platelet count.  
 
8.4.11 Availability.  
Commercially available in vials containing 100 mg, 200 mg, or 500 mg of 
lyophilized drug.  
 
9.0  
CORRELATIVES/SPECIAL STUDIES 
Several correlative studies are included in the clinical trial protocol. Expression of PD-1 and PD-
L1 has been identified on malignant cells and cells of the tumor microenvironment in hematologic 
malignancies including Hodgkin’s lymphoma48. We will analyze the previously obtained biopsy 
specimens from patients’ diagnostic samples (if available) to determine PD-1 and PD-L1 
expression. An optional biopsy specimen will also be collected 2-4 weeks after the first dose of 
pembrolizumab for patients who provide consent. Expression of both PD-1 and PD-L1 has been 
correlated with responses following anti-PD-1 therapy. For HL, mutations at chromosome 9p24.1 
led to amplification of gene expression of PD-L1 and PD-L231. We will perform FISH testing to 
identify mutations in chromosome 9p24.1 and attempt to correlate with both PD-L1 expression as 
well as clinical outcomes. Prior studies using anti-PD-1 blockade have shown alterations in the T-
lymphocytes subsets following therapy43. The correlative investigations will determine lymphocyte 
subset changes during treatment with pembrolizumab. Levels of serum markers associated with 
inflammatory and immune response will include TNF-α, IFN-γ, IL-2, IL-6, IL-7, and galectin-1. 
Correlation of these biomarkers will be investigated as potential measures to determine response 
to therapy. More recently the use of an ELISA assay for soluble PD-L1 (sPD-L1) has emerged as 
a potential biomarker for response to PD-1 blockade in DLBCL49. The role of sPD-L1 in HL is 
unclear and this will be part of our correlative investigations.   
 
9.1 
Diagnostic Biopsy – Specimen Procurement & Shipping 
Tissue will be obtained for correlative studies from the diagnostic biopsy performed at 
baseline, if available. Archival tissue will be approved if appropriately preserved in 
paraffin embedded block, and if the specimen is deemed adequate for correlative studies 
by the onsite pathologist. An optional biopsy specimen will also be collected 2-4 weeks 
after the first dose of pembrolizumab for patients who provide consent. The biopsy 
samples for each patient will be obtained for PD-1 pathway marker analysis and 
chromosome 9p24.1 alterations. For each biopsy specimen, either 10 unstained slides (5 
microns) or a paraffin-embedded block will be submitted for : 
o 
Immunohistochemical (IHC) analysis of PD-1 and PD-L1 expression.  
o 
A block section is also required to complete FISH analysis for alterations at 
chromosome 9p24.1.  
See separate lab manual for details on processing and shipping. 
 
9.2 
Biopsy Specimen Analysis  
Immunohistochemical stains for PD-1 and PD-L1 will be performed by the Northwestern 
PathCore facility with proper controls. We will also perform IHC for CD3 and CD20 for 
identification of tumor cells and the tumor microenvironment. Samples will be reported as 
“present” or “absence” of marker expression. Expression will be quantified by percentage 
of cells with differentiation between malignant cell expression and/or tumor 
microenvironment expression. We will consider >20% as "positive" for PD-1 or PD-L1 
expression. 
 
FISH 
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Fluorescence in situ hybridization (FISH) will be performed by the Northwestern 
pathology department on tissue sections to assess alterations of chromosome 9p24.1. 
Chromosomal alterations will be characterized as amplification, copy gain, polysomy, or 
normal copy number (disomy). The bacterial artificial chromosome probes (CHORI; 
www.chori.org) RP11-599H2O, which maps to 9p24.1 and includes CD274 (encoding 
PD-L1, labeled with Spectrum Orange), and RP11-635N21, which also maps to 9p24.1 
and includes PDCD1LG2 (encoding PD-L2, labeled with Spectrum Green), will be co-
hybridized. A control centromeric probe, Spectrum Aqua–labeled CEP9 (Abbott 
Molecular) that maps to 9p11-q11, will be used. An additional probe, Spectrum-Green-
labeled RP11-6010G2, which maps upstreatm of PDCD1LG2, will be used to confirm a 
possible chromosomal translocation.  
 
Double Immunohistochemistry Staining 
Slides will be double stained for the presence of PD-L1 and PAX5 (24/Pax-5;BD 
Biosciences, San Jose, CA) as well as PD-L2 clone  and pSTAT3 (D3A7; Cell Signaling, 
Danvers, MA). These stains will be performed with an automated staining system (Bond 
Ill; Leica Biosystems, Buffalo Grove, IL). Stained slides will be scored by an expert 
hematopathologist for average percentage of positive cells and intensity of staining on a 
scale (1-3+).  
  
9.3 
Peripheral Blood Correlatives 
9.3.1 
Flow Cytometry – Sample Procurement 
Lymphocyte subsets will be evaluated by flow cytometry on peripheral blood 
obtained at specified time points through the treatment period. See separate lab 
manual for collection and processing details.   
 
 
9.3.3 
Flow Cytometry Analysis 
Flow cytometry analysis will include the following surface markers: CCR7, CD3, 
CD4, CD8, CD14, CD16, CD20, CD25, CD45RO, CD56, CD57, CD62L, CD107a, 
CD127, FoxP3, B7-H1 (PD-L1), B7-DC (PD-L2), HLADR, and PD-1. The following 
intracellular markers will be evaluated: TIA1, granzyme, perforin. We will complete 
an 8-10 color flow cytometry analysis to properly group biomarkers for 
determination of specific lymphocyte populations. Two specific lymphocyte 
populations will be evaluated as the primary endpoint and include CD4+CD25+PD-
L1+ T lymphocytes and CD4+CD62L+CD127+ T lymphocytes. Further groupings 
of marker expression will be performed to best identify activated T-cell and NK-cell 
populations, cytotoxic T-cells, monocyte populations, and lymphocyte populations 
with PD-1 or PD-L1 expression 
9.3.4 
Correlative Inflammatory and Immune Markers 
Peripheral blood samples will be obtained at specified time points per the 
treatment protocol. Serum marker evaluations will include TNF-α, IFN-γ, IL-2, IL-
6, IL-7, and galectin-1. See separate lab manual for collection and processing 
details. For each specified time point, peripheral blood sampling will require an 
8.5mL SST tube. Samples will be spun, frozen and stored appropriately until 
testing is performed. Values will be reported with units and reference ranges 
based on the respective commercially available tests. All patient samples will be 
stored until final tissue acquisition, following by batch analysis. 
Blood fractions, including serum and PBMCs will be stored for analysis 
Samples will be stored until study completion 
 
9.3.4 
Thymus and Activation-Regulated Chemokine/CCL17 (TARC) 
For the CCL17 ELISA (https://www.rndsystems.com/products/human-ccl17-tarc-
quantikine-elisa-kit_ddn00.), peripheral blood samples will be obtained at 
specified time points per the treatment protocol along with the inflammatory 
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markers. See separate lab manual for collection and processing details. 
 
