Phase II Trial of Pembrolizumab in Combination With ICE Salvage Chemotherapy for Relapsed/Refractory Hodgkin Lymphoma
Phase: PHASE2
Conditions: Lymphocyte-Rich Classical Hodgkin Lymphoma, Recurrent Lymphocyte-Depleted Classical Hodgkin Lymphoma, Recurrent Mixed Cellularity Classical Hodgkin Lymphoma, Recurrent Nodular Sclerosis Classical Hodgkin Lymphoma, Refractory Lymphocyte-Depleted Classical Hodgkin Lymphoma, Refractory Mixed Cellularity Classical Hodgkin Lymphoma, Refractory Nodular Sclerosis Classical Hodgkin Lymphoma
Sponsor: Northwestern University

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
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 Trial of Pembrolizumab in Combination with ICE Salvage Chemotherapy 
for Relapsed/Refractory Hodgkin Lymphoma
Principal Investigator:
Sub Investigator:
Jane N. Winter, M.D.
Locke J. Bryan, M.D.
Northwestern University
Augusta University
676 N St Clair, Suite 850
1120 15th Street, BA-5414
Chicago IL 60611
Augusta, GA 30912
Phone: (312) 695-4538
Phone: (706) 721-2505
Fax: (312) 695-6189
lbryan@augusta.edu
j-winter@northwestern.edu
Sub-Investigators:
Leo I. Gordon, M.D.
Shuo Ma, M.D., Ph.D.
Barbara Pro, M.D.
Reem Karmali, M.D.
Northwestern University
Carla Casulo, M.D.
University of Rochester
601 Elmwood Ave, Box 704
Rochester, NY 14642
Phone: (585) 273-3258
carla_casulo@urmc.rochester.edu 
Scott E. Smith M.D., Ph.D.
Loyola University
2160 S. First Ave.
Maywood, IL 60153
Phone: (708) 327-3142
ssmith8@lumc.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  
 
Biostatistician:  Joan S. Chmiel, Ph.D. 
Northwestern University, Department of Preventive Medicine (Biostatistics)
jchmiel@northwestern.edu
Collaborators:    Kristy L. Wolniak, M.D., Ph.D and Xinyan Lu, M.D.
     Northwestern University, Department of Pathology
     Gary L. Dillehay, M.D., Hatice Savas, M.D.
Northwestern University, Department of Radiology
Study Intervention(s):
Pembrolizumab (Keytruda®)
IND Number/Holder:
131946 / Jane Winter, M.D. 
Funding Source: 
Merck
Version Date:
February 21st, 2022 (Amendment 9)
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
http://cancer.northwestern.edu/research/clinical-trials-
office/index.html
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Initial Version: 11/30/2016 
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS .............................................................................................................4
STUDY SCHEMA ............................................................................................................................6
STUDY SUMMARY .........................................................................................................................7
4.2
INTRODUCTION - BACKGROUND & RATIONALE..........................................................10
1.1
Disease Background .....................................................................................................10
1.2
Treatment of Relapsed/Refractory Hodgkin's Lymphoma.............................................10
1.3
Role of FDG-PET/CT in Hodgkin's Lymphoma .............................................................11
1.4
The PD-1 Pathway ........................................................................................................11
1.5
Pembrolizumab..............................................................................................................12
1.6
Clinical Investigations with Pembrolizumab...................................................................12
1.7
Pembrolizumab Safety and Tolerability.........................................................................13
1.8
Concept and Rationale for the Current Study................................................................13
1.9
Rationale for Pembrolizumab Dose Selection/Regimen/Modification ...........................14
1.10
Exploratory Studies .......................................................................................................15
4.3
STUDY OBJECTIVES........................................................................................................16
2.1
Primary Objective ..........................................................................................................16
2.2
Secondary Objectives....................................................................................................16
2.3
Exploratory Objectives...................................................................................................16
3.0
PATIENT ELIGIBILITY.......................................................................................................16
3.1
Inclusion Criteria............................................................................................................17
3.2
Exclusion Criteria...........................................................................................................18
4.0
TREATMENT PLAN...........................................................................................................19
4.1
Overview........................................................................................................................19
4.2
Treatment Administration ..............................................................................................20
4.3
Toxicity Management & Dose Delays/Modifications......................................................21
4.4
Concomitant Medications/Treatments ...........................................................................31
4.5
Autologous Stem Cell Transplant..................................................................................32
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4.6
Provider Discretion ........................................................................................................32
4.7
Use in Pregnancy ..........................................................................................................32
4.8
Duration of Therapy.......................................................................................................33
4.9
Duration of Follow Up....................................................................................................33
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole .........................33
4.11
Patient Replacement .....................................................................................................34
4.12
Suspension of Accrual...................................................................................................34
5
STUDY PROCEDURES.....................................................................................................35
6.0
RESPONSE ASSESSMENT..............................................................................................39
6.1
Deauville Criteria for FDG-PET/CT Interpretation .........................................................39
6.1.1
Central Review of PET/CT ............................................................................................39
6.2
Toxicity Endpoints .........................................................................................................39
6.3
Efficacy Endpoints.........................................................................................................39
6.4
Exploratory Endpoints ...................................................................................................40
7.0
ADVERSE EVENTS...........................................................................................................41
7.1
Adverse Event Monitoring .............................................................................................41
7.2
Definitions & Descriptions..............................................................................................41
7.3
Severity of AEs ..............................................................................................................42
7.4
Serious Adverse Events (SAEs)....................................................................................42
7.5
Unanticipated Problems Involving Risks to Subject or Others ......................................43
7.6
Events of Clinical Interest..............................................................................................43
7.7
Reporting of Pregnancy and Lactation to the Sponsor and to Merck............................43
7.8
Adverse Event Reporting...............................................................................................43
8
DRUG INFORMATION ......................................................................................................45
8.1
Pembrolizumab..............................................................................................................45
8.2
Ifosfamide ......................................................................................................................47
8.3
Carboplatin ....................................................................................................................49
8.4
Etoposide.......................................................................................................................51
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8.5
Mesna............................................................................................................................52
8.6
G-CSF ...........................................................................................................................53
9
CORRELATIVES/SPECIAL STUDIES...............................................................................54
9.1
Archival Tissue Biopsy ..................................................................................................54
9.2
Flow Cytometry..............................................................................................................54
10
STATISTICAL CONSIDERATIONS...................................................................................54
10.1
Evaluability ....................................................................................................................55
10.2
Study Design and Study Endpoints...............................................................................55
10.3
Sample Size and Accrual ..............................................................................................55
10.4
Stopping Rule for Toxicity..............................................................................................56
10.5
Data Analyses Plans .....................................................................................................56
11
STUDY MANAGEMENT ....................................................................................................57
11.2
Institutional Review Board (IRB) Approval and Consent...............................................57
11.3
Amendments .................................................................................................................58
11.4
Registration Procedures................................................................................................58
11.5
Instructions for Participating Sites .................................................................................58
11.6
Data Management and Monitoring/Auditing ..................................................................59
11.7
Adherence to the Protocol.............................................................................................59
11.8
Investigator Obligations.................................................................................................59
11.9
Publication Policy ..........................................................................................................60
REFERENCES ..............................................................................................................................61
APPENDIX A .................................................................................................................................63
APPENDIX B .................................................................................................................................64
APPENDIX C .................................................................................................................................65
APPENDIX D .................................................................................................................................66
APPENDIX E .................................................................................................................................67
APPENDIX F..................................................................................................................................69
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LIST OF ABBREVIATIONS
ABVD
Adriamycin, Bleomycin, Vinblastine, Dacarbazine
ADC
Antibody-Drug Conjugate
AE
Adverse Event
AHSCT
Autologous Hematopoietic Stem Cell Transplant
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BEACOPP
Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, 
Procarbazine, Prednisone
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CIV
Continuous IV Infusion
CMP
Comprehensive Metabolic Panel
CNS
Central Nervous System
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse Large B-cell Lymphoma
DLCO
Diffusing Capacity of the Lungs for Carbon Monoxide
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee
ECOG
Eastern Cooperative Oncology Group
EFS
Event Free Survival
FDG
Fluorodeoxyglucose
FISH
Fluorescence In Situ Hybridization
FOCBP
Female of Child Bearing Potential
G-CSF
Granulocyte Colony Stimulating Factor
H&P
History & Physical Exam
HL
Hodgkin’s Lymphoma
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ICE
Ifosfamide, Carboplatin, Etoposide Chemotherapy
IPS
International Prognostic Score
IV (or iv)
Intravenously
MDS
Myelodysplastic Syndrome
MTD
Maximum Tolerated Dose
MUGA
Multigated Acquisition Scan
NCI
National Cancer Institute
NOTIS
Northwestern Oncology Trial System
ORR
Overall Response Rate
OS
Overall Survival
PCM
Plasma Cell Myeloma
PD-1
Programmed death-1
PET/CT
Positron Emission Tomography–Computed Tomography
PD
Progressive Disease
PD-1
Programmed Death-1
PFS
Progression Free Survival
PFT’s
Pulmonary Function Tests
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
QA
Quality Assurance 
RR-HL
Relapsed/Refractory Hodgkin’s Lymphoma
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
WHO
World Health Organization
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STUDY SCHEMA
Treatment Details (1 cycle = 21 days)
*Pembro-ICE Treatment:
Pembrolizumab 200mg IV day 1
Ifosfamide 5g/m2 24hr CIV day 2
Carboplatin AUC 5 IV day 2
Etoposide 100 mg/m2 IV days 1-3
G-CSF support starting day 4
**Pembro Monotherapy:
Pembrolizumab 200mg IV day 1
Cycle 1
Cycle 2
Cycle 3
Optional 
Cycle 4
Registration
Peripheral Blood 
Stem Cell Harvest
FDG-PET/CT 
Pembro-ICE*
Pembro-ICE*
Pembro**
Pembro-ICE* (on-study) 
or provider discretion
Patient Population:
Classical Hodgkin’s 
Lymphoma
Relapsed/Refractory Disease
Age ≥ 18 yrs
ECOG ≤ 1
No CNS Disease
Provider discretion 
(Off-study)
Deauville 
Score
≤3
>3
AHSCT

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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STUDY SUMMARY
Title
Phase II Trial of Pembrolizumab in Combination with ICE Salvage 
Chemotherapy for Relapsed/Refractory Hodgkin Lymphoma
Version
02/21/2022 (Amendment 9) 
Study Design
A single-stage Phase II, prospective, open-label, single-arm, 
multi-centered clinical trial.
Study Center(s)
Northwestern University, Chicago, IL
Augusta University, Augusta, GA
Loyola University, Maywood, IL
University of Rochester, Rochester, NY
Emory University, Atlanta, GA
Concept and Rationale
     Therapy for advanced stage Hodgkin's lymphoma (HL) 
continues to improve however up to 10% of patients have 
refractory disease never achieving a complete remission. Another 
20-30% of advanced stage HL patients will ultimately relapse after 
initial treatment. In the event of relapsed or refractory HL (RR-HL), 
patients are treated with salvage chemotherapy. While salvage 
chemotherapy has demonstrated good overall response rates, the 
risk of relapse remains high and AHSCT remains the standard of 
care for transplant eligible patients. 
     Programmed death-1 (PD-1) is a member of the B7 receptor 
family that plays an important role in the regulation of the immune 
response. The PD-1 receptor in conjunction with receptor ligands, 
PD-LI and PD-L2, functions to regulate the immune response 
primarily by down regulating T-cell receptor signaling. 
Suppression of the immune response by the PD-1 pathway 
functions as a mechanism for malignant cells to escape immune 
surveillance. A broad spectrum of malignancies including 
Hodgkin's lymphoma mitigate anti-tumor immune response 
through the PD-1 pathway. 
     Pembrolizumab is a humanized IgG-4 kappa isotype 
monoclonal antibody currently FDA approved in unresectable or 
metastatic melanoma. The target for pembrolizumab is PD-1 
receptor on human T-cells. Hodgkin’s lymphoma have been 
demonstrated to carry a recurrent genetic abnormality in 
chromosome 9p24.1. The amplification of chromosome 9p24.1 
results in overexpression of the PD-1 ligands, PD-L1 and PD-L2. 
Twenty-three patients with HL enrolled on the Keynote-013 trial 
were treated with pembrolizumab resulting in responses including 
22% CR and 43% PR for a 65% ORR. Important clinical 
responses with nivolumab, a different anti-PD-1 antibody, were 
demonstrated in RR-HL following AHSCT. The study included 23 
patients with an overall response rate of 87% including 17% 
complete responses and 70% with partial responses. Anti-PD-1 
therapy for HL has thus emerged as a promising option. 
     We propose using the combination of pembrolizumab with ICE 
salvage chemotherapy for relapsed/refractory HL. We hypothesize 
that the addition of PD-1 blockade to standard ICE chemotherapy 
will enhance the efficacy of treatment for RR-HL. We expect an 
improvement in the CR rate as defined by a negative FDG-
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PET/CT, a measure that is correlated with improvement in both 
EFS and OS. The protocol will also evaluate the toxicity and 
tolerability of combining pembrolizumab with high-dose 
chemotherapy. We feel this therapy represents an important step 
in improving management of this aggressive lymphoma and will 
ultimately be incorporated into future treatment algorithms.
Objectives
Primary Objective:

To determine the CR rate by FDG-PET/CT prior to AHSCT 
with the combination of pembrolizumab and ICE salvage 
chemotherapy for relapsed/refractory Hodgkin lymphoma 
Secondary Objectives:

To determine the safety and tolerability of pembrolizumab 
in combination with salvage high-dose chemotherapy

To estimate the event free survival (EFS) at 2 years

To estimate the overall survival (OS) at 2 years
Exploratory Objectives:

To characterize PD-1 pathway specific expression and 
correlate with response

To characterize T-lymphocyte subset changes to treatment 
with pembrolizumab

To investigate the prevalence and clinical correlation of 
chromosome 9p24.1 mutations for this population

To evaluate the effect on stem cell harvest following 
treatment with pembrolizumab
Sample Size
Up to 43 patients for 37 evaluable 
Diagnosis & Key 
Eligibility Criteria
Inclusion criteria include:

Relapsed/refractory classical Hodgkin lymphoma;

Previously completed at least one line of chemotherapy for 
their Hodgkin lymphoma (but ≤ 2 lines);

Measurable FDG-PET/CT avid disease;

Age ≥ 18 yrs;

Performance status ECOG 0 or 1.
Exclusion criteria include:

Known CNS involvement;

Known HIV, HBV, HCV infection;

Prior exposure to anti-PD-1 or anti-PD-L1 agents;

Prior autologous or allogeneic stem cell transplant;

Concurrent immunosuppressive therapy.
Treatment Plan
Patients with relapsed/refractory classical Hodgkin lymphoma 
following standard up-front chemotherapy will be eligible for 
participation. Patients with FDG-PET/CT avid disease will be 
treated with combination pembrolizumab and ICE (ifosphamide, 
carboplatin, etoposide)* salvage chemotherapy for 2 cycles (1 
cycle = 21 days). On cycle 3 day 1, patients will receive 
pembrolizumab monotherapy. A FDG-PET/CT will be obtained 14-
22 days after pembrolizumab monotherapy to assess response by 
Deauville criteria. Patients with Deauville ≤3 will proceed to 
AHSCT which may include a fourth optional cycle of Pembro-ICE 
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prior to transplant per investigator discretion. Patients with 
Deauville >3 will be treated per provider's discretion which may 
also include stem cell transplant. 
*Pembrolizumab 200 mg IV will be administered on day 1. 
Standard ICE salvage chemotherapy includes ifosfamide 5 g/m2 
with equivalent dose of MESNA given over 24 hours by CIV on 
day 2, carboplatin AUC 5 IV with a maximum of 800 mg on day 2, 
and etoposide 100 mg/m2/day IV on days 1 to 3. G-CSF support 
will be administered 24 hours following completion of 
chemotherapy.
Statistical 
Methodology
The standard response rate is assumed to be 0.5 (under the null 
hypothesis) by historical controls; and the new therapy is 
considered worthy of further research if we can reject the null 
hypothesis in favor of the alternative hypothesis, where the 
response rate is 0.7. The consequent decision rule provides the 
sample size (n=37) and minimum number of responders (r) as ≥24 
thus warranting further investigation of the new therapy, such that 
statistical significance is achieved. If r<24, then this is the 
maximum number of responders for which statistical significance 
is not achieved. This design yields a type I error rate of 0.05 and 
power of 0.80 when the true response rate is 0.70. For our 
secondary objectives, we will tabulate the number and percentage 
of toxicities by type, grade, severity, and attribution. We will 
generate Kaplan-Meier curves of EFS and OS including lifetables 
of point estimates and associated standard errors, which would 
include the presentation of the 2-year estimate.
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4.2INTRODUCTION - BACKGROUND & RATIONALE
1.1
Disease Background
Hodgkin’s lymphoma (HL) is a neoplasm of lymphoid tissue defined by the 
presence of malignant Hodgkin Reed-Sternberg cells in a background of 
inflammatory cells1. Approximately 9050 new cases of HL are diagnosed in the 
United States annually and 1,150 people will die of their disease2. Advanced 
stage HL, defined as Ann Arbor stage III or IV disease, is characterized by 
widespread involvement and is associated with diminished survival. From the 
International Hodgkin Lymphoma Database, the median overall survival (OS) is 
approximately 18 years for stage III patients and only 9 years for stage IV 
patients. The median age of diagnosis is only 38 thus these projected rates of 
OS are unacceptable. 
Prognosis is predicted using the international prognostic score (IPS) developed 
for advanced stage HL3. The treatment goal remains curative therapy often using 
a combination of chemotherapy and radiation. Patients with advanced stage HL 
are treated with combination chemotherapy that includes an anthracycline and an 
alkylating agent. ABVD has been defined as the most preferred front-line 
regimen with alternative regimens including BEACOPP and Standford V4. 
 
