A Phase II Trial of Ipilimumab With and Without Nivolumab in Patients With Relapsed/Refractory Classic Hodgkin Lymphoma
Phase: PHASE2
Conditions: Hodgkin Lymphoma, Relapsed Hodgkin's Disease, Adult, Refractory Hodgkin Lymphoma
Sponsor: Dana-Farber Cancer Institute

 
 
NCI Protocol #: N/A 
DF/HCC Protocol #: 21-204 
 
TITLE:  A phase II trial of ipilimumab with and without nivolumab in patients with 
relapsed/refractory classic Hodgkin lymphoma 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
Principal Investigator (PI): 
Reid Merryman, MD 
 
Dana-Farber Cancer Institute  
 
450 Brookline Avenue 
 
Boston, MA 02215 
 
Reid_Merryman@dfci.harvard.edu   
 
Senior Investigator: 
Philippe Armand, MD, PhD 
 
Dana-Farber Cancer Institute 
 
Philippe_Armand@dfci.harvard.edu  
 
 
Margaret Shipp, MD 
 
Dana-Farber Cancer Institute 
 
Margaret_Shipp@dfci.harvard.edu  
 
Statistician:  
Robert Redd 
 
Dana-Farber Cancer Institute 
 
Robert_Redd@DFCI.HARVARD.EDU 
 
 
 
 
Agent(s): Nivolumab (investigational, supplied by Bristol-Myers Squibb); Ipilimumab 
(investigational, supplied by Bristol-Myers Squibb) 
 
 
IND #: 151589 
IND Sponsor: Reid Merryman, MD 
 
Protocol Version # / Version Date: Version 8 / 06 September 2023  

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
1 
SCHEMA 
 
 
  
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
2 
TABLE OF CONTENTS 
 
SCHEMA 
1 
1. 
OBJECTIVES 5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................5 
1.4 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Classic Hodgkin Lymphoma....................................................................................6 
2.2 
Ipilimumab ...............................................................................................................6 
2.3 
Nivolumab................................................................................................................8 
2.4 
Rationale ................................................................................................................11 
2.5 
Correlative Studies Background ............................................................................12 
3. 
PARTICIPANT SELECTION ...........................................................................................14 
3.1 
Eligibility Criteria ..................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................17 
4. 
REGISTRATION PROCEDURES ...................................................................................17 
4.1 
General Guidelines for DF/HCC Institutions ........................................................17 
4.2 
Registration Process for DF/HCC Institutions .......................................................17 
4.3 
General Guidelines for Other Investigative Sites ..................................................17 
4.4 
Registration Process for Other Investigative Sites.................................................18 
5. 
TREATMENT PLAN ........................................................................................................18 
5.1 
Treatment Regimen ................................................................................................19 
5.2 
Pre-Treatment Criteria ...........................................................................................20 
5.3 
Agent Administration.............................................................................................20 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................20 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................22 
5.6 
Continuation of Treatment Beyond Progression....................................................23 
5.7 
Duration of Follow Up ...........................................................................................23 
5.8 
Criteria for Taking a Participant Off Study ...........................................................24 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................24 
6.1 
Management of Adverse Events ............................................................................24 
6.2 
Immune Related Adverse Events (irAEs) ..............................................................24 
6.3 
Non-Immune Related Adverse Events ...................................................................35 
6.4 
Treatment Delays ...................................................................................................36 
6.5 
Dose Reductions ....................................................................................................36 
6.6 
Management of Infusion-Related Reactions ..........................................................36 
6.7 
Discontinuation of One Study Drug ......................................................................38 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
3 
6.8 
Study-wide early stopping rules .............................................................................38 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................38 
7.1 
Expected Toxicities ................................................................................................38 
7.2 
Adverse Event Characteristics ...............................................................................41 
7.3 
Adverse Event Reporting .......................................................................................42 
7.4 
Reporting to Bristol-Myers Squibb ........................................................................43 
7.5 
Reporting to the Food and Drug Administration (FDA) .......................................44 
7.6 
Reporting to Hospital Risk Management ...............................................................44 
7.7 
Routine Adverse Event Reporting .........................................................................44 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
Ipilimumab .............................................................................................................45 
8.2 
Nivolumab..............................................................................................................47 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................49 
10. 
STUDY CALENDAR .......................................................................................................51 
10.1 Required Data for Study Screening ...........................................................................51 
10.2 Required Data During Study ......................................................................................51 
10.3 Required at Progression or Treatment Discontinuation and Follow-Up ...................52 
11. 
MEASUREMENT OF EFFECT........................................................................................57 
11.1 
Antitumor Effect ....................................................................................................57 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................58 
12.1 
Data Reporting .......................................................................................................58 
12.2 
Data Safety Monitoring..........................................................................................58 
12.3 
Multi-Center Guidelines ........................................................................................59 
13. 
STATISTICAL CONSIDERATIONS...............................................................................59 
13.1 
Study Design/Endpoints.........................................................................................59 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................60 
13.3 
Analysis of Primary Endpoints ..............................................................................60 
13.4 
Analysis of Secondary Endpoints ..........................................................................60 
13.5 
Reporting and Exclusions ......................................................................................61 
14. 
PUBLICATION PLAN .....................................................................................................61 
REFERENCES 
62 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................65 
APPENDIX B 
DANA-FARBER/HARVARD CANCER CENTER 
MULTI-CENTER DATA SAFETY MONITORING PLAN............................................66 
INTRODUCTION 
66 
1.1 
Purpose ...................................................................................................................66 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
4 
2 
GENERAL ROLES AND RESPONSIBILITIES .............................................................66 
2.1 
External Site ...........................................................................................................66 
3 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................67 
3.1 
Protocol Revisions and Closures ...........................................................................67 
3.2 
Informed Consent Requirements ...........................................................................67 
3.3 
IRB Re-Approval ...................................................................................................68 
3.4 
DF/HCC Multi-Center Protocol Confidentiality ...................................................68 
3.5 
Participant Registration ..........................................................................................68 
3.6 
Data Management ..................................................................................................69 
3.7 
Protocol Reporting Requirements ..........................................................................70 
4 
MONITORING: QUALITY CONTROL ..........................................................................70 
4.1 
Ongoing Monitoring of Protocol Compliance .......................................................70 
4.2 
Monitoring Reports ................................................................................................71 
4.3 
Accrual Monitoring ................................................................................................71 
5 
AUDITING: QUALITY ASSURANCE ...........................................................................71 
5.1 
DF/HCC Internal Audits ........................................................................................71 
5.2 
Audit Notifications.................................................................................................71 
5.3 
Audit Reports .........................................................................................................71 
5.4 
External Site Performance .....................................................................................72 
APPENDIX C 
RESPONSE CRITERIA FOR LYMPHOMA: LUGANO 
2014 AND LYRIC .............................................................................................................73 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
5 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is an open-label phase II study of ipilimumab with or without nivolumab for patients with 
relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL).  
 