9.3.5 
Soluble PDL-1 
Peripheral blood samples will be obtained at specified time points per the 
treatment protocol. See separate lab manual for collection and processing 
details.  
 
9.4 
Specimen Banking 
Patient samples collected for this study will be retained at Robert H Lurie Cancer 
Center of Northwestern University Pathology Core Facility. Specimens will be stored 
indefinitely or until they are used up. If future use is denied or withdrawn by the patient, 
best efforts will be made to stop any additional studies and to destroy the specimens. 
 
Dr. Jane Winter will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of Northwestern University. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement 
or recharge agreement) that states specimens will only be released for use in disclosed 
research. Any data obtained from the use of clinical specimen will be the property of 
Northwestern University for publication and any licensing agreement will be strictly 
adhered to. 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
• Diagnosis 
• Collection time in relation to study treatment 
• Clinical outcome – if available 
 
 
• Demographic data 
 
 
10.0 STATISTICAL CONSIDERATIONS 
This is a Phase II trial to estimate the clinical response (complete response rate) following 
administration of pembrolizumab with AVD chemotherapy for patients with de novo Hodgkin’s 
lymphoma. We will also describe toxicity and gather preliminary data about efficacy (EFS and 
OS). Biologic correlates will be studied in an exploratory fashion. 
 
10.1 
Evaluability 
To be evaluable for inclusion in the analysis to address the primary objective, patients 
must: 
• 
have received at least one dose of pembrolizumab 
AND 
• 
have a FDG-PET/CT scan following cycle #3 of pembrolizumab (PET#2)  
 
10.2 
Sample Size and Accrual 
This is a Phase II study in which the primary aim will be to determine the complete response 
rate to up front pembrolizumab.  The treatment paradigm of this trial will be considered 
worthy of further evaluation if at least 40% of patients achieve CR at PET#2 (defined as 
Deauville 1-3).   
 
The target sample size for the primary response analysis is 26 patients, with 4 additional 
patients to be accrued to account for dropout, so that the total target sample size is 30 
patients in order to increase the CR rate to single agent pembrolizumab from the baseline 
level of 20% in relapsed/refractory patients, to 40% with a power of 84% at an alpha level 
of 10%.  For the analysis of complete response by PET, a single arm single stage Bayesian 
design with 26 patients may also be used.  Response is defined as a Deauville score of 1-
3 after the initial treatment with pembrolizumab alone.  The posterior probability of a 
response rate being greater than 50% will be calculated using a non-informative prior 
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distribution.  With 26 patients, the following table gives this posterior probability for an 
observed number of responses. 
 
Observed number of responses/26: 
 
11 
12 
13 
14 
15 
Probability that response rate > 40%: 
 
0.61 
0.75 
0.86 
0.92 
0.96 
 
Therefore, to be more than 80% sure that the response rate exceeds 40%, at least 13 of 
26 responses would need to be observed in the total population.  After PET#3, patients will 
be analyzed as a total population as well as by age cohort for response rate, PFS, and OS.   
 
10.3 
Data Analyses Plans 
 
10.3.1 Analytic Plan for Primary Objective 
To assess the primary objective of response rate following PET (2) performed 
after 3 doses of pembrolizumab, we will assess PET response using the 5 point 
Deauville criteria. Patients with a Deauville score of 1-3 will be considered a 
complete response. Patients will be evaluable for response assessment if they 
have received at least one dose of pembrolizumab.  Response will be 
determined in all patients after induction (PET # 2) and after chemotherapy (PET 
# 3) using a proportion and an exact binomial 95% confidence interval.  It will be 
observed whether 50% is in the confidence interval.  Continuous futility 
monitoring will occur using the method of Lee & Liu.50   While this method may be 
used to identify a futile level of response after each patient, it will begin 
monitoring after 10 patients.  Futility will be indicated if at most 1/10, 3/15 or 5/20 
evaluable patients have a response, assuming 26 total evaluable patients will be 
observed.  For these calculations, futility means that the posterior probability that 
the response rate exceeds 50% is less than 10%. 
 
 
10.3.2 Analytic Plan for Secondary Objectives 
To assess safety and tolerability, all adverse events will be summarized in terms 
of type, grade, timing and attribution to treatment. All enrolled patients who receive 
at least one injection of study drug or undergo a study-related procedure will be 
included in the safety analysis. The highest toxicity grades per patient will be 
tabulated for AEs and laboratory measurements, and the number and percent of 
patients reporting AEs will be quantified. Listings will be required for all on-study 
deaths, SAEs and AEs that lead to withdrawal from study. Narratives for all SAEs 
and deaths on-study will be required. These summaries will be done by age cohort. 
Continuous toxicity monitoring will occur using the method of Ivanova et al.51  While 
this method may be used to identify an unacceptable level of toxicity after each 
patient, only values for every 5 patients will be given here.  The following table 
gives the number of unacceptable toxicities that need to be observed after 5, 10, 
15, 20, 25, 30 patients to identify an adverse toxicity rate exceeding 20% with a 
false positive rate (after each patient) of 2% and a desired probability of early 
stopping of 5%. Unacceptable toxicity is defined as any toxicity requiring 
discontinuation of pembrolizumab, as defined in Table 4.1.  
Number of patients observed: 
5 
10 
15 
20 
25 
30 
Number of observed toxicities: 4 
6 
8 
9 
11 
12 
Response assessment: Anti-tumor activity will be assessed using the LUGANO 
2014 Response Criteria (Appendix C). Patients who receive consolidation with 
pembrolizumab will also have disease assessed by the Immune Response Criteria 
(Appendix F) as an exploratory assessment. To assess progression free survival 
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(PFS) and overall survival (OS), Kaplan Meier curves for progression and survival 
will be calculated for each cohort. The 3-year PFS will be determined from this 
curve for all patients  
10.3.3 Analytic Plan for Exploratory Objectives 
All enrolled patients who receive at least one injection of study drug and have a 
correlative sample will be included in the exploratory immune biomarker analysis. 
Tabulation, summarization and descriptive statistics will be performed describing 
the baseline and post pembrolizumab biomarkers.  To assess whether PD-1 and 
PD-L1 and related pathway expression on paired biopsy samples prior to and 
following single agent pembrolizumab is related to response, the difference in 
biomarker expression will be calculated.  A signed rank test will determine 
whether this change is significant and a rank sum test will determine whether the 
level of biomarker change before and after pembrolizumab is related to response 
as measured by PET#2.  A similar analysis will be done for changes in serum 
cytokines, markers of immune/inflammatory response changes in lymphocyte 
subsets by flow cytometry and cysteine-cysteine thymus and activation related 
chemokine (TARC). 
 