1.2
Treatment of Relapsed/Refractory Hodgkin's Lymphoma
Therapy for advance stage HL continues to improve however up to 10% of 
patients have refractory disease never achieving a complete remission. Another 
20-30% of advanced stage HL patients will ultimately relapse after initial 
treatment5. In the event of relapsed or refractory HL (RR-HL), patients are treated 
with salvage chemotherapy. While salvage chemotherapy has demonstrated high 
overall response rates, the risk of relapse remains high and AHSCT remains the 
standard of care for transplant eligible patients6,7. 
There are multiple salvage chemotherapy regimens supported by Phase II 
clinical trials however no direct comparison exists to provide a census 
recommendation on the best therapy8. The goal of salvage chemotherapy 
remains a balance of high response rates with acceptable toxicity profiles and 
uncompromised stem cell mobilization at the time of harvest. Likewise, the 
optimal number of cycles of salvage chemotherapy is poorly defined but most 
institutions give 2-3 cycles with disease assessment following cycle 2 at the time 
of stem cell harvest. 
A commonly utilized salvage regimen is ICE which includes a combination of 
ifosfamide, carboplatin, and etoposide. The previously reported overall response 
rate (ORR) is 85% and includes a 26% complete response rate (CR) when 
response was assessed by CT imaging9. Similarly, two sequential prospective 
trials reported 23% complete response with ICE chemotherapy10. Although the 
regimen has anticipated side effects, ICE is well tolerated in comparison to other 
salvage options. ICE chemotherapy is administered as 14 or 21 day cycles. The 
addition of G-CSF support has made the 14 day cycle feasible without worsening 
the rate of hematologic adverse events. 
Brentuximab vendotin (SGN-35) is a promising antibody-drug conjugate (ADC) 
that selectively delivers a toxic agent to CD30-expressing cells. Several clinical 
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trials have now demonstrated efficacy and safety in heavily pre-treated patients 
with RR-HL patients. An international, open-label, Phase II study evaluated 
brentuximab in RR-HL patients following AHSCT with ORR of 75% including CR 
of 34%11,12. These results and emerging data from ongoing clinical trials may 
support the use of brentuximab vendotin in RR-HL patients preceding AHSCT.  
1.3
Role of FDG-PET/CT in Hodgkin's Lymphoma
Functional imaging by FDG-PET/CT has increasingly become a tool for response 
assessment prior to AHSCT. Disease response is measured by Deauville criteria, 
a defined radiographic guideline for interpreting functional imaging. Utilization of 
functional imaging with FDG-PET/CT defines complete response by Deauville 
criteria ≤313,14. Updated guidelines for management of HL have recently 
incorporated the use of Deauville criteria for disease assessment by FDG-
PET/CT15. 
A positive FDG-PET/CT following salvage chemotherapy entering AHSCT is 
predictive of poorer outcomes. The 3-year OS is reduced to 58% from 87% in 
those with a positive FDG-PET/CT16. In a series here at Northwestern, the 
complete responses by FDG-PET/CT correlated with improved outcomes 
following AHSCT including a 5-year PFS and OS of 85% and 100%, 
respectively17. Similarly a smaller series reported the 2 year PFS of 10% for pre-
AHSCT FDG-PET/CT positive disease compared to 93% for FDG-PET/CT 
negative disease18. The use of ICE as a salvage regimen prior to AHSCT has 
demonstrated a 5-year event free survival (EFS) of 31% if the pre-AHSCT FDG-
PET/CT is negative compared to 75% if the pre-AHSCT FDG-PET/CT is 
positive19. 
The use of functional imaging to evaluate the response to ICE chemotherapy has 
been defined in several series. Moskowitz, et al reported a complete response 
rate at 60% in 97 patients treated with ICE/augmentedICE20. The enrolled 
patients were younger with good performance status and lower risk disease. We 
reported a 50% complete response rate by FDG-PET/CT with salvage 
chemotherapy in a retrospective analysis of 51 patients at our institution17. This 
patient population was more representative of a typical clinical practice including 
patients with higher risk disease.    
1.4
The PD-1 Pathway
Programmed death-1 (PD-1) is a member of the B7 receptor family that plays an 
important role in the regulation of the immune response. The PD-1 receptor is a 
288 amino acid type I transmembrane protein that is part of the immunoglobulin 
superfamily21,22. The PD-1 receptor in conjunction with receptor ligands, PD-LI 
and PD-L2, functions to regulate the immune response primarily by down 
regulating T-cell receptor signaling processes called immune checkpoints. 
Immune checkpoints are key elements in the physiologic process that limits 
autoimmunity in the normal host but that also limits immune surveillance in 
cancer, allowing tumor escape.
The interaction of PD-1 and the receptor ligands induce processes resulting in 
apoptosis of activated T lymphocytes23-26. PD-1 is expressed on progenitor T-
cells, activated T and B lymphocytes, natural killer cells, and myeloid cells. While 
PD-1 has broad expression across multiple immune cell types, the primary 
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function of PD-1 is on effector/memory T lymphocytes resulting in regulation of T-
cell activation and apoptotic pathways22,27. The end result of the PD-1 pathway is 
a regulatory role in peripheral tolerance28. 
Co-optation of the PD-1 pathway by malignant cells was first described in the 
early 2000s, leading to investigations into PD-1 blockade as a possible 
mechanism for cancer therapy29,30. The pathway has been demonstrated in a 
broad spectrum of solid malignancies including breast, colon, esophageal, lung, 
pancreatic, renal cell, and skin cancers. Furthermore, hematologic malignancies 
including lymphomas and leukemia have adopted the PD-1 pathway to mitigate 
anti-tumor immune response. The aberrant expression of PD-L1 has been 
demonstrated on tumor-infiltrating lymphocytes of lymphomas31. The result of 
stimulation through the PD-1 pathway is T-cell exhaustion thus inhibition of the 
anti-tumor response. Blockade of the PD-1 pathway through the use of PD-1 or 
PD-1 ligand (PD-L1) antibodies releases this brake on the immune response.
Hodgkin’s lymphoma has been demonstrated to carry a recurrent genetic 
abnormality in chromosome 9p24.1. Mutations of chromosome 9p24.1 result in 
amplification of the PD-1 ligands, PD-L1 and PD-L232. The Epstein-Barr virus 
(EBV) is associated with HL and also will increase the expression of the PD-1 
ligands33. Important clinical responses with anti-PD-1 blockade by nivolumab 
were demonstrated in RR-HL following AHSCT with a majority of patients who 
has also previously received brentuximab vendotin. The study included 23 
patients with an overall response rate of 87% including 17% complete responses 
and 70% with partial responses34. 
1.5
Pembrolizumab
Pembrolizumab is a humanized IgG-4 kappa isotype monoclonal antibody35. The 
drug was developed by Merck and currently has FDA approval in unresectable or 
metastatic melanoma and disease progression following ipilimumab and, if BRAF 
V600 mutation positive, a BRAF inhibitor. The target for pembrolizumab is PD-1 
receptor on human T-cells. The variable region sequences of a very-high-affinity 
mouse antihuman PD-1 antibody were grafted into a human IgG-4 
immunoglobulin with a stabilizing S228P Fc alteration. The IgG-4 immunoglobulin 
subtype does not engage Fc receptors or activate complement, thus avoiding 
cytotoxic effects of the antibody when binding to T-cells. 
1.6
Clinical Investigations with Pembrolizumab
Pembrolizumab has been studied in solid malignancies including melanoma, 
renal cell cancer, and lung cancer with promising results. Pembrolizumab is an 
emerging therapy for treatment of advanced melanoma with noted durable 
response rates of 38% in patients with prior exposure to immunotherapy 
including ipilimumab35. Pembrolizumab currently has FDA approval for the 
treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. Additionally, pembrolizumab has received “breakthrough status” by the 
FDA for the treatment of non-small cell lung cancers and likely will be approved 
in the near future36.
Merck is currently pursuing clinical trials with pembrolizumab in hematologic 
malignancies. An international Phase Ib trial is currently registered on 
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clinicaltrials.gov for study of pembrolizumab in blood cancers (NCT01953692). 
Eligible patients are those with relapsed/refractory malignancies including 
myelodysplastic syndrome (MDS), plasma cell myeloma (PCM), nodular 
sclerosis or mixed cellularity Hodgkin lymphoma, primary mediastinal large B-cell 
lymphoma, or other non-Hodgkin lymphomas. The study has completed though 
final published results remain pending. Preliminary findings were presented at 
the ASH 54th Annual Meeting in 2014 in abstract form. There was 31 patients 
with HL enrolled and of the 23 evaluable patients, 22% had CR, 43% had PR, 
and there was a 65% ORR37. A second clinical trial recently opened to 
investigate use of pembrolizumab follow AHSCT in patients with HL and DLBCL 
(NCT02362997). A third clinical trial is combining pembrolizumab with 
chemotherapy for advanced lymphomas (NCT02408042).  
1.7
Pembrolizumab Safety and Tolerability
Out of a total of 479 patients treated on clinical trials, 466 (97.3%) experienced 
treatment emergent AEs of which 368 (76.8%) were considered drug-related. 
SAEs were reported in 0.1% of patients, but SAEs that were attributed as 
potentially (possibly, probably, or definitely) drug-related by investigators were 
reported in 6.7% of patients overall. Five patients died within 30 days of the last 
dose of pembrolizumab; none of the deaths were considered drug-related. 
The most prevalent (>30% frequency) adverse events that have occurred in prior 
clinical trials include fatigue, cough, diarrhea, nausea/vomiting, rash, headache, 
and pruritis. Immune-mediated adverse events are possible particularly 
pneumonitis, colitis, hepatitis, endocrinopathies (hypopituitarism, 
hyper/hypothyroidism), and nephritis. Immune-mediated adverse events 
represent <5% of those from clinical trials. The overall AE summary suggests 
that pembrolizumab is generally tolerable and AEs are generally manageable.
There is currently no published data on the safety and tolerability of combining 
pembrolizumab with chemotherapy. Several active clinical trials in melanoma, 
non-small lung cancer, urothelial cancers, and hematologic malignancies include 
pembrolizumab given concurrently with chemotherapy. Chemotherapy agents 
include carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, ifosfamide, nab-
paclitaxel, oxaliplatin, paclitaxel, and pemetrexed. No study has been closed to 
date related to adverse events. The current clinical experience is that 
pembrolizumab can be safely administered concurrently with cytotoxic agents. 
1.8
Concept and Rationale for the Current Study
Hodgkin’s lymphoma remains a disease with a high cure rate however the 
response to further treatment at disease relapse dramatically declines and 
patients require salvage chemotherapy followed by AHSCT. The PD-1 pathway 
is an adaptive strategy by tumors to suppress the anti-tumor immune response. 
Co-optation of the PD-1 pathway by HL has been demonstrated with impressive 
responses in heavily pretreated patients with nivolumab, an anti-PD-1 antibody 
within the same class as pembrolizumab. 
We propose using the combination of pembrolizumab with ICE salvage 
chemotherapy for relapsed/refractory HL. The addition of PD-1 blockade will 
enhance the efficacy of salvage chemotherapy. We expect an improvement in 
CR rate as defined by a negative FDG-PET/CT, a measure that is correlated with 
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improvement in both EFS and OS. The protocol will also evaluate the toxicity and 
tolerability of combining pembrolizumab with high-dose chemotherapy. We feel 
this therapy represents an important step in improving management of this 
aggressive lymphoma and will ultimately be incorporated into future treatment 
algorithms.
The treatment population will include patients ≥ 18 years of age with advanced 
stage RR-HL with measurable disease confirmed by FDG-PET/CT. Patients will 
be treated with pembrolizumab 200 mg IV concurrently with ICE combination 
chemotherapy every 21 days (+/-2) for 2 cycles. Pembrolizumab dosing is based 
on prior clinical experience and recent standardization of dosing by the 
manufacturer, Merck. Following 2 cycles of therapy, a third dose of 
pembrolizumab monotherapy will be administered. Disease response will then be 
assessed by FDG-PET/CT. Our primary objective is to determine the complete 
response rate by functional imaging. We expect an improvement in complete 
response as compared to historical controls. 
Our secondary objectives will evaluate EFS and OS in this population. The 
proposed therapy is expected to improve the EFS and OS for patients with RR-
HL. The safety and tolerability of pembrolizumab given concurrently with ICE 
salvage chemotherapy will be determined. The use of pembrolizumab has a 
limited toxicity profile and we expect limited adverse effects over those 
anticipated with ICE chemotherapy.  
1.9
Rationale for Pembrolizumab 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 Pembrolizumab.  The dose escalation 
portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All 
three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of Pembrolizumab showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg, and 10 mg/kg Q2W).  No MTD has been identified to 
date.  Recent data from other clinical studies within the Pembrolizumab program 
has shown that a lower dose of Pembrolizumab and a less frequent schedule 
may be sufficient for target engagement and clinical activity.
PK data analysis of Pembrolizumab administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (Merck 
Pembrolizumab Investigators Brochure).  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 subjects. Within the resulting population PK 
model, clearance and volume parameters of pembrolizumab were found to be 
dependent on body weight. The relationship between clearance and body weight, 
with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed 
dose across all body weights.  Pembrolizumab has been found to have a wide 
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therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. 
The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the alternate dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, 
there are no anticipated changes in exposure between different indication 
settings.
The 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 subject exposures in the exposure 
range established in melanoma as associated with maximal efficacy response 
and 3) will maintain individual subject 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.
1.10
Exploratory 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 lymphoma38. 
We will analyze the previously obtained biopsy specimens from patients’ 
diagnostic samples to determine PD-1 and PD-L1 expression. 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 lead to amplification of gene 
expression of PD-L1 and PD-L234. We will perform FISH analysis 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 therapy39. The 
correlative investigations will determine lymphocyte subset changes during 
treatment with pembrolizumab.
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4.3STUDY OBJECTIVES
2.1
Primary Objective
To determine the complete response rate by FDG-PET/CT prior to AHSCT with 
the combination of pembrolizumab and ICE salvage chemotherapy for 
relapsed/refractory Hodgkin lymphoma. Response will be assessed using 
Lugano criteria 2014. 
2.2
Secondary Objectives
2.2.1
To determine the safety and tolerability of pembrolizumab in combination 
with salvage high-dose chemotherapy according to CTCAE v4.03.
2.2.2
To estimate the event free survival (EFS) at 2 years from start of 
treatment.
2.2.3
To estimate the overall survival (OS) at 2 years from start of treatment.
2.3
Exploratory Objectives
2.3.1
To characterize PD-1 pathway specific expression and correlate with 
response
2.3.2
To characterize T-lymphocyte subset changes to treatment with 
pembrolizumab
2.3.3
To investigate the prevalence and clinical correlation of chromosome 
9p24.1 mutations for this population
2.3.4
To evaluate the effect on stem cell harvest following treatment with 
pembrolizumab
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with relapsed/refractory Hodgkin's 
lymphoma with intention to proceed to autologous stem cell transplant following salvage 
chemotherapy. This will be a multicenter trial. Northwestern University will serve as the 
lead site and coordinating center for this study. Participating sites will include Augusta 
University, Loyola University, University of Rochester, and Emory. 
A total of 40 subjects will be needed for this trial given the low incidence of RR-HL, this 
will be a multi-institutional clinical trial.  Potential patients may be referred to the Principal 
Investigator (PI) at Northwestern University, Dr. Jane N. Winter, at (312) 695-6180, 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 for complete instructions regarding 
registration procedures.
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3.1
Inclusion Criteria
3.1.1
Patients must have 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 2008.40
3.1.2
Patients must have disease with FDG-PET/CT avidity.
3.1.3
Patients must have relapsed/refractory disease, with at least one line of 
prior chemotherapy, but ≤ 2 prior lines of treatment, for Hodgkin 
lymphoma. 
NOTE: Patients must not have had prior immune checkpoint inhibitors. 
However, there are no other limitations to prior agent or regimen types. 
3.1.4
Patients must be ≥ 18 years of age.
3.1.5
Patients must have ECOG performance status 0 or 1 (Appendix A)
3.1.6
Patients must have adequate organ and bone marrow function prior to 
registration, as defined below: 

absolute neutrophil count
≥ 1,000/mcL (in the absence of 
GCSF for ≥14 days)

platelets
≥ 75,000/mcl (in the absence of 
platelet transfusion for ≥14 days)

hemoglobin
≥ 7g/dL (transfusion permitted)

total bilirubin
≤ 2 x institutional upper limit of 
normal (ULN); if total bilirubin is >2 x 
ULN, direct bilirubin must be normal

AST(SGOT)/ALT(SPGT)
≤ 2.5 x institutional ULN

creatinine
≤ 2 x ULN or CrCl > 30 ml/min
3.1.7
Female subjects of childbearing potential should have a negative urine or 
serum pregnancy within 72 hours prior to registration. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.  
3.1.8
Females of childbearing potential (FOCBP) should be willing to use 2 
methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after 
the last dose of study medication. 
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets 
the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 
months)
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
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3.1.9
Male subjects should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the last 
dose of study therapy.
3.1.10 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 who have had chemotherapy, radiotherapy, monoclonal antibody 
(mAb), or targeted small molecule therapy within 4 weeks of study 
registration are not eligible. Those who have not recovered from adverse 
events (Grade 1 or baseline) due to such agents administered more than 
4 weeks earlier are not eligible.
3.2.2
Patients may not be currently receiving any other investigational agents 
within 4 weeks of study registration.
3.2.3
Patients must not have had prior exposure to any immune checkpoint 
inhibitors including anti-PD-1, anti-PD-L1 agents, anti-PD-L2 agents, or 
anti-CTLA-4 monoclonal antibodies.
3.2.4
Patients must not have known central nervous system (CNS) 
involvement.
3.2.5
Patients must not have had prior stem cell transplantation (autologous or 
allogeneic).
3.2.6
Patients must not have persistent diarrhea greater than NCI CTCAE 
grade 2 at the time of study registration, despite medical management.
3.2.7
Patients must not have a history of (non-infectious) pneumonitis that 
required steroids, evidence of interstitial lung disease or active, non-
infectious pneumonitis. 
3.2.8
Patients with known immunodeficiency, known autoimmune disease, or 
concurrent use of immunomodulatory agents including systemic steroids 
within 7 days prior to registration, are ineligible
3.2.9
Patients must not have co-morbid systemic illnesses or other severe 
concurrent disease which, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of safety and toxicity of the 
prescribed regimens. This includes, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.
3.2.10 Patients must not have a known additional malignancy that is progressing 
or requires active treatment. Exceptions include basal cell carcinoma of 
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the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer.
3.2.11 Patients with known HIV infection or active TB (Bacillus Tuberculosis) are 
not eligible.
3.2.12 Patients with known active HBV or HCV infection are not eligible.
3.2.13 Patients must not have a hypersensitivity to pembrolizumab or any of its 
excipients
3.2.14 Patients must not have received a live vaccine within 30 days of 
registration 
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.
3.2.15 Patients must not be pregnant or breastfeeding, or expecting to conceive 
or father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 120 days after the last dose of 
trial treatment.
3.2.16 Patients who are unwilling or unable to comply with the protocol or have 
known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial are not eligible.
4.0
TREATMENT PLAN
4.1
Overview
Patients with relapsed/refractory classical Hodgkin lymphoma following standard 
up-front chemotherapy will be eligible for participation. Patients will be treated 
with combination intravenous pembrolizumab and ICE (ifosfamide, carboplatin, 
etoposide) salvage chemotherapy for two cycles (1 cycle = 21 days) followed by 
a third dose of pembrolizumab monotherapy. During combination treatment, 
pembrolizumab 200 mg IV will be administered on Day 1. Standard ICE salvage 
chemotherapy will begin on Day 1 and includes ifosfamide 5 g/m2 with equivalent 
dose of MESNA given over 24 hours by CIV on Day 2, carboplatin AUC 5 IV with 
a maximum of 800 mg Day 2, and etoposide 100 mg/m2/day IV on Days 1 to 3. 
G-CSF support per institutional protocol will be administered 24 hours following 
completion of chemotherapy. Pembrolizumab monotherapy will then be 
administered on Day 1 of Cycle 3. A FDG-PET/CT will be obtained 14-22 days 
after Cycle 3 pembrolizumab treatment to assess response by Deauville criteria. 
See section 4.7 for central review requirements for this PET/CT.  Patients with 
Deauville ≤3 will proceed to AHSCT which may include an optional third cycle of 
Pembro-ICE (Cycle 4 on study) prior to transplant per investigator discretion. 
Patients with Deauville >3 will be treated off trial, per provider's discretion which 
may include stem cell transplant.
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4.2
Treatment Administration
Table 4.1: Treatment Administration Summary
Agent
Pre-medications1
Dose
Route
Schedule
Cycle Length
Pembrolizumab
Acetaminophen 650 mg po; 
diphenhydramine 50 mg po 
200 mg
IV over 30 
minutes (-5 / + 
10 minutes)
Day 1 
Ifosfamide +
Mesna
Anti-emetics3
5 gm/m2 
+ 
5 gm/m2 
Continuous IV 
infusion x 24 
hrs 
Day 2
Carboplatin
Anti-emetics3 
AUC 5
(800 mg 
max dose)
IV over 
approximately 
60 minutes
Day 2
Etoposide
Anti-emetics3
100 
mg/m2
IV over 
approximately 
60 minutes
Days 1 to 34
G-CSF2
N/A
variable
SQ
Starts Day 4
21 days
(+/-2 days)
1 Pre-medications for pembrolizumab are required on protocol. The remaining pre-medications listed are 
recommendations for ICE chemotherapy  but may vary per institutional standard.
2 G-CSF support will start following completion of chemotherapy per institutional standards. Drug selection per 
institutional protocol for ICE chemotherapy. 
3 It is recommended that steroids be omitted from the pre-medications for PEM-ICE. Institutional guidelines 
should prevail for alternative pre-medications. One option is as follows:
Day 1
Ondansetron 16 mg IV prior to chemotherapy 
Day 2
Ondansetron 16 mg IV prior to chemotherapy, followed by 8 mg PO every 8 hours 
Day 2, 3, & PRN at 
discharge
Aprepitant 125 mg PO prior to chemotherapy on D2 then aprepitant 80 mg PO D3, D4 
(alternative: fosaprepitant)
4 Etoposide will be given approximately 1 hour after pembrolizumab on day 1.
The pre-medications listed are a guidelines for anti-emetic therapy and may vary per 
institutional preference and formulary. Substitutions are allowed per treating provider 
discretion. The only required pre-medications on the protocol are acetaminophen 650 
mg po and diphenhydramine 50 mg po prior to administration of pembrolizumab. 
4.2.1
Day 1 of Treatment
For both combination and monotherapy cycles, pembrolizumab will be 
administered on Day 1. Patients will receive pre-treatment with 
acetaminophen 650 mg po and diphenhydramine 50 mg po given 
approximately 30 minutes prior to the pembrolizumab infusion. 
Pembrolizumab 200 mg IV will be infused over approximately 30 minutes. 
See section 8.1 for preparation instructions.
During combination therapy, etoposide will be administered approximately 
1 hour following pembrolizumab dose on Day 1. A suggested anti-emetic 
premedication regimen includes ondansetron 16 mg IV prior to 
chemotherapy on Day 1 given approximately 30 minutes prior to 
chemotherapy. Etoposide 100 mg/m2 IV will be infused over 
approximately 60 minutes.
4.2.2
Day 2 of Combination Treatment 
Etoposide, carboplatin, and ifosfamide with mesna will be administered 
on Day 2. A suggested anti-emetic premedication regimen includes 
ondansetron 16 mg IVP and aprepitant (or fosaprepitant) 125 mg PO prior 
to chemotherapy followed by ondansetron 8 mg PO every 8 hours. 
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Carboplatin AUC 5 IV will be infused first over approximately 60 minutes. 
Once the carboplatin infusion is complete, then etoposide 100 mg/m2 IV 
will be infused over approximately 60 minutes. Ifosfamide 5 g/m2 IV 
mixed with mesna 5 g/m2 IV will be administered as a continuous infusion 
over approximately 24 hours. The ifosfamide with mesna can be started 
concurrently with the etoposide.
4.2.3
Day 3 of Combination Treatment
Etoposide will be administered on Day 3. A suggested anti-emetic 
premedication regimen includes aprepitant 80 mg PO prior to 
chemotherapy and ondansetron 8 mg po every 8 hours. Etoposide 100 
mg/m2 IV will be infused over approximately 60 minutes. 
4.2.4
Day 4 of Combination Treatment
Patients will receive G-CSF support starting after completion of 
chemotherapy per institutional standards. G-CSF (filgastrim, tbo-
filgrastim, or pegfilgastrim) will be given as a subcutaneous injection per 
institutional protocol. 
4.2.5
Mobilization and Stem Cell Collection
Patients are to have a Peripheral Blood Stem Cell Harvest (PBSCH) 
preferably within 10-20 days after the second pembro-ICE combination 
treatment (C2D10-21). If delayed for medical, insurance, or scheduling 
reasons, harvest may be performed after pembrolizumab monotherapy 
Cycle 3 or after the optional additional cycle of pembrolizumab- ICE. Per 
institutional guidelines, patients will receive growth factor as indicated for 
mobilization of peripheral blood progenitor cells (filgrastim / tbo-filgrastim). 
Additional growth factor support with plerixafor may be given per 
institutional guidelines.
Patients must have ≥2.0x106 CD34+ cells/kg to move forward with stem 
cell transplant. If the initial collection is inadequate, PBSCH may be 
collected after the study PET/CT either with growth factor stimulation 
alone (within 30 days of  C3 pembrolizumab monotherapy for patients 
who do not have additional pembro-ICE), or 10-20 days after the 
(optional) third pembro-ICE combination treatment. 
4.2.6
Pembrolizumab Monotherapy Cycle
Only pembrolizumab will be administered on Day 1 of Cycle 3, following 
two cycles of Pembro-ICE chemotherapy. Patients will receive pre-
treatment with acetaminophen 650 mg po and diphenhydramine 50 mg 
po given approximately 30 minutes prior to the pembrolizumab infusion. 
Pembrolizumab 200 mg IV will be infused over approximately 30 minutes.
4.3
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of pembrolizumab will be evaluable 
for toxicity endpoints. Toxicity will be assessed according to the timeframe 
referenced in the Schedule Procedures Table that can be found in Section 7.0.
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Toxicity will be assessed according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, which 
is available on the NCI website at http://evs.nci.nih.gov/ftp1/CTCAE/About.html.
4.3.1
Pembrolizumab 
4.3.1.1 Dose Delays 
Adverse events (both non-serious and serious) associated with 
pembrolizumab exposure may represent an immunologic etiology.  
These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab 
must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table 3 below. See Section 4.3.1.2 for 
supportive care guidelines, including use of corticosteroids.
For patients who miss a treatment for a reason unrelated to 
toxicity, treatment may be resumed within 7 days of the originally 
planned treatment. If a delay of more than 21 days from the 
planned treatment occurs for reasons of toxicity, the patient will be 
taken off study. If removal from study is secondary to toxicity from 
pembrolizumab, the patient should receive further treatment per 
provider discretion which could include continuation of ICE 
chemotherapy without combination pembrolizumab.    
Table 4.2: Pembrolizumab Dose Delays for Toxicity
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 
(CTCAEv4.0)
Action taken 
to pembro
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Monitor participants for signs 
and symptoms of pneumonitis
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment
Add prophylactic antibiotics 
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for opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with 
or without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus).
Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion.
Grade 2
Withhold
Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed by 
taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids (initial 
dose of 1-2 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
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell failure
Withhold
Initiate insulin 
replacement therapy for 
participants with T1DM 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency) 
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Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper.
Monitor changes of renal 
function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue
Based on severity of AE 
administer 
corticosteroids
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
Intolerable/ 
persistent 
Grade 2
Withhold
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
All other immune-
related AEs
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
Based on type and 
severity of AE administer 
corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
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).  
Pembrolizumab will be withheld for drug-related toxicities, 
including SAEs. There are no dose modifications for 
pembrolizumab on the study protocol.
4.3.1.2 Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as 
deemed necessary by the treating investigator including but not 
limited to the items outlined below:
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Diarrhea: 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). In symptomatic 
subjects, infectious etiologies should be ruled out, and if 
symptoms are persistent and/or severe, endoscopic evaluation 
should be considered.
In subjects with severe enterocolitis (Grade 4), pembrolizumab will 
be permanently discontinued and treatment with systemic 
corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent. When symptoms improve to Grade 1 or 
less, corticosteroid taper should be started and continued over at 
least 1 month.
In subjects with moderate enterocolitis (Grade 2 or 3), 
pembrolizumab should be held per Table 4.2 and anti-diarrheal 
treatment should be started. If symptoms are persistent for more 
than one week, systemic corticosteroids should be initiated (e.g., 
1-2 mg/kg/day of prednisone or equivalent). When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started 
and continued over at least 1 month. 
All subjects who experience diarrhea 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.
Nausea/vomiting: Nausea and vomiting should be treated 
aggressively, and consideration should be given in subsequent 
cycles to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake.
Anti-infectives: Subjects with a documented infectious 
complication should receive oral or IV antibiotics or other anti-
infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard 
institutional practice.
4.3.1.3 Management of Immune-Related Adverse Events
Non-inflammatory causes must be ruled out for each suspected 
immune-related adverse event. If an immune-related adverse 
event is confirmed, treatment of moderate or severe immune-
related adverse events requires interruption or permanent 
discontinuation of treatment with pembrolizumab and the use of 
corticosteroid immunosuppression. Use of mycophenolic acid or 
infliximab may be appropriate in specific circumstances. 
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Treatment is based on the severity of the observed toxicity. When 
corticosteroids are indicated, the following points should be 
considered:

Treatment with prophylactic antibiotics to prevent opportunistic 
infections, in particular Pneumocystis jiroveci pneumonia, 
should be considered, particularly if treatment with 
corticosteroids will last for more than 5 weeks.