Genetic alterations in chromosome 9p24.1 (amplification, increased copy 
number, polysomy, and disomy) measured at baseline will be related to response 
using logistic regression. 
 
 
11.0 STUDY MANAGEMENT 
11.1 
Institutional Review Board (IRB) Approval and Consent  
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
 
 
11.2 
Amendments 
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
Janssen Scientific Affairs. Amendments will be distributed by the lead institution 
(Northwestern) to all affiliate sites upon approval by the Northwestern University IRB. 
 
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NU Study Number: NU 16H08 
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11.3 
Registration Procedures 
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Trials Office at Northwestern University before 
enrollment to study. Please contact the assigned Quality Assurance Monitor (QAM) or 
email the QA Department (croqualityassurance@northwestern.edu) for questions 
regarding patient registration.   
 
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system. 
 
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number: 
• 
Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart) 
• 
Eligibility checklist (signed and dated by the treating physician – upload to NOTIS) 
• 
Eligibility eCRF (complete in NOTIS) 
• 
Copy of the pathology report (upload to NOTIS) 
Training on eCRF completion will be provided at the time of site activation. Please refer 
to the eCRF demonstration videos on the CTO website for additional instructions on 
registering a patient. 
 
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment. 
 
11.4 
Instructions for Participating Sites 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Trials Office at Northwestern University: 
• 
Signed and completed Letter of Invitation to participate in the study. 
• 
Signed copy of Northwestern University’s Data and Safety Monitoring Committee 
policy pertaining to data submission. 
• 
Draft informed consent form should for review/approval prior to submission to the 
local IRB 
• 
A copy of the official IRB approval letter for the protocol and informed consent.  
• 
CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site. 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation. 
 
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation. 
 
11.5 
Data Management and Monitoring/Auditing 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The 
level of risk attributed to this study requires high risk monitoring as outlined in the DSMP. 
The assigned QAM, with oversight from the Data and Safety Monitoring Committee, will 
monitor this study in accordance with the study phase and risk level. Generally, for all 
phase II patients, data are due within 10 days of completion of every cycle. 
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63 
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11.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
 
11.6.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.  
 
11.6.2 Other Protocol Deviations 
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
• 
Is generally noted or recognized after it occurs. 
• 
Has no substantive effect on the risks to research participants. 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.7 
Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.  
 
11.8 
Publication Policy 
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. The assigned QAM 
will prepare a preliminary data summary (to be approved by the DSMC) no later than 3 
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months after the study reaches its primary completion date (the date that the final subject 
is examined or receives an intervention for the purposes of final data collection for the 
primary endpoint). If the investigator’s wish to obtain DSMC-approved data prior to this 
point (or prior to the point dictated by study design), the PI must send a written request 
for data to the QAM which includes justification. If the request is approved, data will be 
provided no later than 4 weeks after this request approval. The data will be presented to 
the DSMC at their next available meeting, and a final, DSMC-approved dataset will be 
released along with any DSMC decisions regarding publication. The investigators are 
expected to use only DSMC-approved data in future publications. The investigators 
should submit a copy of the manuscript to the biostatistician to confirm that the DSMC-
approved data are used appropriately.  Once the biostatistician gives final approval, the 
manuscript may be submitted to external publishers. 
 
 
 
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IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
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the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. 
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Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection 
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CH M. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in 
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Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-
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IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

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Moskowitz AJ, Cho S, Fleisher M, et al. TARC Predicts PET-Normalization and Event 
Free Surival in Relapsed/Refractory Hodgkin Lymphoma Patients Treated with 
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Swerdlow SH, International Agency for Research on Cancer., World Health 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
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Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification 
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Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ 
tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced 
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49. 
Rossille D, Gressier M, Damotte D, et al. High level of soluble programmed cell death 
ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell 
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50. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin 
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51. 
Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
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52. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
2009;15(23):7412-7420. 
 
 
 
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APPENDIX A: 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. 
 
 
 
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APPENDIX B: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.03 
(CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf ) 
 
 
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APPENDIX C: 2007 REVISED RESPONSE CRITERIA FOR MALIGNANT 
LYMPHOMA 
LUGANO 2014 RESPONSE CRITERIA 
 
Lugano 2014 response criteria will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, PET-CT is the preferred imaging technique in this study. 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
 
Complete 
Lymph nodes and 
extralymphatic sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nonmeasured lesion  
 
Organ enlargement  
 
New lesions 
 
Bone marrow 
 
Complete metabolic response 
Score 1, 2, or 3* with or without 
a residual mass on 5PS† 
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 
greater than surrounding normal 
tissue even if the tissue has 
high physiologic uptake 
 
Not applicable  
 
Not applicable  
 
None 
 
No evidence of FDG-avid 
disease in marrow 
Complete radiologic response 
(all of the following) 
Target nodes/nodal masses 
must regress to < 1.5 cm in LDi 
No extralymphatic sites of 
disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent 
 
Regress to normal  
 
None 
 
Normal by morphology; if 
indeterminate, IHC negative 
 
Partial 
Lymph nodes and 
extralymphatic sites 
 
 
 
 
 
 
 
 
 
Nonmeasured  lesions  
 
 
Organ enlargement 
 
 
 
Partial metabolic response 
Score 4 or 5† with reduced 
uptake compared with baseline 
and residual mass(es) of any 
size 
At interim, these findings 
suggest responding disease 
At end of treatment, these 
findings indicate residual 
disease 
 
 
 
 
Not applicable  
 
 
Not applicable 
Partial remission (all of the 
following) 
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm x 
5 mm as the default value 
When no longer visible, 0 x 0 
mm 
For a node > 5 mm x 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
 
Absent/normal, regressed, but 
no increase 
 
Spleen must have regressed by 
> 50% in length beyond normal 
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72 
Amendment 6: March 29th, 2019 
New lesions  
 
Bone marrow 
 
 
None 
 
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 
 
None 
 
Not applicable 
No response or stable disease 
Target nodes/nodal masses, 
extranodal lesions 
 
 
 
 
Nonmeasured  lesions  
 
 
Organ enlargement  
 
 
New lesions 
 
Bone marrow 
No metabolic response 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
 
 
Not applicable  
 
 
Not applicable  
 
 
None 
 
No change from baseline 
Stable disease 
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
 
No increase consistent with 
progression  
 
No increase consistent with 
progression  
 
None 
 
Not applicable 
 
Progressive disease 
 
Individual target nodes/nodal 
masses 
 
 
Extranodal lesions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progressive metabolic disease 
 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
 
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment   assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progressive disease requires 
at least 1 of the following  
 
PPD progression: 
 
 
 
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 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
Nonmeasured lesions 
 
 
 
New lesions  
 
 
 
 
 
 
 
 
 
 
Bone marrow  
 
None 
 
 
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 
 
 
 
 
 
New or recurrent FDG-avid foci 
 
New or clear progression of 
preexisting nonmeasured lesions 
 
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 
 
New or recurrent involvement 
 
 
 
 
 
 
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Amendment 6: March 29th, 2019 
APPENDIX D: UNFAVORABLE RISK FACTORS - NCCN GUIDELINES 
 
Unfavorable Risk Factors for Stage I-II Classic Hodgkin Lymphoma (NCCN) 
 
MMR = Mediastinal mass ratio, maximum width of mass/maximum intrathoracic diameter 
 
NOTE: Under NCCN criteria, lymph node regions are defined using Ann Arbor definitions listed below.  
 