IV steroids may be switched to an equivalent dose of oral 
corticosteroids (e.g., prednisone) at the start of tapering or 
earlier after sustained clinical improvement is observed.

Standard IV to oral corticosteroid conversion should be used 
to account for the lower bioavailability of oral corticosteroids 
when switching to the equivalent dose of oral corticosteroids. 
Steroid tapers should be gradual and the case should be 
followed closely to monitor for adrenal insufficiency.
Pembrolizumab should be permanently discontinued under the 
following circumstances:

Grade 4 anaphylaxis

A grade 4 immune-related adverse event, with the exception of 
endocrinopathies stabilized on replacement hormonal therapy

A grade 3 immune-related adverse event that does not 
improve to grade 0 or 1 within 10 days after the last dose of 
pembrolizumab, with the exception of endocrinopathies that 
can be treated with replacement hormonal therapy

Any grade 3 or 4 immune-related adverse event that recurs at 
grade 2 or higher after resuming pembrolizumab

Any uveitis event

Grade 4 enterocolitis
4.3.1.4 Management of Infusion Reactions 
Acute infusion reactions (which can include cytokine release 
syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs. Signs and symptoms 
usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity 
(including drug fever); Arthralgia (joint pain); Bronchospasm; 
Cough; Dizziness; Dyspnea (shortness of breath); Fatigue 
(asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; 
Rash/desquamation; Rigors/chills; Sweating (diaphoresis); 
Tachycardia; Tumor pain (onset or exacerbation of tumor pain due 
to treatment); Urticaria (hives, welts, wheals); Vomiting.
Treatment for infusion reactions includes methylprednisolone, 
acetaminophen, diphenhydramine, epinephrine, and supportive 
measures with IV fluids or pressors support when needed. Table 
4.3 below shows treatment guidelines for subjects who experience 
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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 
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:

IV fluids

Antihistamines

NSAIDS
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated

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.
Appropriate resuscitation equipment should be available in the room and a 
physician readily available during the period of drug administration.
4.3.1.5 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 4.4. 
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 
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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. 
4.3.2
Recommended ICE Chemotherapy Dose Management
The standard salvage regimen ICE includes a combination of ifosfamide, 
carboplatin, and etoposide. Management of these commonly used agents 
should be guided by standard institutional practice. Included here are 
management recommendations for more common or severe adverse 
events. In general, there are no dose reductions recommended for 
hematologic toxicities.
Table 4.5: Guidelines for Dose Modification for Toxicity
Ifosfamide
Carboplatin
Etoposide
Original Dose
5 g/m2 CIV
AUC 5 IV
100 mg/m2 IV
1st Dose Reduction
4 g/m2 CIV
AUC 4 IV*
80 mg/m2 IV
2nd Dose Reduction
3 g/m2 CIV
AUC 3 IV*
60 mg/m2 IV
*AUC 4 maximum dose = 640mg; AUC 3 maximum dose = 480mg 
Patients experiencing significant (Grade 3-4) ifosfamide-related hematuria 
should have the dose of ifosfamide reduced 1 level. If hematuria persists 
on the urinalysis prior to the next cycle, reduce one additional level. If 
symptoms persist, remove patient from study therapy. 
If Grade 2 ifosfamide-related neurologic symptoms develop (e.g., 
confusion), reduce ifosfamide dose 1 level. If Grade 3 or 4 neurologic 
symptoms develop, remove patient from study therapy. 
Grade 3 (or greater) hepatic toxicity with elevations in SGOT (AST), 
SGPT (ALT), alkaline phosphatase or bilirubin requires reduction of one 
dose level of the agent felt to be responsible for the elevation and delay in 
subsequent therapy for a maximum of 14 days until recovered to Grade 1.
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4.3.3
Treatment Stopping Criteria
4.3.3.1 Pembrolizumab Stopping Criteria:
Treatment with pembrolizumab must be discontinued for the 
following toxicities:
Adverse Event
Severity
Infusion reaction
Grade 3 or 4
Anaphylaxis
Grade 4
Immune-related AE
Grade 4* 
Grade 3* that does not improve to 
grade 0 or 1 within 10 days of last dose 
of pembrolizumab
Grade 3 or 4 that recurs at grade 2 or 
higher after resuming pembrolizumab
*with the exception of endocrinopathies 
stabilized on replacement hormonal 
therapy
Uveitis
Any grade
Enterocolitis
Grade 3 or 4
AST, ALT, or 
Increased Bilirubin
Grade 3 or 4
(For patients with liver metastasis who 
begin treatment with Grade 2 AST or 
ALT, if AST or ALT increases by greater 
than or equal to 50% relative to 
baseline and lasts for at least 1 week 
then patients should be discontinued
Hypophysitis
Grade 4
Hyperthyroidism
Grade 4
Pneumonitis
Grade 3 or 4
Renal failure / 
Nephritis
Grade 3 or 4
All other drug-related 
toxicities
Grade 4
Any drug-related 
toxicity requiring drug 
to be held >21 days
Any grade
Cardiac toxicity
Grade 2 with confirmed myocarditis, 
Grade 3 or 4
Confirmed Stevens-
Johnson Syndrome 
(SJS) 
Any grade
Confirmed Toxic 
Epidermal Necrolysis 
(TEN)
Any grade
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4.3.3.2 Combination (Pembrolizumab-ICE) Stopping Criteria:
Treatment with combination pembrolizumab-ICE must be 
discontinued for the following toxicities:
Adverse Event
Severity
Ifosfamide-related 
hematuria 
Grade 3 or 4 and persisting after dose 
reduction 
Neurologic symptoms
Grade 3 or 4
4.3.3.3 Stopping rules for engraftment delays/failure and transplantation 
related toxicity: 
Engraftment and transplantation-related toxicity will be monitored 
monthly. The stopping guidelines serve as a trigger for 
consultation with all investigators and the DSMC for additional 
review and are not formal stopping rules that would mandate 
automatic closure of study enrollment.

>1 patients have engraftment delay/failure >28 days post-
transplant based on CIBMTR engraftment definitions for ANC 
and platelets. 
(https://www.cibmtr.org/manuals/fim/1/en/topic/2450)

>2 patients experience Grade 4 non-hematologic toxicity 
excluding alopecia, fatigue, anorexia, dysphagia, mucositis, 
vomiting or diarrhea.

>1 patient experiences any Grade 5 toxicity.
4.4
Concomitant Medications/Treatments
4.4.1 Permitted 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 and the protocol. All 
concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. All concomitant medications received within 28 days 
before the first dose of trial treatment and 30 days after the last dose of trial 
treatment should be recorded.  
4.4.2 Cautionary Medications
Caution should be taken with anticoagulation, aspirin, and NSAIDs during 
4.4.3 Prohibited Medications
Patients should not be on other investigational agents, immunomodulatory 
drugs, or other cancer directed therapies as outlined in the exclusion 
criteria for study eligibility. Patients should also not receive any live 
vaccines within 30 days of starting treatment. If there is a clinical indication 
for one of these or other medications or vaccinations specifically prohibited 
during the trial, discontinuation from trial therapy or vaccination may be 
required. The investigator should discuss any questions regarding this with 
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the PI/QAM. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. 
4.5
Autologous Stem Cell Transplant
Following completion of therapy, patients with a FDG-PET/CT that has a 
Deauville score ≤ 3 will proceed to autologous stem cell transplant (AHSCT). 
Conditioning regimens prior to AHSCT may include an additional cycle of 
pembrolizumab-ICE combination on-study, or may be based on institutional 
standards and not be regulated by the study protocol. Details of conditioning 
regimen including dosing must be clearly detailed in the patient's medical record. 
Details of the stem cell pre-treatments or modifications and the stem cell 
amounts for reinfusion must be included in the medical record. A minimum of 
2.0x106 CD34+ cells/kg must have been collected during stem cell harvest to 
proceed with stem cell transplant (see section 4.2.5 for details). Patients are 
recommended to meet the following criteria before initiating autologous stem cell 
transplant, however institutional practice will take precedence:

Corrected DLCO of 60% 

FEV1 or FVC >60%

Ejection fraction 5% less than institutional lower limits of normal 

Calculated creatinine clearance > 30mL/min (using Cockcroft-Gault 
formula; see Appendix D)

Liver function <2.5 x ULN (unless related to neoplastic involvement)
4.6
Provider Discretion
Following completion of therapy, patients with a FDG-PET/CT that has a 
Deauville score >3 will be treated by provider discretion. Anticipated options 
include other combination chemotherapy, brentuximab vendotin, AHSCT, 
allogeneic stem cell transplant, vs some combination of these therapies. Any 
treatments including details about dosing must be clearly documented in the 
medical record.  
4.7
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 Northwestern and to Merck without delay and 
within 24 hours to Northwestern and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to 
Merck.  If a male subject impregnates his female partner the study personnel at 
the site must be informed immediately and the pregnancy reported to the 
Northwestern and to Merck and followed as described above and in Section 7.7.
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4.8
Duration of Therapy
Patients will be treated with 2 cycles of combination pembrolizumab and ICE 
salvage chemotherapy (Pembro-ICE) on protocol followed by a third dose of 
pembrolizumab monotherapy. All patients will have a FDG-PET/CT 14-22 days 
after the pembrolizumab monotherapy dose. Patients with a Deauville score ≤3 
may proceed to further treatment with Pembro-ICE combination (Cycle #4), if 
appropriate. Cycle #4 is not required on the study protocol. If the AHSCT can be 
arranged preferably within 21-35 days of the third pembrolizumab dose (but 21-
42 days will be acceptable), the patient may proceed directly to transplant 
otherwise cycle #4 will be administered per protocol. Alternatively, if the patient’s 
FDG-PET/CT has a Deauville score >3, they will come off protocol, receive no 
further study agent, and be treated per investigator discretion. 
4.9
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. Patients who 
complete the protocol regimen will have an off-treatment visit approximately 30 
days after stem cell transplant as well as visits at 60, 90, and 180 days (±14 
days) post-transplant. Thereafter, they will be followed with at least one clinic visit 
every 3 months for to 2 years and then annually for 2 years (one visit at 3rd year 
and one visit at 4th year of follow up) for 4 years total post-transplant or post-
study treatment. Patients removed from treatment for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event.
Adverse events will be followed for 30 days after last dose of study therapy or 
final stem cell transplant. Serious adverse events will be followed for 90 days 
after the last dose of pembrolizumab (or 30 days after starting subsequent 
therapy, whichever occurs first). Immune-related AE’s will be recorded for 90 
days after the last dose of pembrolizumab - these may include pneumonitis, 
colitis, hepatitis, endocrinopathies (hypopituitarism, hyper/hypothyroidism), and 
nephritis. For patients who undergo ASCT, AE’s ≥ Grade 3 will be recorded for 
180 days post-transplant. See section 7.7.1 for reporting requirements.
 
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time 
at their own request, or they may be withdrawn at the discretion of the 
investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation must be clearly documented on the appropriate eCRF and may 
include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in 
the patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would 
interfere with this study

Patient becomes lost to follow-up (LTF) 
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4.11
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 POD or toxicity will 
still be considered evaluable for toxicity endpoints; however, for the purpose of 
efficacy endpoints, another patient may be added to the accrual goal 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.
4.12
Suspension of Accrual
This study will be monitored in accordance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University. The DSMC will review all toxicity data, and in the event of an 
excessive toxicity, the DSMC may require suspension of accrual.
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5
STUDY PROCEDURES
Trial Period:
Screening 
Treatment Cycles1
Post-Treatment
Cycle 1
Cycle 2 
Cycle 3
Optional Cycle 42
ASCT3
Treatment Cycle/Title:
Main Study 
Screening
D1
D2-4
D1
D2-4
D10-21
D1
D14-22
D1
30 days post 
Transplant
Follow up
Cumulative Days on Study
1
2-4
22
23-25
32-42
43
59-64
64
64-8520
Scheduling Window (Days):
Within 28 days of 
registration18
--
± 2
--
± 2
± 2
± 2
± 3
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
Survival Status
X17
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X17
X17
Physical Examination4
X
X
X
X
X
X
X
X17
IPS Score5
X
ECOG Performance Status6
X
X
X
X
X
X
X
ECHO/MUGA
X19
X
ECG
X19
X
PFT’s with DLCO
X
Laboratory Procedures/Assessments
Pregnancy Test7 
X
CBC with differential and Chemistry panel8
X8
X
X
X
X
X
X
Urinalysis9
X9
X9
X9
Quantiferon-gold TB blood test
X
Study labs10
X
X
X
X
X
Study Treatment
Pembrolizumab14
X
X
X
X2
ICE Chemotherapy15
X
X
X
X
X2
PBSCH16
X16
X16
Efficacy Measurements
CT Scans11
X11
X11
FDG-PET/CT12
X12
X12
Tumor Biopsies/Archival Tissue Collection

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Archival Tissue Collection13
X

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1 A cycle is defined as 21 days (+/- 2 days) depending on CBC recovery as defined by ANC>1.5 and platelet count >75K
2 Cycle #4 is not required on the study protocol. Patients with a Deauville score ≤3 may proceed directly to AHSCT per provider discretion if the procedure can 
be arranged within 21-35 days after cycle #3. Alternatively, if the patient’s FDG-PET/CT has a Deauville score >3, they will come off protocol, receive no 
further study agent, and be treated per investigator discretion. 
3 Autologous Stem Cell Transplant will take place 21-42 days after the final study regimen pembrolizumab dose (optional pembro-ICE combination or otherwise, 
per provider discretion). Transplant visit parameters should be obtained on the initial day of induction chemotherapy or within 21-42 days following final 
study regimen but prior to the autologous stem cell transplant procedure
4 Patients will have a physical exam, including vital signs, weight and height (screening only) at each treatment visit.
5 See Appendix C
6 See Appendix A
7 Required for all FOCBP at baseline (within 72 hours of registration) and only as clinically indicated thereafter.
8 Labs must be completed within 10 days of study registration. Labs include a CBC w/ differential and CMP (Na, K, Cl, CO2, Glucose, Calcium, BUN, Cr, AST, 
ALT, Alkaline Phosphatase, Total Bilirubin)
9 Urinalysis will be performed on Day 2 of ICE chemotherapy to evaluate for hematuria (prior to ifosfamide treatment and per institutional standard thereafter).
10 Study labs will be collected pre-dose at each of the specified time points and will include (2) 5ml sodium heparin tubes for FlowCore See section 6.4 and 9.0 
for specific analysis.   
11 Diagnostic quality CT scan of the chest/abdomen/pelvis is required at baseline (within 6 weeks / 42 days prior to study registration). CT scan (with or without 
diagnostic quality) prior to ASCT is optional at the discretion of the treating investigator. If completed it should be preferably within 7 days prior to autologous 
stem cell transplant but 2-3 weeks prior to transplant will be acceptable. If there is involvement of the neck, then a CT Neck should be completed at the 
discretion of the treating investigator. 
12 FDG-PET/CT is required for eligibility (within 6 weeks / 42 days prior to study registration) and interim tumor assessment for the primary endpoint analysis. 
The interim assessment FDG-PET/CT must be obtained on day 14-22 of cycle 3 (at least 14 days after the pembrolizumab monotherapy dose) and uploaded 
into LifeImage within 30 days for central review as outlined in section 6.1.1 (see NOTIS for LifeImage Submission Manual).  
13 Tumor biopsy specimens are required for correlative analysis (if available). Patients are not required to have a repeat biopsy for eligibility unless no prior 
tissue is available. Tumor specimen can be from their biopsy at diagnosis or from a repeat biopsy at relapse. The most recent biopsy is preferred. 
14 Pembrolizumab will be administered at 200mg on day 1 of cycle 1, 2, and 3 for all patients (cycle 1 and 2 in combination with ICE chemotherapy, cycle 3 as 
monotherapy). For patients with a Deauville score ≤3, pembrolizumab may be given cycle 4 day 1 in combination with ICE therapy at physician’s discretion.
15 Patients will receive pembrolizumab in combination with ICE chemotherapy during cycle 1 and 2, as well as cycle 4 if applicable (see footnote 2). The ICE 
regimen will be given over days 1-4 and consists of ifosfamide + mesna, carboplatin, etoposide and G-CSF as detailed in section 6.2 of the protocol. 
16 Patients who will undergo ASCT are required to have a Peripheral Blood Stem Cell Harvest (PBSCH) preferably 10-20 days after the second pembro-ICE 
combination treatment See Section 4.2.5 for details. If stem cell collection is inadequate (<2x106 cells/kg) or there are issues with coordination and/or 
insurance verification, PBSCH may be collected after the study PET/CT either with growth factor stimulation alone (within 30 days of C3 pembrolizumab 
monotherapy dose for patients who do not have additional pembro-ICE), or 10-20 days after the (optional) third pembro-ICE combination treatment.
17 Patients will have follow-up clinic visits at 60, 90, and 180 days (±14 days) post-transplant (or post-study treatment) to assess adverse events according to 
the table in section 7.7.1. Engraftment will also be assessed as per section 4.3.3.3. Thereafter patients will be followed (either by routine clinic visit or by 
phone call) every 3 months for 2 years and then annually for 2 years (one visit at 3rd year and one visit at 4th year of follow up) for 4 years total post-transplant 
or post-study treatment to document survival and disease progression. 
18 Unless otherwise noted 
19 Echocardiogram and/or ECG should be performed as clinically indicated for patients with a history of congestive heart failure or at risk because of underlying 

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cardiovascular disease or exposure to cardiotoxic drugs Cardiac toxicities should be closely monitored and managed per section 4.3.1.5.
20 If optional Cycle 4 of PEM-ICE is completed the window for Autogous Stem Cell Transplant and study related procedures will be Days 85-106.