 
 
APPENDIX E: DEAUVILLE CRITERIA 
Deauville Criteria for Evaluating FDG-PET/CT Imaging 
Score  
Description 
1 
No residual uptake 
2 
Slight uptake, but below blood pool (mediastinum) 
3 
Uptake above mediastinum, but below or equal to 
uptake in the liver 
4 
Uptake slightly to moderately higher than liver 
5 
Markedly increased uptake or any new lesions 
 
 
 
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NU Study Number: NU 16H08 
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75 
Amendment 6: March 29th, 2019 
 
APPENDIX F: IMMUNE RESPONSE CRITERIA 
 
Immune response criteria will also be assessed in all patients who receive consolidation with 
pembrolizumab in addition to standard assessments with Lugano response criteria. 
 
Response 
designation 
Definition 
irCR 
(complete 
remission) 
Complete disappearance of all lesions (whether measureable or not, and no new 
lesions), confirmed by a repeat, consecutive assessment no less than 4 weeks 
from the date first documented 
irPR (partial 
remission) 
Decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation 
irSD (stable 
disease) 
Not meeting criteria for irCR or irPR, in absence of irPD 
irPD 
(progressive 
disease) 
Increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden), confirmed by a repeat, consecutive assessment no less than 4 weeks 
from the date first documented 
 
 
 
Adapted from Wolchok et al. ir, immune response 52. 
 
 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
76 
Amendment 6: March 29th, 2019 
APPENDIX G: PROTOCOL SUMMARY OF CHANGES 
 
Amendment 1 (Pre-IRB) – December 16, 2016  
Approved by Scientific Review Committee: January 23, 2017 
Section(s) Affected 
Prior Version 
Amendment 1 Changes 
Rationale 
Cover Page 
n/a 
Adds Reem Karmali as a 
sub-investigator 
Administrative; new faculty 
member to be involved in 
study 
Cover Page 
IND Number/Holder 
listed as “TBD” 
Includes IND Number 
(132372) and Holder (Jane 
Winter, MD) 
Administrative; IND 
information is now available 
Study Schema 
Diagram included two 
arms after PET#3: 
Stage I/II and Stage 
III/IV 
Diagram now includes 
separate treatment plans for 
two age cohorts (Ages <60 
and ≥60), and the options 
for different stages (Stage I-
II vs III/IV) within those, 
Clarifications; new diagram is 
more inclusive of the two age 
cohorts and clearly lays out 
the treatment plan for each 
possible situation. 
Study Schema; Study 
Summary;  
4.1 (Overview); 4.2.2 
(AVD); 4.6.1 
(Duration of Therapy); 
5.0 (Study 
Procedures) 
Pembrolizumab 
consolidation was to 
be given for a 
maximum of one year 
Pembrolizumab 
consolidation can continue 
for up to two years for 
patients ≥60 who do not 
achieve a CR after AVD 
To align with Merck’s 
standard regimen for 
pembrolizumab after 
discussion between Merck 
and study PI. 
Study Summary 
Included short title: 
“Frontline PD-1 and 
Hodgkin Lymphoma” 
Removes short title 
To align with current NU 
protocol template; short title is 
no longer required 
Study Summary 
Listed objectives of 
PFS and OS 
separately by age 
and disease stage 
Lists two separate 
objectives for PFS and OS; 
one is for the overall study 
population, and one 
separates the patients by 
age cohort (patients <60 
and ≥60 years old) 
Clarification requested by 
Merck. It was previously 
unclear whether the age 
cohorts also included 
separate assessments of 
PFS, OS and response.  
Study Summary;  
3.1.6 (Inclusion 
Criteria) 
n/a 
Adds inclusion criteria “All 
stages and International 
Prognostic Score (IPS) risk 
groups” 
Clarification to verify that all 
stages of lymphoma are 
eligible 
Study Summary;  
10.2 (Sample Size 
and Accrual) 
The treatment 
paradigm of this trial 
will be considered 
worthy of further 
evaluation if at least 
50% of patients 
achieve CR at PET#2 
(defined as Deauville 
1-3).  In order to have 
at least a 78% 
chance of detection 
at the 10% alpha 
level, and increase 
from the historical 
control of 20% rates 
of CR for patients 
with rel/ref cHL 
The treatment paradigm of 
this trial will be considered 
worthy of further evaluation 
if at least 40% of patients 
achieve CR at PET#2 
(defined as Deauville 1-3).  
In order to have 84% power 
to detect an increase from 
the historical control of 20% 
rates of CR for patients with 
rel/ref cHL treated with 
pembrolizumab, at a one-
tailed alpha of 10%, 
approximately 26 evaluable 
patients will be required 
total. 
Statistical clarifications for 
accuracy 
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NU Study Number: NU 16H08 
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Initial Version date: March 10th, 2017 
 
77 
Amendment 6: March 29th, 2019 
treated with 
pembrolizumab 
approximately 26 
evaluable patients 
will be required total. 
2.2 (Secondary 
Objectives); 6.3 
(FDG-PET/CT 
Guidelines) 
References A(B)VD 
Removes B, referencing 
AVD 
Bleomycin is part of the 
standard chemotherapy 
regimen but is omitted from 
this study due to possible 
toxicities 
2.3 (Exploratory 
Objectives) 
• Peripheral blood 
will be tested for 
serum levels of 
TNF-α, IFN-γ, IL-2, 
IL-7, IL-9, and 
galectin-1. 
• Referenced 
lymphocyte 
subsets as the 
primary objective 
• Peripheral blood will be 
tested for serum levels of 
TNF-α, IFN-γ, IL-2, 
galectin-1, TGF-β, IL-10, 
IL-13, and indoleamine 
2 3-dioxygenase (IDO). 
• Removes reference to 
primary objective 
• To account for additional 
analysis of correlative 
samples. 
• Correction of error; 
lymphocytes are being 
analyzed as an exploratory, 
rather than primary, 
objective. 
3.1.8 (Inclusion 
Criteria) 
Definition for 
Females of child-
bearing potential was 
taken from the 
Northwestern 
template 
Replaces language to 
match section 4.5.2  
Clarification to align with 
Merck requirements and 
definitions 
3.2.9 (Exclusion 
Criteria) 
“Patients who have a 
known history of, or 
any evidence of 
active, non-infectious 
pneumonitis are not 
eligible.” 
“Patients who have a 
history of (non-infectious) 
pneumonitis that required 
steroids or current 
pneumonitis are not 
eligible.” 
To align with Merck’s required 
language for pneumonitis. 
4.1 (Overview);  
4.2.1 
(Pembrolizumab) 
Consolidation was to 
be given to patients 
≥60 with: 
• Stage III/IV disease 
who receive <6 
cycles of AVD 
• DV score of 4 or 5 
on interim PET 
Consolidation will take 
place for patients ≥60: 
• With stage III/IV disease 
who receive ≤6 cycles of 
AVD 
• Who are not in CR at the 
completion of 
chemotherapy 
Clarifications;  
4.3.1 (Pembrolizumab 
Dose Modifications) 
n/a 
Adds note to pneumonitis to 
specify that recurrent grade 
2 pneumonitis should lead 
to discontinuation of 
pembrolizumab. 
Clarification requested by 
Merck. 
4.6.2 (Duration of 
Follow Up); 4.6.3 
(Subject Withdrawal / 
Discontinuation 
Criteria from 
Treatment and/or 
Overall Study);  
5.0 (Study 
Procedures #7,18) 
n/a 
Adds additional monitoring 
of patients who undergo 
allogeneic stem cell 
transplant within 24 months 
of study treatment. Specific 
adverse events and 
transplant parameters will 
be collected for 18 months 
from the date of the 
transplant. 
Additional safety parameters 
requested by Merck. 
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Initial Version date: March 10th, 2017 
 