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6.0
RESPONSE ASSESSMENT
6.1
Deauville Criteria for FDG-PET/CT Interpretation
Deauville criteria is an internationally recommended scale for assessment of treatment 
response in Hodgkin's lymphoma. Deauville criteria will be used to assess treatment response 
in participants following treatment with combination pembrolizumab and ICE salvage 
chemotherapy. Deauville criteria is a tool based on interpretation of FDG uptake in comparison 
to two reference organs, the mediastinum and the liver. The scale ranges from 1 to 5 and 
Appendix B defines the Deauville scoring criteria. Scores of 1 to 3 are considered a complete 
response. Scores 4 and 5 may represent partial response, stable disease, or progressive 
disease. 
6.1.1
Central Review of PET/CT
All patients will have a retrospective central review of the interim PET/CT for research 
purposes. As scans are performed in real time, a de-identified image of the PET should 
be uploaded within 30 days to LifeImage to be reviewed at the Northwestern University 
Imaging Core. A copy of the diagnostic CT scan may be requested if needed for further 
interpretation, but only the PET is routinely required. The LifeImage Submission Manual 
is located in NOTIS.
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. 
In the event that a site is unable to upload PET/CT scans to LifeImage, contact QAM at 
Northwestern for an alternative method of providing PET/CT scans for central review.
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 
6.2
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.
6.3
Efficacy Endpoints
Response and progression will be evaluated using the Lugano criteria 201415. See Appendix E 
for specific response assessment criteria. All patients who undergo the interim assessment 
during Cycle 3 will be evaluable for response. For patients who discontinue the study prior to 
this point for any reason other than PD or toxicity, another patient may be added to the accrual 
goal with the approval of the Data and Safety Monitoring Committee (DSMC). 
6.3.1
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 more than 1.0. Lymph 
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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 (e.g., 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.
6.3.2
Event Free Survival (EFS)
EFS 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.
6.3.3
Overall Survival (OS)
OS will be defined as time from study enrollment until death, or until last contact if the 
patient did not die.
6.4
Exploratory Endpoints
Each enrolled patient’s most recent diagnostic biopsy sample will be obtained for additional 
marker expression analysis. Peripheral blood will be obtained at specified time points for flow 
analysis
6.4.1
PD-1 Pathway Marker Expression
Tissue sample slides from the most recent diagnostic 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.
NOTE: If a patient does not have tissue available, they are not required to have a fresh 
biopsy.
6.4.2
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 
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cytometry analysis to properly group biomarkers for determination of specific lymphocyte 
populations. Two specific lymphocyte populations that will be evaluated as the primary 
endpoint and include CD4+CD25+PD-L1+ T lymphocytes and CD4+CD62L+CD127+ T 
lymphocytes. Lymphocyte subsets are continuous measurements in cells/μL.
6.4.3
Chromosome 9p24.1 Mutation
Tissue sample slides from the most recent diagnostic biopsy will be evaluated by FISH 
break-apart probes for mutations at chromosome 9p24.1. Samples will be deemed either 
positive or negative. Presence/absence (binary) of chromosome 9p24.1 mutations will 
be correlated with response to pembrolizumab and clinical outcomes.
6.4.4
Stem Cell Harvest 
Patients will proceed to the stem cell harvest, per institutional guidelines, preferably 
within 10-20 days following cycle #2 pembrolizumab-ICE treatment (See Section 4.2.5 
for details). The number of required pheresis sessions and total amount of stem cells 
collected will be correlated with institutional experience. 
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 NOTIS for 
additional information). The level of risk attributed to this study requires High Intensity 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 time points). 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.
For subjects receiving treatment with pembrolizumab all Aes of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of a 
potentially immunologic etiology (termed immune-related adverse events, or irAEs). See section 
7.7.1 for further details.
7.2
Definitions & Descriptions
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. 
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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).
7.3
Severity of AEs
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.
7.4
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, or 30 days after patient starts new anti-cancer 
therapy, whichever occurs first, 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“. 
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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.
7.5
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.   
7.6
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the NU CTO SAE Form and reported within 24 hours to 
the assigned QAM and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) Events of clinical interest for this trial include: 

an overdose of Merck product, as defined as any dose of 1,000 mg or greater (≥5 times 
the indicated dose), that is not associated with clinical symptoms or abnormal laboratory 
results. 

an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
7.7
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) 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 study treatment, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must 
be reported as serious events (Important Medical Events). If the pregnancy continues to term, 
the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).
7.8 Adverse Event Reporting
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7.8.1
Overall Adverse Event Reporting Schedule
All adverse events will be monitored and recorded from the time of consent until 30 days 
after stem cell transplant or study treatment. Other types of adverse events will be 
recorded according to the following schedule:
Adverse Event Type
Duration of Reporting
Serious adverse events (SAE’s)
90 days after last dose of pembrolizumab
Immune-mediated adverse events*
90 days after last dose of pembrolizumab
≥Grade 3 adverse events
180 days after stem cell transplant
*Examples of immune-mediated adverse events are pneumonitis, colitis, hepatitis, 
endocrinopathies (hypopituitarism, hyper/hypothyroidism), and nephritis. 
7.8.2
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. 
7.8.3
Determining if Expedited Reporting is Required
This includes all events that occur within 30 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 a 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
7.8.4
Expedited Reporting of SAEs/Other Event
7.8.4.1
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
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
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.
7.8.4.2
Reporting to the Northwestern University IRB
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 10 
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.
7.8.4.3
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.
7.8.4.4
Reporting to Merck
Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time the consent is signed through 90 days 
following cessation of treatment, or 30 days after patient starts subsequent 
therapy, whichever occurs first, whether or not related to Merck product, must 
be reported to Merck within one business day. The NU SAE form is to be 
used for reporting to Merck. SAE reports and any other relevant safety 
information are to be forwarded to the Merck Global Safety facsimilie number: 
+1-215-993-1220.
8
DRUG INFORMATION
8.1
Pembrolizumab
8.1.1
Other names
MK-3475; Keytruda®
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
8.1.2
Classification - type of agent
Immunotherapy; Humanized X PD-1_mAb (H409A11) IgG4
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
Pembrolizumab injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), 
single-use vial (NDC  006-3026-02) Store vials under refrigeration at 2°C to 8°C (36°F to 
46°F) in original carton to protect from light. Do not freeze. Do not shake. Store the 
diluted solution from the pembrolizumab 100 mg/4 mL vial either: 

At room temperature for no more than 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.

Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 20 hours. If 
refrigerated, allow the diluted solution to come to room temperature prior to 
administration.
8.1.5
Protocol dose specifics
For the clinical trial there will be a set dose of 200 mg IV for all cycles regardless of 
weight. There are no dose modifications for toxicity.  
8.1.6
Preparation
Pembrolizumab is provided as a liquid solution (100 mg/vial) in Type I glass vials 
intended for single use only. Pembrolizumab is formulated with L-histidine as buffering 
agent, polysorbate 80 as surfactant, sucrose as stabilizer/tonicity modifier, and 
hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH adjustment (if 
necessary).
The product after reconstitution with sterile water for injection and the liquid drug 
product is a clear to opalescent solution, which may contain extraneous and 
proteinaceous particulates. The reconstituted drug product solution and liquid drug 
product are to be further diluted with normal saline in polyvinyl chloride (PVC) or non-
PVC IV bags to achieve final concentration between 1 mg/mL and 10 mg/mL.
Reconstituted vials and infusion solutions should be immediately administered after 
preparation. If not used immediately, reconstituted vials and/or IV bags may be stored at 
2-8 °C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or IV bags 
should be allowed to equilibrate to room temperature prior to subsequent use. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up 
to 4 hours. This includes room temperature storage of reconstituted drug product 
solution and liquid drug product in vials, storage of infusion solution in the IV bag and the 
duration of infusion. 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
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. 
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 pembroliuzmab (investigational / clinical supply) directly to the NU 
Investigational Pharmacy and affiliate sites 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 an 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 the most prevalent (>30% frequency) adverse events that have 
occurred in prior clinical trials. 

Fatigue

Cough

Diarrhea

Nausea/Vomiting

Rash

Headache

Pruritis
Special attention should be made to immune-related adverse events (<5% frequency), 
particularly dermatitis, pneumonitis, colitis, hepatitis, endocrinopathies (hypopituitarism, 
hypothyroidism), and nephritis. Please see the current IB for a comprehensive list of side 
effects and known frequencies of occurrence.
8.1.11 Nursing implications
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.
8.1.12 Return and Retention of Study Drug
Pembrolizumab will be supplied at no charge by Merck for patients on the protocol. In 
the event of patient has dosing delays, the study agent will remain at the treating 
institution per storage guidelines (8.1.4). The drug will be returned to Merck if a patient 
withdraws from the trial. 
8.2
Ifosfamide
8.2.1
Other names
IFEX
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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8.2.2
Classification - type of agent
Alkylating Agents: Nitrogen Mustards
8.2.3
Mode of action
Ifosfamide is classified as an alkylating agent of the nitrogen mustard type. After 
metabolic activation, active metabolites of ifosfamide alkylate or bind with many 
intracellular molecular structures, including nucleic acids. The cytotoxic action is 
primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein 
synthesis.
8.2.4
Storage and stability
IFEX (ifosfamide for injection, USP) is available in single-dose vials as follows:

NDC 0338-3991-01 1-gram Single-Dose Vial

NDC  0338-3993-01 3-gram Single-Dose Vial
Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Protect from 
temperatures above 30°C (86°F). Constituted or constituted and further diluted solutions 
of ifosfamide should be refrigerated and used within 24 hours.
8.2.5
Protocol dose specifics
For the clinical trial there will be a set dose of 5 g/m2 CIV over 24hrs on day 2 for all 
cycles. Dose modifications are outlined in Section 4.3; Table 2 and Table 3. 
8.2.6
Preparation
Injections are prepared for parenteral use by adding Sterile Water for Injection, USP, or 
Sterile Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to 
the vial and shaking to dissolve. Use the quantity of diluent shown below to constitute 
the product:
Dosage 
Strength
Quantity of 
Diluent
Final Concentration
1 gram
20 mL
50 mg/mL
3 grams
60 mL
50 mg/mL
Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 
20 mg/mL in the following fluids:

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

Lactated Ringer's Injection, USP

Sterile Water for Injection, USP
Because essentially identical stability results were obtained for Sterile Water admixtures 
as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and 
Lactated Ringer's Injection), the use of large volume parenteral glass bottles, Viaflex 
bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients 
(eg, 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 
0.9% Sodium Chloride Injection) is also acceptable. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration.
8.2.7
Route of administration for this study
Administer ifosfamide at 5 g/m2 IV mixed with equal dose of mesna via continuous 
intravenous infusion over 24 hours beginning on day 2 of each cycle. 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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8.2.8
Incompatibilities
Ifosfamide is incompatible with diazepam, pantoprazole, and potassium phosphate. Do 
not co-administer these drugs through the same infusion line.
8.2.9
Availability & Supply 
Ifosfamide is commercially available from multiple manufacturers and not supplied by the 
study.
8.2.10 Side effects
In patients receiving ifosfamide as a single agent, the dose-limiting toxicities are 
myelosuppression and urotoxicity. Dose fractionation, vigorous hydration, and a 
protector such as mesna can significantly reduce the incidence of hematuria, especially 
gross hematuria, associated with hemorrhagic cystitis. Leukopenia, when it occurs, is 
usually mild to moderate. Other significant side effects include alopecia, nausea, 
vomiting, and central nervous system toxicities. The most commonly reported adverse 
events include:
Adverse Reaction
Incidence (%)
Alopecia
83
Nausea-Vomiting
58
Hematuria
46
Gross Hematuria
12
CNS Toxicity 
12
Infection
8
Renal Impairment
6
Liver Dysfunction
3
Phlebitis
2
Fever
1
8.2.11 Nursing implications
Procedures for proper handling and disposal of anticancer drugs should be considered. 
Skin reactions associated with accidental exposure to ifosfamide may occur. The use of 
gloves is recommended. If ifosfamide solution contacts the skin or mucosa, immediately 
wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts 
of water. Several guidelines on this subject have been published. There is no general 
agreement that all of the procedures recommended in the guidelines are necessary or 
appropriate. 
Advise patients on the possible side effect profile. Follow infusion rate protocol with 
vigilant monitoring for possible infusion-related effects. At least 2 L/day of oral or IV 
fluids should be given to prevent bladder toxicity. Patients require a urinalysis to 
evaluate for hematuria prior to administration of ifosfamide then  monitoring per 
institutional standard. 
8.3
Carboplatin
8.3.1
Other names
CBDCA; Paraplatin®
8.3.2
Classification - type of agent
Antineoplastic Agent: Alkylating Agent, Platinum Compound
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
8.3.3
Mode of action
Carboplatin cytotoxic activity is a result of DNA binding to form intrastrand crosslinks and 
adducts that cause changes in the conformation of the DNA and affect DNA replication. 
Carboplatin readily crosses the cell membrane. Once inside the cell, the ring structure of 
carboplatin is hydroxylated by water to form the active moiety. Once in the active form, 
carboplatin binds with DNA, RNA, or other macromolecules at two sites to form 
interstrand and intrastrand links. Carboplatin forms irreversible covalent bonds which 
inhibit DNA replication, RNA transcription, and protein synthesis.
8.3.4
Storage and Stability
Product is stable for up to 14 days at 77 oF following multiple uses
Protect from light. Store at 77 oF; excursions permitted to 59-86 oF.
Reconstituted vials are stable for 24 hours at room temperature (25 oC). Paraplatin 
multidose (10 mg/ml) vials are stable for up to 14 days following initial entry into the vial.
 