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Amendment 6: March 29th, 2019 
5.0 (Study 
Procedures #17);  
9.4 (Specimen 
Banking) 
n/a 
Adds specimens for 
banking to correlative blood 
samples 
Future studies may be 
valuable in this study 
population, and extra blood 
will be collected for this 
possibility. 
6.2 (Lymphoma 
Response Criteria); 
6.4.2 (Secondary 
Endpoints); Appendix 
G 
n/a 
“Patients who receive 
consolidation with 
pembrolizumab will also 
have disease assessed by 
the Immune Response 
Criteria (Appendix G)” 
Additional response criteria 
included for exploratory 
response assessment for 
immune response 
6.4.2 (Secondary 
Endpoints) 
Patients were to be 
evaluated using 2007 
Revised Response 
Criteria for Malignant 
Lymphoma (RRCML) 
Patients will be evaluated 
using Lugano 2014 
Response Criteria 
To align with current criteria 
for assessing response in 
lymphoma 
10.2 (Sample Size 
and Accrual) 
Included a sample 
size of 20 patients 
and analysis of 
patients by age 
cohort after PET #3 
Changes sample size to 30 
patients and includes power 
calculations for the 
probability that response 
rate is > 40%. Clarifies that 
patients will be analyzed as 
a total population as well as 
by age cohort, and this 
includes PFS, OS, and 
response. 
Clarifications requested by 
Merck and to be consistent 
with prior sections 
Amendment 2 (Pre-IRB) – March 10, 2017  
Approved by Scientific Review Committee: March 27, 2017 
Section(s) 
Affected 
Prior Version 
Amendment 2 Changes 
Rationale 
Cover Page; 
Study Summary 
(Centers) 
Included Memorial Sloan 
Kettering Cancer Center 
as affiliate site with Paul 
Hamlin as PI 
Removes Memorial Sloan 
Kettering and adds Stanford 
Cancer Institute as affiliate 
site, with Ranjana Advani as 
the PI 
Administrative, changes in 
affiliates 
Cover Page 
Included Derek 
Wainwright as a study 
collaborator 
Removes Derek Wainwright 
as study collaborator 
Administrative; the 
Wainwright laboratory is 
currently at capacity for new 
studies 
Study Schema; 
Study Summary 
(Study Design, 
Treatment Plan); 
4.1 (Overview); 
4.2.3 
(Pembrolizumab 
Consolidation); 
4.6.1 (Duration of 
Therapy) 
Pembrolizumab 
consolidation was to take 
place for 1 or 2 years for 
certain patients ≥60  
Adds that pemrolizumab 
consolidation should take 
place for 1 or 2 years total 
(where total treatment = 3 
cycles of induction pembro + 
14 or 32 cycles of 
consolidation pembro) 
Clarification requested by 
Merck; it was previously 
unclear whether the 
induction doses were to be 
counted among the 1 or 2 
years of pembrolizumab 
treatment. 
Study Schema;  
4.1 (Overview) 
Pembrolizumab 
consolidation was 
reserved for patients who 
did not achieve a CR 
during chemotherapy 
Pembrolizumab consolidation 
will now be based on PET#3 
results, and response to AVD 
will not be accounted for. 
Patients >60 who are PET(+) 
and those who are PET(-) and 
The protocol is intended to 
be PET-driven. A positive 
early PET (#3, following two 
cycles of AVD) generally 
predicts for treatment 
failure.   Consequently, for 
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79 
Amendment 6: March 29th, 2019 
receive <6 cycles of AVD will 
proceed to pembrolizumab 
consolidation 
the elderly, the results of 
PET #3 will determine which 
patients get PEM 
consolidation in an attempt 
to improve outcomes.  
Rather than limiting PEM 
consolidation to those 
patients who have a positive 
PET at the conclusion of 
chemotherapy (AVD), all 
elderly patients  with a 
positive PET#3 will have 
PEM consolidation 
Study Schema; 
4.2.2.2.3 (Repeat 
Imaging (PET#4 
or CT Scan)); 6.3 
(FDG-PET/CT 
Guidelines) 
An end of treatment PET-
CT or CT was listed as a 
vague recommendation 
All patients will have imaging 
2-6 weeks after completing 
chemotherapy to establish 
treatment response. Imaging 
will be a PET-CT (PET#4), 
except for patients who have 
Stage I/II disease and a 
negative PET#3, who will 
have a diagnostic CT scan. 
To be sure of disease status 
at the completion of 
chemotherapy, patients will 
be reimaged.   
Study Schema 
Patients could receive 2 
years of consolidation or 
2 cycles beyond PET-CR  
Removes option for 2 cycles 
beyond PET-CR 
Requested by Merck; 
patients should receive the 
full two years 
pembrolizumab even after 
achieving a CR 
Study Summary 
(Objectives) 
n/a 
Re-words third secondary 
objective for clarity 
Grammatical clarification 
Study Summary 
(Treatment Plan) 
Listed treatment options 
into three groups of 
patients (Stage I/II vs 
Stage III/IV vs elderly).   
Separates treatment options 
into four groups of patients by 
age (younger patients Stage 
I/II vs Stage III/IV and elderly 
patients Stage I/II vs Stage 
III/IV) Re-words treatment 
plan to make it very clear 
which patients receive what 
treatment. 
Also rewords descriptions of 
treatment for clarity. 
Previous language was 
unclear and inaccurate. 
New language clearly 
delineates which patients 
should receive what 
treatment.  
2.3 (Exploratory 
Objectives);  
9.0 (Correlative/ 
Special Studies) 
Included serum 
biomarkers of immune 
and inflammatory 
response as an 
exploratory study 
Removes serum biomarkers 
as an exploratory study 
Dr. Wainwright’s lab will no 
longer be able to run the 
analysis for this study since 
it is at capacity 
4.0 (Treatment 
Plan) 
Tables were numbered 1, 
2, 3 etc. 
Re-numbers tables 4.1, 4.2, 
4.3 etc. 
Clarification 
4.2 (Treatment 
Administration) 
n/a 
Re-orders treatment 
descriptions and sections to 
align with the order in which 
they are given 
(Pembrolizumab Induction  
Chemotherapy  AVD or 
escBEACOPP  Pembro 
Consolidation); also adds 
Revised for clarity 
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80 
Amendment 6: March 29th, 2019 
“Cycle numbers” to section 
titles 
4.2.2.1 (Cycle 1 & 
2: AVD 
Chemotherapy 
post 
pembrolizumab 
induction) 
States that all trial 
treatments will be 
administered on an 
outpatient basis.  
Removes statement that all 
trial treatments will be 
administered on an outpatient 
basis. 
Clarification; if needed, 
chemotherapy or 
pembrolizumab may be 
given inpatient. 
n/a 
Adds specific timing for 
PET#3 (day 117-120 / day 26-
29 of AVD cycle 2) 
Clarification 
Listed specific 
recommendations for 
prophylactic antibiotics 
(oral thrush and PCP 
prophylaxis) 
Removes specific 
recommendations and states 
that antibiotic use is at the 
discretion of the treating 
physician 
It is clinically appropriate to 
leave antibiotic prophylactic 
at the discretion of the 
treating physician  
4.2.2.2 (Cycle 3-
6: AVD (or 
escBEACOPP)) 
Contained language for 
both AVD and 
escBEACOPP treatment 
in the same section 
Separates treatment details 
by patients with a negative 
(4.2.2.2.1) vs positive 
(4.2.2.2.2) PET #3; 
Clarifies total cycles of AVD 
received by each set of 
patients 
Clarification; previous 
language was unclear 
4.2.3 
(Pembrolizumab 
Consolidation);  
5.0 (Study 
Procedures #14); 
6.3 (FDG-PET/CT 
Guidelines) 
Patients were to have 
CT’s every 3 months 
during consolidation 
Patients are recommended to 
have PET/CT every 3 months 
during consolidation, and CT’s 
once the PET is negative 
Additional imaging will be 
obtained every three 
months during consolidation 
to determine duration of 
response for those 
beginning consolidation with 
a negative PET/CT, and to 
identify patients who convert 
from PET-positive to PET-
negative during 
consolidation. 
4.2.3 
(Pembrolizumab 
Consolidation) 
Contained redundant 
language about patients 
with PET-CR vs not PET-
CR.  
Removes language to 
distinguish between PET-CR 
and no PET-CR  
Clarification 
4.3.1 
(Pembrolizumab 
Dose 
Modifications) 
n/a 
Adds pembrolizumab dose 
modification guidelines for 
cardiac dysfunction (related to 
myocarditis), Stevens-
Johnson Syndrome, and Toxic 
Epidermal Necrolysis 
Additional guidelines 
provided by Merck as a 
result of new safety events 
4.5.2 
(Management of 
Cardiac 
Toxicities) 
n/a 
Adds language for managing 
cardiac toxicities, specifically 
related to myocarditis 
Guidelines provided by 
CTEP as a result of 
myocarditis safety events 
related to nivolumab, an 
immunotherapy agent 
similar to pembrolizumab 
5.0 (Study 
Procedures) 
Pembrolizumab 
consolidation cycles were 
listed as 1-34 
Re-numbers consolidation 
cycles as 4-35 
Clarification; total 
pembrolizumab treatment 
should be up to 35 cycles 
including pembrolizumab 
induction (Cycles 1-3) 
#5: Pembrolizumab for 2 
years in elderly patients 
#5: Elderly patients may 
receive consolidation for a 
Clarifications 
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81 
Amendment 6: March 29th, 2019 
with DV score >3 on PET 
#3 or elderly patients with 
stage III/IV disease 
receiving < the intended 
6 cycles of AVD 
total of up to 1 or 2 years 
pembrolizumab treatment. 
Elderly patients who do not 
achieve CR after additional 
AVD will have pembrolizumab 
consolidation for up to 32 
additional doses. Elderly 
patients with Stage III/IV 
disease who achieve CR after 
<6 cycles AVD will receive 
pembrolizumab consolidation 
for up to 14 additional doses. 
See section 4.2.3 for details.    
#14: Language on 
PET/CT timing was 
vague, referring to the 
primary endpoint. 
#14: Clarifies timing of PET#2 
and PET#3. Also adds that 
PET/CT will be performed 2-6 
weeks after the completion of 
chemotherapy and every 3 
months until PET-negative. 
Clarifications 
IRB Comments – June 29th, 2017  
 Approved by Scientific Review Committee: July 3, 2017 
Section(s) 
Affected 
Prior Version 
Changes 
Rationale 
5.0 (Study 
Procedures, #14, 
16, 17) 
n/a 
Adds designations for 
“Research” vs “Standard of 
Care” procedures (PET/CT’s, 
correlative tissue and 
correlative blood) 
Clarification requested by 
the IRB 
Amendment 3 – June 29th, 2017  
Approved by Scientific Review Committee: July 3, 2017  
Section(s) 
Affected 
Prior Version 
Amendment 3 Changes 
Rationale 
5.0 (Study 
Procedures, #17) 
Listed blood volumes for 
correlatives and 
“specimens for banking” 
as a separate blood draw 
Removes blood volumes, 
adds “SST for CCL17”, 
purpose of each SST tube 
(Inflammatory and Immune 
Markers, Soluble PD-L1) and 
removes “Specimens for 
banking” 
Details for correlatives will 
be kept in the study lab 
manual and not the protocol 
to avoid unnecessary 
protocol deviations and 
amendments. Also corrects 
discrepancies.  
6.2 (Lymphoma 
Response 
Criteria); 9.3.5 
(Soluble PD-L1); 
Appendix F; 
Appendix G 
Included Appendix F with 
details on processing the 
DuoSet ELISA assay for 
soluble PD-L1  
Removes Appendix F, any 
references to Appendix F and 
renumbers subsequent 
appendices 
Details for correlatives, 
including processing details, 
will be kept in the study lab 
manual  
9.2 (Biopsy 
Specimen 
Analysis) 
FISH was to be 
performed at the 
Northwestern PathCore 
facility 
FISH will be performed in the 
Northwestern pathology 
department 
To correct discrepancy; 
PathCore facility no longer 
performs FISH analysis 
9.3 (Peripheral 
Blood 
Correlatives) 
Section included specific 
language on sample 
collection, processing, 
and storage.  
Removes all details on 
sample collection, processing, 
and storage. 
Details for correlatives, 
including collection, 
processing, and storage, will 
be kept in the study lab 
manual   
Amendment 4 – March 8th, 2018 
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NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
82 
Amendment 6: March 29th, 2019 
Approved by Scientific Review Committee: May 2, 2018 
Section(s) 
Affected 
Prior Version 
Amendment 4 Changes 
Rationale 
Cover Page 
Listed Pamela Allen and 
Jason Kaplan as 
Northwestern sub-I’s 
Removes Jason Kaplan and 
adds Pamela Allen as the sub-
I at Emory University 
Administrative faculty 
changes 
Cover Page; 
Study Summary; 
3.0 (Patient 
Eligibility) 
Affiliate sites were Tufts 
and Stanford 
Removes Tufts, adds Rutgers 
Cancer Institute and Emory 
University 
Andrew Evens transferred 
from Tufts to Rutgers and 
remains sub-I. Pam Allen 
transferred from 
Northwestern to Emory and 
remains sub-I 
Study Schema 
n/a 
Clarifies that patients who 
receive escBEACOPP will be 
in follow-up at that stage 
Adds cycle duration 
throughout 
Adds follow-up after 
pembrolizumab consolidation 
Clarifies that consolidation is 
for 1 year total 
Clarifications  
Study Schema; 
Study Summary 
4.1 (Overview); 
4.2.2.2 (Cycle 3-6 
AVD) 
Patients with Stage I/II 
disease and a negative 
PET #3 were to receive 2 
cycles of AVD 
Adds an exception; patients 
with bulky disease at baseline 
may receive 4-6 cycles of 
AVD per physician discretion 
Patients with bulky disease 
may require additional 
treatment. The PI feels it is 
clinically appropriate to 
allow for additional 
treatment as needed. 
Study Summary; 
2.2 (Secondary 
Objectives);  
10.3.2 (Analytic 
Plan for 
Secondary 
Objective) 
Included an objective to 
look specifically at PFS 
and OS by age (Cohort 1: 
< 60 years old; Cohort 2: 
≥ 60 years old) 
Removes analysis of separate 
cohorts. PFS and OS will be 
analyzed in the study 
population as a whole. 
To avoid enrollment 
barriers, patient accrual 
goals are no longer evenly 
stratified by age groups 
Study Summary; 
3.1.6, 3.1.7 
(Inclusion Criteria) 
Allowed for all stages and 
International Prognostic 
Score (IPS) risk groups 
Specifies that Stage III and IV 
disease may have any IPS, 
but Stage I and II must have 
at least one NCCN 
unfavorable risk factor 
Clarification of allowable 
disease stages using 
updated NCCN guidelines 
3.2.1 (Exclusion 
Criteria) 
Patients were not eligible 
who had received prior 
therapy within 2 weeks 
prior to registration or 
who have not recovered 
from adverse events. 
Patients are not eligible who 
have had any prior therapy. 
Removes window. 
To address discrepancy; 
study aims to treat patients 
with no prior treatment as a 
frontline therapy. 
3.2.5 (Exclusion 
Criteria) 
Patients with congestive 
heart failure, unstable 
angina pectoris or 
cardiac arrhythmia were 
not eligible.  
Adds that ejection fraction 
must be above institutional 
lower limit of normal. 
Clinical clarification  
4.2.2.2 (Cycle 3-
6: AVD or 
escBEACOPP) 
Referred to positive PET 
#3 as DV score 1,2, or 3 
Changes to state that DV 
score 4 or 5 is considered 
positive for PET#3  
To fix typographical error  
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
83 
Amendment 6: March 29th, 2019 
4.3.1 
(Pembrolizumab 
Dose 
Modifications) 
Contained a table for 
pembrolizumab dose 
delays that was provided 
by Merck 
Replaces table for 
pembrolizumab dose delays. 
Response to action letter 
from Merck due to updated 
safety information. 
4.4.2 (Prohibited 
Concomitant 
Medications) 
The use of 
corticosteroids may be 
approved after 
consultation with the 
Sponsor 
Changes Sponsor to PI 
The PI should be consulted 
for such issues since this is 
an investigator-initiated 
study, and NU is the 