Carboplatin solutions further diluted with D5W or NS are stable for 8 hours at room 
temperature (25 oC). Since carboplatin solutions are preservative-free the manufacturer 
recommends discarding any unused carboplatin solution after 8 hours.
8.3.5
Protocol dose specifics
For the clinical trial there will be a set dose carboplatin AUC 5 IV on day 2 (maximum of 
800 mg). Dose modifications are outlined in Section 4.3.2, Table 4.5.
8.3.6
Preparation
Aluminum needles, or IV sets containing aluminum should not be used for carboplatin 
preparation or administration because aluminum reacts with carboplatin to form a 
precipitate, causing loss of potency.
Reconstitution of vials:

Reconstitute carboplatin 50, 150, or 450 mg vials with 5, 15, or 45 ml, 
respectively, of sterile water for injection, D5W, or sodium chloride injection. The 
reconstituted vials should have a concentration of 10 mg/ml of carboplatin.
Further dilution for infusion:

Further dilute carboplatin solution (10 mg/ml) with D5W or NS to concentrations 
of 0.5-4 mg/ml.
8.3.7
Route of administration for this study
Carboplatin will be given IV at a dose of AUC 5 (max 800 mg) over 60 minutes on day 2 
of each cycle.
8.3.8
Incompatibilities
Carboplatin is incompatible with diazepam and lansoprazole. Do not co-administer these 
drugs through the same infusion line.
8.3.9
Availability & Supply 
Carboplatin is commercially available from multiple manufacturers and is not supply by 
the study.
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
8.3.10 Side effects
Most likely (>30%) side effects are myelosuppression, alopecia, nausea/vomiting, taste 
changes, weakness, and low magnesium. Less likely (10-29%) side effects include 
abdominal pain, diarrhea/constipation, mouth sores, increased risk of infections, 
peripheral neuropathy, ototoxicity, electrolyte imbalances, abnormal LFTs, 
nephrotoxicity, and allergic reactions. Rare side effects are life-threatening 
cardiovascular events. 
8.3.11 Nursing implications
Administer pre-treatment medications per protocol. Advise patients on the possible side 
effect profile. Routine hydration is not required with carboplatin therapy. Hydration 
should be considered in patients with renal impairment or in those receiving concurrent 
nephrotoxic agents. Visually inspect parenteral products for particulate matter and 
discoloration prior to administration whenever solution and container permit.
8.4
Etoposide
8.4.1
Other names
VP-16, Vepesid®
8.4.2
Classification - type of agent
Antineoplastic Agents: Natural and Semi-synthetic Antineoplastics: Epipodophyllotoxin 
8.4.3
Mode of action
Etoposide inhibits the enzyme topoisomerase II, nucleoside transport, and incorporation, 
and causes DNA breakage. 
8.4.4
Storage and stability
The injection should be stored at room temperature. Following dilution in 0/9% sodium 
chloride or 5% dextrose to concentrations of 0.2-0.4 mg/ml the drug is chemically stable 
for 48 and 96 hrs at room temperature, respectively. 
8.4.5
Protocol dose specifics
For the clinical trial, there will be a set dose etoposide of 100 mg/m2 on days 1 to 3 of 
each cycle. Dose modifications are outlined in Section 4.3.2, Table 4.5.
8.4.6
Preparation
The desired dose is diluted to a concentration of <0.4 mg/ml in normal saline or 5% 
dextrose to a volume of 250-500 ml. 
8.4.7
Route of administration for this study
Etoposide will be given IV at a dose of 100 mg/m2 over 60 minutes daily on days 1 to 3 
of each cycle. The dose on day 1 will be administered 1 hour following completion of 
pembrolizumab. 
8.4.8
Availability & Supply 
Etoposide is commercially available from multiple manufacturers and is not supply by the 
study. 
8.4.9
Side effects
Most likely (>30%) side effects include myelosuppression, alopecia, nausea/vomiting, 
and infertility. Less likely (10-29%) side effects include mouth sores, diarrhea, anorexia, 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
and skin reactions. Other rare side effects include metallic taste, peripheral neuropathy, 
and a slight increase risk of blood cancers. 
8.4.10 Nursing implications
Administer pre-treatment medications per protocol. Advise patients on the possible side 
effect profile. Visually inspect parenteral products for particulate matter and discoloration 
prior to administration whenever solution and container permit. 
Etoposide is administered by IV infusion. Avoid any contact with skin. Use Luer Lok 
fittings to prevent accidental leakage of etoposide during administration. If contact with 
skin occurs, wash immediately with soap and water.
Monitor blood pressure every 15 minutes during IV infusion of etoposide concentrate. If 
hypotension occurs, stop the infusion and notify physician. Infusion may be restarted at 
a slower rate after stabilization of blood pressure with IV fluids and supportive measures. 
Epinephrine, an antihistamine, and resuscitation equipment should be readily available 
in case of an anaphylactic reaction.
Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene 
and styrene) have been reported to crack and leak when used with undiluted etoposide 
for injection.
8.5
Mesna
8.5.1
Other names
Mesnex®
8.5.2
Classification - type of agent
Detoxifying agent. 
8.5.3
Mode of action
Binds to urotoxic ifosfamide metabolites thereby acting as a detoxifying agent. 
8.5.4
Storage and stability
When mesna is exposed to oxygen, mesna is oxidized. Any unused drug remaining in 
the ampules after dosing should be discarded and new ampules used for each 
administration. Store ampules and vials at room temperature. Multidose vials may be 
stored and used for up to 8 days after initial entry. Syringes prepared for oral 
administration are stable for 9 days at room temperature and under refrigeration. Diluted 
solution is sterile for 24 hours at 25C (77F). It is recommended that solutions of mesna 
be refrigerated and used within six hours. 
8.5.5
Protocol dose specifics 
The mesna dose must equal the calculated dose of ifosfamide for each cycle, starting at 
5g/m2.
8.5.6
Preparation
For IV administration, the drug can be diluted by adding the contents of a mesna ampule 
to any of the following solutions: 5% D/W, 5% D/NaCl injection, 0.9% NaCl injection, and 
lactated ingers injection. The vial should be inspected visually for particulate matter and 
discoloration prior to administration. 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
53
Amendment 9: 02/21/2022
8.5.7
Route of administration for this study
Administer mesna at 5 g/m2 IV mixed with equal dose of ifosfamide via continuous 
intravenous infusion over 24 hours beginning on day 2 of each cycle. 
8.5.8
Availability & Supply 
Mesna is commercially available from multiple manufacturers and not supplied by the 
study.
8.5.9
Side effects
Mesna should not be given to patients known to be hypersensitive to mesna or other 
thiol compounds. Mesna in high doses can cause acetone in the urine, occasional 
irritation at the infusion site, and nausea and vomiting. 
8.5.10 Nursing Implications
Visually inspect parenteral products for particulate matter and discoloration prior to 
administration whenever solution and container permit.
8.6
G-CSF   
8.6.1
Other names
Filgastrim; Neupogen®; tbo-Filgastrim; Granix®; peg-filgastrim; Neulasta®
8.6.2
Classification - type of agent
Colony Stimulating Factor
8.6.3
Mode of action
Binds to receptors on hematopoietic cells, increasing neutrophil production and 
activation.
8.6.4
Storage and stability
The intact vials of filgrastim should be stored under refrigeration (2-8ºC). Avoid shaking.
8.6.5
Protocol dose specifics
Filgastrim 5 mcg/kg/day will be administered. Pre-filled syringes of 300 mcg and 480 
mcg are available. Round up to the closest dispensed dose. Alternatively, peg-filgastrim 
6 mg can be administered as a single dose on day 4. Doses may be altered during stem 
cell mobilization per institutional protocol. 
8.6.6
Preparation
Filgrastim will be given subcutaneously directly from the vial.
8.6.7
Route of administration for this study
G-CSF will be administered as a subcutaneous injection starting day 4 per institutional 
protocol. G-CSF will start 24hrs after and within 48 hrs of completing chemotherapy with 
each cycle. 
8.6.8
Availability & Supply 
Filgastrim is commercially available Amgen and not supplied by the study.  
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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8.6.9
Side effects
The most prevalent (>10% frequency) adverse events include nausea/vomiting and 
abnormal lab elevations (AST, Alk Phos, LDH, and uric acid). Common (1-10%) adverse 
events include fatigue, generalized weakness, headache, constipation/diarrhea, 
anorexia, chest pain, musculoskeletal pain, alopecia, and skin rash. 
9
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 lymphoma38. We will analyze the previously obtained biopsy specimens from 
patients’ most recent samples to determine PD-1 and PD-L1 expression. 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-L234. 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 therapy39. The correlative investigations will determine 
lymphocyte subset changes during treatment with pembrolizumab. 
9.1
Archival Tissue Biopsy
An archival biopsy sample (preferably from the patient’s most recent biopsy) will be obtained for 
each patient for PD-1 pathway marker analysis, if available. For each biopsy specimen, 5 
unstained slides from a formalin-fixed, paraffin-embedded (FFPE) samples are required for 
immunohistochemical (IHC) analysis of PD-1 and PD-L1 expression (at QualTek Molecular 
Laboratories). A FFPE block section is also required to complete FISH analysis for alterations at 
chromosome 9p24.1 (at Northwestern University). See separate lab manual for processing and 
shipping details.
9.2
Flow Cytometry
Lymphocyte subsets will be evaluated by flow cytometry on peripheral blood obtained on Day 1 
of Cycles 1-3, at the time of ASCT, and at the 30-day follow-up visit. For each specified time   
point, peripheral blood sampling will require 5 mL in a sodium heparin tube. See separate lab 
manual for processing details.
9.2.1
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.
10 STATISTICAL CONSIDERATIONS
This is a Phase II trial to estimate a clinical response (complete response rate) following administration 
of pembrolizumab with salvage ICE chemotherapy for patients with relapsed/refractory 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.
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
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Amendment 9: 02/21/2022
10.1
Evaluability
To be evaluable for inclusion in the analysis to address the primary objective, patients must:

have received at least dose of pembrolizumab
AND

have a FDG-PET/CT scan following cycle #3
10.2
Study Design and Study Endpoints
The trial design is a single-stage Phase II, prospective, open-label, single-arm, multi-centered 
clinical trial. The standard response rate is assumed to be 0.5 (under the null hypothesis) by 
historical controls; and the new therapy is considered worthy of further research if we can reject 
the null hypothesis in favour of the one-sided alternative hypothesis, where the response rate is 
0.7. The consequent decision rule provides the sample size (n=37) and minimum number of 
responders (r) as ≥24 thus warranting further investigation of the new therapy, such that 
statistical significance is achieved. If r<24, then this number is the maximum number of 
responders for which statistical significance is not achieved. This design yields a type I error 
rate of 0.05 and power of 0.80 when the true response rate is 0.70.
Study endpoints are further defined in Section 6. For the primary objective, the endpoint will be 
complete response as defined by PET/CT with a Deauville score ≤3. For the secondary 
objectives, the endpoints will include the frequency, grade, timing, and attribution of AEs 
according to the NCI-CAE version 4.03. Efficacy endpoints for response and disease 
progression will be evaluated by the 2007 Revised Response Criteria for Malignant Lymphoma 
(RRCML).  
For the exploratory endpoints, patient’s tumor biopsy will be evaluated for PD-1 and PD-L1 
expression by immunohistochemistry. Samples will be deemed either positive or negative for 
marker expression. Tumors will also be analyzed by FISH to determine presence or absence of 
chromosomal abnormalities at chromosome 9p24.1. Peripheral blood obtained at specific time 
points through treatment will be used to test serum levels for immune markers and soluble PD-
L1. The immune marker and soluble PD-L1 assays include standardized reference ranges. 
10.3
Sample Size and Accrual
Per the sample size calculations, 37 patients will be required. At Northwestern University, we 
see ~30 patients with RR-HL annually. We expect at least 20 patients will meet eligibility criteria. 
Given the low incidence of RR-HL, this will be a multi-institutional clinical trial. Accrual rate will 
include 6 patients per year at Northwestern and 15 patients per year at participating sites. The 
required patient accrual will be met by 2 years with the total study duration within 3 years.
Statistical sample size calculations and definitions41:

P0 = 0.5 = Historical complete response rate of salvage chemotherapy by FDG-PET/CT 
in RR-HL.

P1 = 0.7 = Proposed improvement in complete response rate by addition of 
pembrolizumab to salvage chemotherapy in RR-HL.

n = Number of patients needed for enrollment

r = Number patients with complete response needed to reject the null hypothesis.

α = Probability of making a Type I error. 

P = Power
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10.4
Stopping Rule for Toxicity
There is no planned interim analysis of toxicity. Ongoing review by the treating investigators for 
unexpected toxicity is required. Participants will be closely monitored for grade ≥ 3 AEs, high 
rates of autoimmune SAEs, and inability to obtain adequate stem cell harvest. 
10.5
Data Analyses Plans
10.5.1 Analytic Plan for Primary Objective
To address the primary aim, we will calculate the proportion of patients with complete 
responses (defined as FDG-PET/CT Deauville score ≤ 3) as (number of responders) / 
(number of evaluable patients). We will place a 95% confidence interval on this 
proportion.
10.5.2 Analytic Plan for Secondary Objectives
To address the secondary objective 2.2.1, we will tabulate the number and percentage 
of toxicities by type, grade, severity, and attribution.
To address the secondary objectives 2.2.2 and 2.2.3, we will generate Kaplan-Meier 
curves of EFS, OS, and TSLC, including lifetables of point estimates and associated 
standard errors, which would include the presentation of the 2-year estimate.
10.5.3 Analytic Plan for Exploratory Objectives
To address the exploratory objective 2.3.1, we will perform a Fisher’s exact test of 
patients achieving complete remission (yes/no) versus presence/absence of expression 
of (a) PD-1 and (b) PD-L1. Kaplan-Meier curves of EFS and OS for presence versus 
absence of expression, will be generated, and a log rank test will be performed, for (a) 
PD-1 and (b) PD-L1.
To address the exploratory objective 2.3.4, we will perform a Fisher’s exact test of 
patients achieving complete remission (yes/no) versus (a) CD4+CD25+PD-L1+ T 
lymphocytes and (b) CD4+CD62L+CD127+ T lymphocytes responders (yes/no). Kaplan-
Meier curves of EFS and OS for presence versus absence of response, will be 
generated, and a log rank test will be performed, for (a) CD4+CD25+PD-L1+ T 
lymphocytes and (b) CD4+CD62L+CD127+ T lymphocytes.
To address the exploratory objective 2.3.5, we will perform a Fisher’s exact test of 
patients achieving complete remission (yes/no) versus presence/absence chromosome 
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9p24.1 mutation. Kaplan-Meier curves of EFS and OS for presence versus absence of 
chromosome 9p24.1 mutation, will be generated, and a log rank test will be performed. 
To address the exploratory objective 2.3.6, descriptive statistics will be generated to 
describe the ability to collect stem cells at the time of harvest as defined by number of 
pheresis sessions and amount of cells collected. 
11 STUDY MANAGEMENT
11.2
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.
11.2.1 Protected Health Information (PHI and HIPAA)
HIPAA authorization will be discussed with the participants during the consenting 
process and participant agreement will be documented by signature on the IRB 
approved consent form. The participants' PHI that will be collected for this study will be 
from their medical record (EMR), information collected from lab tests, procedures, 
imaging, and research samples (blood, tumor tissue) as well as information from the 
participants medical history related to their disease. PHI that may be collected from the 
medical record includes the patient date of birth, MRN, initials, address, phone number 
and elements of diagnosis treatment and death dates.
Data will be stored per the Feinberg School of Medicine IT Data Security Plan. Any data 
abstracted from the EMR will be entered directly into a password protected database. 
Only those with training and access to the database approved through the study may 
enter and review the data. Data entered into the databases are de-identified, and only 
patient initials and study numbers (study ID) are included. In cases where data is 
captured on paper case report forms, patient initials and study numbers are used on 
these forms. Paper case report forms and any printed source are kept in a patient 
specific research folder that is stored in a locked file cabinet.
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11.3
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 Merck. Amendments will be 
distributed by the lead institution (Northwestern) to all affiliate sites upon approval by the 
Northwestern University IRB.
11.4
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will be 
registered centrally through the Clinical Research 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.fsm.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.
Training on eCRF completion will be provided prior to 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.
11.5
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be provided to 
the Clinical Research 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.
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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.
11.6
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. 
11.7
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. 
11.7.1 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. 
11.7.2 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.
11.8
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.
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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. 
11.9
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 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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Andre M, Henry-Amar M, Pico JL, et al. Comparison of high-dose therapy and autologous stem-cell 
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Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in 
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Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging, and Response 
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Gentzler RD, Evens AM, Rademaker AW, et al. F-18 FDG-PET predicts outcomes for patients receiving total 
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Castagna L, Bramanti S, Balzarotti M, et al. Predictive value of early 18F-fluorodeoxyglucose positron emission 
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Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplantation functional imaging predicts outcome following 
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Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin 
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IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
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23.
Blank C, Kuball J, Voelkl S, et al. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in 
vitro. Int J Cancer 2006;119:317-27.
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Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34.
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Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25:9543-53.
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Seo SK, Seo HM, Jeong HY, et al. Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune 
response. Immunol Lett 2006;102:222-8.
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Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against 
cancer. Br J Cancer 2013;108:1560-5.
28.
Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends in immunology 2006;27:195-
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29.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape 
from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of 
Sciences of the United States of America 2002;99:12293-7.
30.
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous 
cell carcinoma. Cancer Res 2003;63:6501-5.
31.
Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell 
lymphomas and virus-associated malignancies. Clin Cancer Res 2013;19:3462-73.
32.
Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 
ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large 
B-cell lymphoma. Blood 2010;116:3268-77.
33.
Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin 
lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 
2012;18:1611-8.
34.
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's 
lymphoma. The New England journal of medicine 2015;372:311-9.
35.
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. The 
New England journal of medicine 2013;369:134-44.
36.
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. The New 
England journal of medicine 2015.
37.
Moskowitz AJ. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical 
Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013). 
ASH 54th Annual Meeting 2014;Abstract 290.
38.
Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ tumor-infiltrating lymphocytes in 
classical Hodgkin lymphoma substantiate reduced overall survival. Human pathology 2009;40:1715-22.
39.
Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with 
pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an 
international phase II trial. J Clin Oncol 2013;31:4199-206.
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Swerdlow SH, International Agency for Research on Cancer., World Health Organization. WHO classification of 
tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 
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Khan I, Sarker SJ, Hackshaw A. Smaller sample sizes for phase II trials based on exact tests with actual error 
rates by trading-off their nominal levels of significance and power. Br J Cancer 2012;107:1801-9.
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APPENDIX A
ECOG Performance Status
Description
Grade    
Fully active, able to carry on all pre-disease performance without 
restriction.
0
Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature, i.e. light 
housework or office work.
1
Ambulatory and capable of self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
2
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours
3
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
4
Dead
5
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APPENDIX B
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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APPENDIX C
International Prognostic Score (IPS) for Advanced Hodgkin’s Lymphoma
Component
Description
Points
No
0
Age ≥ 45
Yes
1
Female
0
Sex
Male
1
No
0
Albumin 
< 40 g/L
Yes
1
No
0
Hemoglobin 
< 105 g/L
Yes
1
Stage III
0
Stage
Stage IV
1
No
0
Leukocytosis 
> 15,000 per mm3
Yes
1
Lymphocyte ct > 600/mm3 and 
≥ 8% of WBC ct
0
Lymphopenia
Lymphocyte ct ≤ 600/mm3 and 
< 8% of WBC ct
1
Total
The Hasenclever International Prognostic Score (IPS) was designed to predict five-year freedom from 
progression of disease3. With each additional adverse prognostic factor, the predicted rate is reduced by 
approximately 8%. The score was developed and validated based on a set of patients being treated in the 
1980s with regimens including ABVD, MOPP and ABVD, and similar hybrid regimens. Treatment variations did 
not appear to affect the validity of the prognostic score. 
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APPENDIX D
Cockcroft-Gault Formula for Creatinine Clearance
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                                                           72 x serum creatinine in mg/dL 
       Male CrCl = (140 - age in years) x weight in kg x 1.00 
                                                           72 x serum creatinine in mg/dL
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APPENDIX E - Lugano 2014 Response Criteria
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
Radiologic CR (all of 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
New lesions 
Bone marrow
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
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 
PR (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
None
Not applicable
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
68
Amendment 9: 02/21/2022
response, consideration should be 
given to further evaluation with 
MRI or biopsy or an interval scan
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
Nonmeasured lesions
New lesions 
Bone marrow 
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
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
PD (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
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
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
69
Amendment 9: 02/21/2022
APPENDIX F – PROTOCOL SUMMARY OF CHANGES
Amendment 1 – September 23, 2016 (FDA Response Part-1) 
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover Page
Locke Bryan listed as Co-
Primary Investigator
Lists Locke Bryan as Co-
Sub Investigator
Administrative – there 
cannot be more than one PI 
on the study
Cover Page
n/a
Adds IND Number/Holder 
information (131946 / Jane 
Winter, M.D.)
New information provided 
by FDA
Abbreviations
n/a
Adds DLCO, MUGA, and 
PFT’s as expanded 
abbreviations
New procedures added that 
require abbreviation 
expansion
Study Summary
Listed short title of study
Removes short title
Administrative – no longer 
required 
2.1 (Primary Objective); 6.3 
(Efficacy Endpoints)
Lugano classification
Lugano criteria
Administrative wording 
preference
4.2.5 (Mobilization and 
Stem Cell Collection); 5.0 
(Study Procedures #15)
n/a
Adds two paragraphs to 
describe the mobilization 
regimens and requirements 
for stem cell collection. Also 
clarifies stipulation that if 
the first collection during 
Cycle 2 is inadequate, 
patients may have another 
collection after the study 
PET/CT
FDA requested a 
description of mobilization 
regimens and collection 
procedures for stem cell 
harvest
4.3.1.1 (Dose Delays)
Pembrolizumab could be 
delayed a maximum of 35 
days 
Changes maximum delay 
for pembrolizumab to 21 
days 
The PI feels that a delay of 
21 days is more appropriate 
as it allows for recovery of 
immune-mediated adverse 
events without 
unreasonably delaying 
treatment and disease 
control.
4.3.1.1 (Dose Delays)
“Pembrolizumab will be 
withheld for drug-related 
toxicities and SAEs”
Pembrolizumab will be 
withheld for drug-related 
toxicities, including SAE’s”
Clarification – 
pembrolizumab is to be 
held for drug-related SAE’s 
rather than all SAE’s
4.3.3 (Treatment Stopping 
Criteria)
n/a
Compiles criteria for 
discontinuing treatment into 
two tables specifically for 
“stopping criteria” – one for 
stopping pembrozlizumab 
alone and one for stopping 
combination pembro-ICE
The FDA requested clearly 
outlined stopping rules for 
treatment related toxicity for 
ICE plus pembrolizumab
4.5 (Autologous Stem Cell 
Transplant)
n/a
Adds the following criteria 
required to initiate stem cell 
transplant:
•  ≥ 2x106 cells/kg collected 
• Corrected DLCO of 60% 
• FEV1 or FVC >60%
• Ejection fraction 5% less 
than institutional limits of 
normal 
• Calculated creatinine 
The FDA requested that 
explicit requirements, that 
include end organ function, 
be listed for patients to 
initiate stem cell transplant
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
70
Amendment 9: 02/21/2022
clearance > 30mL/min 
(using Cockcroft-Gault 
formula; see Appendix D)
• Liver function <2.5 x ULN
4.8 (Duration of Follow Up); 
7.7.1 (Overall Adverse 
Event Reporting Schedule)
n/a
Adds additional instructions 
for monitoring and 
recording adverse events:
Immune-mediated 
adverse events are to be 
followed for 90 days after 
last dose of 
pembrolizumab
≥ Grade 3 adverse 
events are to be followed 
for 180 days after stem 
cell transplant
The FDA requested 
additional monitoring since 
immune effects are 
expected and it is unknown 
how pembrolizumab will 
impact toxicity in the peri-
transplantation period 
5.0 (Study Procedures)
n/a
Adds ECHO/MUGA and 
Pulmonary Functions Tests 
(PFT’s) at the time of 
transplant
Procedures have been 
added to obtain 
recommended values for 
ejection fraction, DLCO, 
and FEV1/FVC in order for 
patients to proceed with 
transplant. 
5.0 (Study Procedures)
Patients were to be 
followed every 3 and then 6 
months months after 
stopping treatment for 
survival only
Adds follow-up visits at 60, 
90, and 180 days post-
transplant or study 
treatment with adverse 
event monitoring
To account for additional 
adverse event monitoring 
requested by the FDA
7.1 (Adverse Event 
Monitoring)
Refers to immune-mediated 
adverse events as Events 
of Clinical Interest (ECI’s) 
and refers to section 8.6
Removes reference to 
ECI’s and replaces 
reference to section 8.6 to 
7.7.1
Immune-mediated AE’s are 
not listed as ECI’s, and 
there is more information in 
section 7.7.1 
Appendix D 
n/a
Adds Cockcroft Gault 
formulas for creatinine 
clearance
Added concurrently with the 
recommended creatinine 
clearance value prior to 
transplant 
Amendment 1 – September 30, 2016 (FDA Response Part 2)
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
4.3.3.3 (Stopping Rules for 
Transplant-Related 
Toxicity);
5.0 (Study Procedures #16)
n/a
Adds criteria for which 
transplant-related toxicities 
(for example, failure or 
delayed engraftment) would 
require a re-evaluation of 
study effectiveness
It is unknown how the 
addition of pembrolizumab 
will impact the function of 
the hematopoietic stem cell 
graft, the preparative 
regimen, or transplantation. 
Therefore, the FDA 
requested more intensive 
monitoring and 
consideration for toxicities 
related to transplant and 
engraftment.
IRB Response – November 30, 2016 
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
5.0 Study Procedures 
Footnote 16
Patients will have follow-up 
clinic visits at 60, 90, and 
Patients will have follow-up 
clinic visits at 60, 90, and 
Follow-up is only up to two 
years.
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
71
Amendment 9: 02/21/2022
180 days (±7 days) post-
transplant (or post-study 
treatment) to assess 
adverse events according 
to the table in section 7.7.1. 
Engraftment will also be 
assessed as per section 
4.3.3.3. Thereafter patients 
will be followed (either by 
routine clinic visit or by 
phone call) every 3 months 
for 2 years and then every 
6 months up to 5 years total 
from start of study 
treatment to document 
survival and disease 
progression. 
180 days (±7 days) post-
transplant (or post-study 
treatment) to assess 
adverse events according 
to the table in section 7.7.1. 
Engraftment will also be 
assessed as per section 
4.3.3.3. Thereafter patients 
will be followed (either by 
routine clinic visit or by 
phone call) every 3 months 
for 2 years from start of 
study treatment to 
document survival and 
disease progression. 
Study Schema diagram
Stem Cell Harvest
Peripheral Blood Stem Cell 
Harvest
For clarity.
Amendment 2 – February 15, 2017 
Approved by Scientific Review Committee – March 9, 2017
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
n/a
Adds Reem Karmali as 
sub-investigator
Administrative; new disease 
team faculty
Cover Page
Listed Yanming Zhang and 
Derek Wainwright as 
collaborators
Removes Yanming Zhang 
and replaces with Xinyan 
Lu; removes Derek 
Wainwright
Yanming Zhang no longer 
works at the university and 
Xinyan Lu is the new 
pathologist in that 
department; the Wainwright 
laboratory is currently at 
capacity for new studies
Study Schema
n/a
Adds cycle length of 21 
days
Clarification
Study Summary; 2.3 
(Exploratory Objectives); 
5.0 (Study Procedures, 
#10); 6.4 (Exploratory 
Endpoints); 9.0 
(Correlatives/ Special 
Studies); 10.5.3 (Analytic 
Plan for Exploratory 
Objectives)
Included exploratory 
objectives for serum 
biomarkers of immune and 
inflammatory response and 
soluble PD-L1
Removes serum 
biomarkers and soluble PD-
L1 as exploratory objectives 
and correlative samples
Since the Wainwright 
laboratory is at capacity, 
these samples cannot be 
analyzed
1.9 (Exploratory Studies)
Included rationale for 
studying serum biomarkers 
and soluble PD-L1 in this 
study
Removes rationale
These correlative samples 
are no longer being 
collected
4.2 (Treatment 
Administration)
Numbered tables 1, 2, 3…)
Re-numbers tables by 
section (4.1, 4.2, 4.3…)
Administrative clarification
4.2.5 (Mobilization and 
Stem Cell Collection)
PBSCH was to take place 
10-20 days after the second 
pembro-ICE treatment
PBSCH is to take place 
within 10-20 days after the 
second pembro-ICE 
treatment
Clarification to allow more 
flexibility
4.3.1.1 (Dose Delays); 
4.3.3.1 (Pembrolizumab 
Stopping Criteria)
n/a
Adds pembrolizumab dose 
delay guidelines for cardiac 
dysfunction (related to 
Additional guidelines 
provided by Merck as a 
result of new safety events
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
72
Amendment 9: 02/21/2022
myocarditis), Stevens-
Johnson Syndrome, and 
Toxic Epidermal Necrolysis
4.3.1.1 (Dose Delays)
“There are no dose 
modifications on the study 
protocol”
“There are no dose 
modifications for 
pembrolizumab on the 
study protocol”
Clarification; ICE may be 
modified per standard 
practice
4.3.1.5 (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
n/a
#9: Adds urinalysis on day 
2 of ICE chemotherapy
To assess for hematuria as 
part of standard of care 
related to ifosfamide 
treatment
#12: Interim FDG-PET/CT 
to be obtained on day 14 
(+/- 2 days), 14 days after 
pembrolizumab 
monotherapy
#12: Interim FDG-PET/CT 
to be obtained on day 14-
22, at least 14 days after 
pembrolizumab 
monotherapy.
Clarification; the intention 
was for the PET/CT to take 
place at least two weeks 
after pembrolizumab
Follow up visits at 60, 90, 
and 180 days had a window 
of ±7 days
Follow up visits now have a 
window of ±14 days
To allow flexibility in visit 
timing
5.0 (Study Procedures)
n/a
#19: Adds ECHO and/or 
ECG as clinically 
indicated at baselined for 
patients with history of 
CHF, and references 
section 4.3.1.5
Guidelines provided by 
CTEP as a result of 
myocarditis safety events 
related to nivolumab, an 
immunotherapy agent 
similar to pembrolizumab
8.3.4 (Storage and 
Stability); 8.5.5 (Protocol 
Dose Specifics); 
8.5.9 (Side Effects); 11.10 
(Publication Policy)
Missing section title
Adds appropriate section 
titles
Correction of typographical 
errors
Amendment 3 – August 8, 2017 
Approved by Scientific Review Committee – August 14 ,2017
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Cover Page; Study 
Summary; 3.0 (Patient 
Eligibility)
Included Hackensack 
University as an affiliate site 
(Andre Goy as sub-
investigator)
Removes Hackensack 
University as affiliate site, 
and adds Emory University 
School of Medicine  
Administrative 
5.0 (Study Procedures)
Cycle 3, Day 14 was listed 
as a time point with PBSCH 
and FDG-PET/CT as 
relevant procedures 
Changes time point to Day 
14-22
Revised for clarity; FDG-
PET/CT is to take place 
Day 14-22 of Cycle 3. 
PBSCH may also take 
place at this time if the 
initial collection is 
inadequate.
5.0 (Study Procedures)
Echocardiogram (+ECG) 
was listed as a procedure 
with time points at baseline 
(as indicated) and EOT
Moves ECG to be a 
separate procedure with a 
single time point at baseline 
(as indicated)
Revised for clarity; 
Echo/MUGA is required as 
part of the ASCT, but ECG 
should only be listed as a 
baseline procedure for 
patients with history of 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
73
Amendment 9: 02/21/2022
congestive heart failure
Amendment 4 – February 26th, 2018 
Approved by Scientific Review Committee –
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page
Included Jason Kaplan as 
Northwestern sub-I and 
Jonathon Cohen as the 
sub-I at Emory
Removes Jason Kaplan 
and Jonathon Cohen, and 
adds Pamela Allen as the 
sub-I at Emory
Administrative updates; 
Jason Kaplan has left 
Northwestern. Pamela Allen 
will be the new PI at Emory
Cover Page; 7.7.4.1 
(Reporting to the 
Northwestern University 
QAM/DSMC); 11.4 
(Registration Procedures)
Coordinating Center was 
listed as the Clinical 
Research Office at 
Northwestern University
Updates to “Clinical Trials 
Office” with appropriate 
contact information
Administrative update
3.0 (Patient Eligibility)
Listed accrual projections, 
estimating 6 patients per 
year would be accrued at 
Northwestern and 16 
across all sites over 3 years
Removes accrual projection 
language.
Language is not necessary 
and has potential to conflict 
with internal contractual 
numbers, which may 
change over time.
3.1.6 (Inclusion Criteria)
Organ and bone marrow 
function was to be 
“adequate” within 10 days 
of registration
Removes specific window 
and just states that levels 
must be adequate prior to 
registration
To avoid deviations in 
eligibility, window for labs 
will be stated only in the 
study procedures
4.2 (Treatment 
Administration); 4.2.1 (Day 
1 of Treatment); 4.2.2 (Day 
2 of Combination 
Treatment); 4.2.3 (Day 3 of 
Combination Treatment)
Listed dexamethasone 10 
mg IVP as a recommended 
pre-medication for ICE. 
Removes dexamethasone 
as a pre-med and lists anti-
emetics, with general 
recommendations for 
ondansetron and aprepitant
Dexamethasone acts to 
suppress immune activity, 
which counteracts the 
mechanism of the study 
drug.
4.3.1.1 (Dose Delays)
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.
4.3.1.2 (Rescue 
Medications & Supportive 
Care); 4.3.1.3 
(Management of Immune-
Related Adverse Events)
Regarding enterocolitis, 
patients with Grade 3 or 4 
were to be permanently 
discontinued, and patinets 
with Grade 2 were to be 
held with corticosteroids 
recommended at 0.5 
mg/kg/day prednisone
Enterocolitis should only 
cause discontinuation at 
Grade 4. Patients with 
Grade 2 or 3 enterocolitis 
should be held with 
corticosteroids at 1-2 
mg/kg/day prednisone
Updated to reflect new 
dose delay table in 4.3.1.1
4.3.1.3 (Management of 
Immune-Related Adverse 
Events)
“Pneumocystis carinii”
Updated to “Pneumocystis 
jiroveci”
To align with updated 
terminilogy
4.3.1.4 (Management of 
Infusion Reactions)
Table reference contained 
an “Error! Reference source 
not found.
Updated to reference Table 
4.3
Administrative to correct 
error
4.3.2 (Recommended ICE 
Chemotherapy Dose 
Management)
Guidelines for dose 
modifications were located 
as a table in section 4.3, 
and included a column for 
pembrolizumab.
Ifosfasmide reductions 
were:
Original dose: 5 g/m2
1st reduction: 3 g/m2
Moves table to section 
4.3.2 and removes column 
for pembrolizumab. 
Ifosfamide reductions are 
changed to be more 
stepwise:
Original dose: 5 g/m2
1st reduction: 4 g/m2
2nd reduction: 3 g/m2
The table portrays 
modifications only for the 
ICE regimen, so it is more 
appropriate in the section 
referencing ICE 
modifications. 
Clinical clarification
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NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
74
Amendment 9: 02/21/2022
2nd reduction: discontinue
Adds statement “In general 
there are no dose 
reductions recommended 
for hematologic toxicities”
4.3.3 (Treatment Stopping 
Criteria); 4.10 (Patient 
Replacement); 4.11 
(Suspension of Accrual); 
6.3 (Efficacy Endpoints); 
7.7.2 (Routine Reporting);
7.7.4 (Expedited Reporting 
of SAE’s); 
11.5 (Instructions for 
Participating Sites); 
11.10 (Publication Policy)
Referenced NU’s internal 
Data Monitoring Committee 
(DMC)
Updates references to the 
Data and Safety Monitoring 
Committee (DSMC)
Administrative update to 
align with new internal 
policies
4.7 (Duration of Therapy); 
5.0 (Study Procedures, 
#2,3)
AHSCT was to be arranged 
within 21 days of the third 
pembrolizumab dose. 
Updates to within 21-35 
days of the third 
pembrolizumab dose
A larger window is more 
realistic and clinically 
appropriate
4.8 (Duration of Follow-Up)
Only referred to off-
treatment visit 30 days after 
stem cell transplant
Adds follow-up visits at 60, 
90, and 180 days post-
transplant
To match requirements in 
study procedures table
n/a
Adds quantiferon-gold TB 
blood test
Patients with active TB are 
excluded due to immune 
suppression; adds baseline 
lab for consistency
#2 & 3: AHSCT was to take 
place within 21 days after 
cycle 3
#2 & 3: AHSCT should take 
place within 21-35 days 
after cycle 3
Previous window was too 
tight in the PI’s opinion
#10: Referenced section 
10.0 for correlative sample 
details
#10: Updates reference to 
sections 6.4 and 9.0
Updated for accuracy 
#11: Diagnostic CT’s were 
required at all time points. 
Baseline scan was required 
within 28 days prior to study 
registration.
#11: CT’s no longer have to 
be diagnostic quality prior 
to ASCT. Baseline scans 
can be within 6 weeks / 42 
days prior to study 
registration.
5.0 (Study Procedures)
#12: PET/CT was required 
within 28 days prior to 
registration
#12: Updates baseline 
window to 6 weeks / 42 
days
Broadens scan allowance 
to benefit patients with 
recent scans; this is 
clinically appropriate and 
allowable per PI.  
5.0 (Study Procedures #9); 
8.2.11 (Ifosfamide Nursing 
Implications)
#9: Required urinalysis 
every 8 hours for 24 hours 
after ifosfamide
#9: changes urinalysis to 
“per institutional standards” 
after ifosfamide
To allow investigator 
discretion in monitoring for 
hematuria post-chemo
7.6 (Events of Clinical 
Interest)
ECI’s were to be reported 
to the “Sponsor” using 
“Adverse Event case report 
forms / worksheets”
ECI’s should be reported to 
the assigned QAM using 
the NU CTO SAE Form 
Updated to align with 
internal policies and SAE 
reporting procedures
8.1.4 (Storage and 
Stability); 8.1.6 
(Preparation)
Referenced instructions for 
both lyophilized powder and 
solution constitutions 
Removes reference to 
lyophilized powder
Merck only provides 
pembrolizumab as a 
solution
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
8.1.9 (Availability & Supply)
Listed Sloan Stribling and 
Tammy Moll as drug 
Removes contacts and 
instead refers to the drug 
Contacts were out of date, 
and reference to drug order 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
75
Amendment 9: 02/21/2022
ordering contacts
order form where contacts 
are listed.
form avoids the need for 
unnecessary amendment in 
the case of staff changes
8.1.12 (Return and 
Retention of Study Drug)
Referenced 9.1.4 for 
storage guidelines
Updates reference to 8.1.4
To fix discrepancy
8.3.5; 8.4.5 (Protocol dose 
specifics: Carboplatin; 
Etoposide)
Referenced Section 4.3, 
Table 2 and Table 3 for ICE 
dose modifications
Updates reference to 
Section 4.3.2, Table 4.5
To fix discrepancy
10.2 (Study Design and 
Study Endpoints
Referenced Section 3 for 
study endpoints
Updates reference to 
Section 6
To fix discrepancy
 11.4 (Registration 
Procedures)
Referenced outdated 
NOTIS hyperlink
Updates hyperlink for 
NOTIS and adds 
instructions for eCRF 
training
Administrative update
11.6 (Data Management 
and Monitoring/Auditing)
Referenced NOTIS for Data 
Safety Monitoring Plan 
(DSMP)
Removes references to 
NOTIS and adds a relevant 
hyperlink to our “DSMP”. 
Adds that data is generally 
due within 10 days of 
completion of every cycle
Administrative clarifications
Amendment 5 – May 25, 2018
Approved by Scientific Review Committee –
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Cover Page
n/a
Adds Hatice Savas as a 
collaborator from 
Northwestern radiology
Central reviews of 
PET/CT’s have been added 
to the study, which will be 
performed by Dr. Savas
4.1 (Overview); 5.0 (Study 
Procedures #12); 6.1.1 
(Central Review of PET/CT)
n/a
Adds a central review of 
PET imaging at the interim 
analysis 
To provide an unbiased 
research analysis of PET 
results 
4.7 (Use in Pregnancy); 7.7 
(Reporting of Pregnancy 
and Lactation to the 
Sponsor and to Merck)
n/a
Adds pregnancy 
requirements from the 
Merck standard template. 
Patients should be removed 
from the study if they 
become pregnant, and the 
investigator must follow and 
report outcomes of such 
pregnancies 
To align with Merck and 
pembrolizumab 
requirements in case of 
pregnancy. Patients should 
not become pregnant while 
taking pembrolizumab due 
to likely side effects 
Amendment 6– May 29, 2019
Approved by Scientific Review Committee –
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
Coverpage
Fred Rademaker listed as 
Biostatistician
Removes Fred Rademaker 
and adds Denise 
Scholtens.
Change in biostatistician for 
the study
List of Abbreviations
DSMB Data and Safety 
Monitoring Board
DSMC Data and Safety 
Monitoring Committee
Updated to reflect current 
abbreviation and name
4.2.5 (Mobilization and 
Stem Cell Harvest) 
5.0 (Study Procedures #16) 
6.4.4 (Stem Cell Harvest)
N/A
States that PBCSH will be 
Adds language to make 
timing of PBSCH more 
general with delays 
permitted.
Changes to PBCSH to be 
collected within 30 days of 
Provides flexibility of timing 
of PBSCH.
Clarification
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
76
Amendment 9: 02/21/2022
collected within 30 days of 
PET/CT’
C3 pembrolizumab 
monotherapy dose
4.8 (Duration of Therapy)
5.0 (Study Procedures #3)
AHSCT can be arranged 
preferably within 21-35 
days of C3 PEM 
monotherapy dose
Updates to allow AHSCT to 
be arranged up to 42 days 
of C3 pembrolizumab 
monotherapy dose 
To provide more flexibility in 
timing and match timing 
changes in 5.0 ASCT timing
5.0 (Study Procedures)
ECG completed at 
screening only
ECG completed at 
screening and prior to 
ASCT
Added for safety monitoring
5.0 (Study Procedures)
Timing of ASCT referenced 
in table as D85-D99
Changed to D64-85
Updated to agree with 
timing being within 21-42 
days of C3 pembrolizumab 
monotherapy dose
5.0 (Study Procedures #3 
and #11)
Transplant visit parameters 
should be obtained on the 
initial day or induction 
chemotherapy and CT scan 
within 7 days of ASCT
Adds that parameters can 
be obtained any time after 
final study regimen but prior 
to ASCT and that loosens 
the timeframe for CT to 
allow for it to be completed 
2-3 weeks prior to ASCT
Provide flexibility in 
scheduling 
5.0 (Study Procedures #11)
CT required prior to ASCT
Changes this to make the 
CT scan optional prior to 
ASCT
Updated due to change in 
practice and insurance 
approval
5.0 (Study Procedures #20)
N/A
Added footnote to clarify 
timeframe of ASCT if 
optional Cycle 4 is 
completed
Clarification
6.1.1 (Central Review of 
PET/CT)
N/A
Adds alternative option for 
providing scans for central 
review
Updated information.
6.1.1.1 (Analysis Using 
Total Metabolic Volume)
Contained specific methods 
for analysis.
Removes specific methods 
and adds general 
methodology.
Provides more general 
overview of how TMTV 
analysis.
6.4.4 (Stem Cell Harvest)
Inferred Stem Cell Harvest 
was optional.
Removes the word 
‘optional’
Updates section to be 
consistent with other 
sections of the protocol.
8.1.10 (Side Effects) 
Pembrolizumab
N/A
Adds ‘Please see the 
current IB for a 
comprehensive list of side 
effects and known 
frequencies of occurrence’
Provides reference to IB for 
known side effects
Amendment 7– March 4, 2020
Section(s) Affected
Prior Version
Amendment  Changes
Rationale
Coverpage
Denise Scholtens listed as 
Biostatistician
Removes Denise Scholtens 
and adds Joan Chmiel.
Change in biostatistician for 
the study
Study Summary
States “up to 40 patients for 
37 evaluable”
Updates to “up to 43 
patients for 37 evaluable”
Increases accrual to ensure 
37 evaluable patients for 
analysis.
Amendment 8– June 10, 2021
Section(s) Affected
Prior Version
Amendment  Changes
Rationale
4.9 (Duration of Follow Up);
5.0 (Study Procedures)
Sections stated that 
“…patients will be followed 
(either by routine clinic visit 
or by phone call) every 3 
Section updated to 
“…patients will be followed 
(either by routine clinic visit 
or by phone call) at least 
Increase the length of time 
patients are followed for 
progression and survival 
and to clarify that the follow 
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.