sponsor 
4.3 (Toxicity 
Management & 
Dose Delay);  
4.6.4 (Patient 
Replacement);  
7.3 (Adverse 
Event Reporting); 
11.8 (Publication 
Policy) 
Referred to Data 
Monitoring Committee 
(DSMC) 
Updates to Data and Safety 
Monitoring Committee 
(DSMC) 
To align with internal 
policies 
5.0 (Study 
Procedures); 
Appendix D 
Patients’ NCCN IPI score 
was to be collected at 
baseline 
Updates to “Unfavorable risk 
factors” referencing Appendix 
D 
To align with current 
practice for evaluating 
disease factors 
5.0 (Study 
Procedures) 
Off treatment visit was to 
take place 30 days after 
last dose 
Adds clarification that this can 
be 30 days after 
pembrolizumab or AVD 
Clarification 
n/a 
Adds Quantiferon-gold TB 
blood test at baseline 
Patients with active TB are 
excluded from the study; 
adds screening requirement  
for consistency 
#3: Physical exam was 
required on Day 1 and 15 
of each cycle of AVD 
#3: Removes Day 15 
requirement  
Does not follow standard 
practice and is not clinically 
necessary 
#14 & 15: Diagnostic CT 
and PET/CT were 
required within 5 weeks 
prior to patient 
registration  
#14 & 15: Extends window to 
6 weeks 
Broadens scan allowance to 
benefit patients with recent 
scans; this is clinically 
appropriate and allowable 
per PI.   
5.0 (Study 
Procedures #16); 
9.0 (Correlative / 
Special Studies) 
#16: Tissue collection 
was listed at AVD Cycle 
1-2 and not listed in 9.0 
#16: Moves tissue collection 
to pembrolizumab 
monotherapy with footnote to 
state that it will be collected 2-
4 weeks after first dose of 
pembrolizumab (optional). 
Adds optional sample to 
section 9.0 
Revised for clarity and to 
ensure tissue is collected 
6.2 (Lymphoma 
Response 
Criteria); 6.4.2 
(Secondary 
Endpoints);  
Patients who receive 
consolidation treatment 
will be evaluated using 
Immune Response 
Criteria 
Clarifies that Immune 
Response Criteria is only 
being used as an exploratory 
assessment 
Clarification  
7.2.2 (Severity of 
AE’s); 7.3.2 
(Determining if 
Expedited 
Reporting is 
Referenced CTCAE 
version 4.0 
Updates to CTCAE version 
4.03 
Administrative update 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
84 
Amendment 6: March 29th, 2019 
Required); 
Appendix B 
8.1.4 (Storage 
and Stability) 
Storage was allowed for 
6 hours at room 
temperature and 24 
hours refrigerated. 
Updates storage allowance to 
4 hours at room temperature 
and 20 hours refrigerated. 
Updated to align with most 
current pharmacy manual. 
8.1.6 
(Preparation) 
Contained instructions for 
pembrolizumab as both a 
lyophilized powder and a 
solution 
Removes references to 
lyophilized powder 
Pembrolizumab is being 
supplied as a solution  
8.1.9 (Availability 
& Supply) 
Listed Sloan Stribling and 
Tammy Moll as drug 
ordering contacts 
Removes contacts and 
instead refers to the drug 
order form where contacts are 
listed. 
Contacts were out of date, 
and reference to drug order 
form avoids the need for 
unnecessary amendment in 
the case of staff changes 
10.3 (Data 
Analyses Plan) 
Analytic plans were 
inconsistent for primary 
and secondary 
endpoints. 
• Updates analytic plans to 
match intended primary and 
secondary endpoints. 
• Adds further detail on 
evaluability and analysis 
methods 
• Adds futility monitoring after 
10 patients and an interim 
safety analysis after 12 
patients  
Requests resulting from 
Emory University internal 
review 
Amendment 5 – October 15th, 2018 
Section(s) 
Affected 
Prior Version 
Amendment 5 Changes 
Rationale 
Cover Page; 7.3 
(Adverse Event 
Reporting);  
7.4 (Other 
Events Requiring 
Reporting);  
11.3 
(Registration 
Procedures) 
Referred to Northwestern 
University’s Clinical Research Office 
(CRO) 
Updates references to Clinical 
Trials Office (CTO) 
Administrative 
update 
Cover Page 
Contained outdated hyperlink for the 
Cancer Center 
(www.cancertrials.northwestern.edu)  
Updates hyperlink to the 
following: 
www.cancer.norhtwestern.edu 
/research/clinical-trials-
office/index.html  
Administrative 
update 
3.0 (Patient 
Eligibility) 
Contained statement about accrual 
rates (approximating 4 patients 
accrued per month) 
Removes accrual rate 
information 
Language was 
not lining up with 
actual accrual 
rate and is not 
required 
4.4.2 (Prohibited 
Concomitant 
Medications) 
Dexamethasone was a required pre-
medication for AVD but 
glucocorticoids were prohibited. 
Glucocorticoids were prohibited 
“within 1 week of treatment’ 
Adds clarifying language that 
dexamethasone is a permitted 
glucocorticoid when used as a 
pre-medication for AVD. Also 
clarifies that glucocorticoids 
are not permitted within 1 
week of treatment and 
throughout treatment 
Clarification to 
address 
discrepancy 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
85 
Amendment 6: March 29th, 2019 
5.0 (Study 
Procedures) 
Timing of PET/CT’s was unclear: 
• “PET/CT within 6 weeks of 
registration” 
• PET#2 and PET#3 were listed 
within the columns for AVD 
treatment, when footnote 14 stated 
that they would take place before 
and after AVD 
• PET/CT was not marked at the 
“Discontinuation” visit, making it 
unclear whether patients not 
undergoing consolidation needed 
a final PET/CT  
Clarifies PET/CT timing: 
• “PET/CT within 6 weeks 
prior to registration” 
• Adds separate columns 
clearly indicating PET#2 
and PET#3 before and after 
AVD with specific timing 
listed in footnote 14 
• Adds a column for “Post-
Chemo Assessment”, an X 
for PET/CT at 
“Discontinuation” and a 
clarifying footnote to state 
that all patients will have 
this scan and that it may fall 
before consolidation or as 
part of the procedures for 
discontinuation 
Clarifications for 
study team.  
• Avoids 
ambiguous 
language 
• PET#2 and 
PET#3 are 
more clearly 
indicated to 
avoid being 
missed by the 
study team  
• The final 
PET/CT is 
more clearly 
indicated to 
avoid being 
missed by the 
study team. 
n/a 
Updates footnote numbering 
To account for 
additional 
footnote 
clarifying PET/CT 
timing 
Appendix D 
Included multiple categories for 
unfavorable risk factors and did not 
specify how to count nodal sites 
Lists only NCCN unfavorable 
risk factors and adds a chart 
for definition of lymph node 
regions, using Ann Arbor  
Clarifications; we 
will only use 
NCCN 
unfavorable risk 
factors and Ann 
Arbor is the 
designated 
definition of 
lymph node 
regions under 
NCCN  
Amendment 6 – March 29th, 2019 
 
Section(s) 
Affected 
Prior Version 
Amendment 6 Changes 
Rationale 
Cover Page 
n/a 
Adds Hatice Savas as a 
collaborator from 
Northwestern radiology 
Central review 
information of 
PET/CT’s have 
been added to 
the study, which 
will be performed 
by Dr. Savas 
Cover Page 
Fred Rademaker listed as 
Biostatistician 
Removes Fred Rademaker 
and adds Denise Scholtens 
Change in 
biostatistician for 
the study 
4.1 (Overview); 
5.0 (Study 
Procedures #14); 
6.3.1 (Central 
n/a 
Adds a central review 
information of PET imaging 
for the study 
To provide an 
unbiased 
research analysis 
of PET results  
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.

NU Study Number: NU 16H08 
Merck Study Number: 53957 
Initial Version date: March 10th, 2017 
 
86 
Amendment 6: March 29th, 2019 
Review of 
PET/CT) 
11.7.2 (Other 
Protocol 
Deviations 
“Promptly reportable non-
compliance” 
Changed to “Reportable new 
information” 
Semantic 
administrative 
update 
 
 
 
 
 
IRB #: STU00203707-CR0002 Approved by NU IRB for use on or after 5/20/2019 through 5/19/2020.