NU Study Number: NU 16H07
Merck Study Number: PN3475-306
Initial Version: 11/30/2016 
77
Amendment 9: 02/21/2022
months for 2 years total 
from start of study 
treatment...”
one clinic visit every 3 
months for to 2 years and 
then annually for 2 years 
(one visit at 3rd year and 
one visit at 4th year of 
follow up) for 4 years total 
post-transplant or post-
study treatment.”
up period does not include 
time on study treatment.
Amendment 9– February 21, 2022
Section(s) 
Affected
Prior 
Version
Amendment  Changes
Rationale
Coverpage
June 10th, 
2021 
(Amendment 
8)
Changed to: February 21st, 2022 (Amendment 9)
Administrative revision
Table of 
Contents
N/A
Updates to page numbers and to include missing 
section headings to reflect current protocol content.
Administrative revision
11.2.1 
(Protected 
Health 
Information)
N/A
Section added as follows: “HIPAA authorization will be 
discussed with the participants during the consenting 
process and participant agreement will be documented 
by signature on the IRB approved consent form. The 
participants' PHI that will be collected for this study will 
be from their medical record (EMR), information 
collected from lab tests, procedures, imaging, and 
research samples (blood, tumor tissue) as well as 
information from the participants medical history related 
to their disease. PHI that may be collected from the 
medical record includes the patient date of birth, MRN, 
initials, address, phone number and elements of 
diagnosis treatment and death dates.
Data will be stored per the Feinberg School of Medicine 
IT Data Security Plan. Any data abstracted from the 
EMR will be entered directly into a password protected 
database. Only those with training and access to the 
database approved through the study may enter and 
review the data. Data entered into the databases are 
de-identified, and only patient initials and study 
numbers (study ID) are included. In cases where data is 
captured on paper case report forms, patient initials and 
study numbers are used on these forms. Paper case 
report forms and any printed source are kept in a 
patient specific research folder that is stored in a locked 
file cabinet. “
Updated to conform with 
data security plan 
language, current informed 
consent addendum and 
institutional requirements.
IRB #: STU00203658-CR0006 Approved by NU IRB for use on or after 6/13/2022 through 6/12/2023.