Patients who have previously failed a PD-1 mAb will receive 4 cycles of ipilimumab 
monotherapy and then undergo a restaging PET scan. Patients achieving an objective response 
will continue ipilimumab maintenance therapy. Patients with SD or progressive disease (PD) (if 
clinically stable) will receive 4 cycles of combination therapy with ipilimumab and nivolumab 
followed by ipilimumab maintenance therapy. Patients who have progressive disease after fewer 
than 4 cycles of ipilimumab are also eligible to proceed to combination therapy with nivolumab 
and ipilimumab, if they are clinically stable. The primary endpoint will be objective response 
rate (ORR) to 4 cycles of ipilimumab monotherapy. 
 
1.2 
Primary Objectives 
 
• To estimate the ORR of ipilimumab monotherapy in patients with R/R cHL who failed a 
PD-1 mAb  
 
1.3 
Secondary Objectives 
 
• Best ORR, PRR, CRR assessed by PET/CT (using Lugano criteria and LYRIC criteria) 
after ipilimumab monotherapy 
• Best ORR, PRR, CRR assessed by PET/CT (using Lugano criteria and LYRIC criteria) 
after ipilimumab and nivolumab combination therapy  
• To evaluate the following outcomes among patients receiving ipilimumab maintenance:  
o DOR and PFS (Lugano criteria and LYRIC criteria) 
o OS  
o Above endpoints, stratified by best response to PD-1 mAb (non-responder versus 
responder) 
• To evaluate the following outcomes among patients receiving re-induction with 
ipilimumab/nivolumab combination therapy: 
o DOR and PFS (Lugano criteria and LYRIC criteria) 
o OS  
o Above endpoints, stratified by best response to PD-1 mAb (non-responder versus 
responder) 
• To evaluate the safety of study treatment (within the entire study popultion, among 
patients receiving ipilimumab maintenance, and among patients receiving 
ipilimumab/nivolumab combination treatment) as measured by: 
o Rate of grade 3 or higher toxicity regardless of attribution 
o Rate of grade 3 or higher toxicity at least possibly related to study treatment 
o Rate of grade 2 or higher toxicity at least probably related to study treatment 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
6 
1.4 
Exploratory Objectives 
 
• To determine if features of the cHL TME are associated with response or resistance to 
study treatment 
• To determine if early reduction in ctDNA is associated with improved PFS.  
• To characterize the genetic bases of immune evasion and correlate these alterations with 
responses to therapy 
 
 
2. BACKGROUND 
 
2.1 
Classic Hodgkin Lymphoma 
 
Classic Hodgkin lymphoma (cHL) is diagnosed in approximately 8,500 people in the United 
States each year and is one of the most common cancers among young adults(1). The majority of 
patients are cured with first-line therapy, but approximately 10-15% of patients with early stage 
cHL and 15-30% of patients with advanced stage cHL will have primary refractory lymphoma or 
experience recurrence. Many of these patients may be cured with salvage chemotherapy and 
consolidative autologous stem cell transplantation (ASCT), but a significant cohort of patients 
are ineligible for these curative treatments due to chemoresistance, age, or comorbidities, or will 
relapse following ASCT.  
 
Historically, patients who are ineligible for or relapse following ASCT have experienced poor 
outcomes with a median OS of approximately 2 years(2). With the development of new, highly 
active agents, however, the prognosis of chemotherapy-resistant disease has improved 
dramatically. Initial trials of brentuximab vedotin (BV) and PD-1 mAbs demonstrated high 
ORRs in patients with chemotherapy-resistant disease, however, CRRs are low (30-35% for BV 
and 15-25% for PD-1 mAbs) and a large majority of patients eventually relapse following these 
treatments(3–5). Currently, there are no therapies approved for progression after BV and PD-1 
blockade. Depth of response appears to be a predictor of response duration for PD-1 mAbs. In 
the phase II trial of nivolumab, patients achieving a CR had more prolonged PFS compared to 
patients achieving a PR or stable disease(3). Novel treatment strategies are needed for patients 
who achieve an incomplete response or who experience progression on PD-1 blockade. 
 
2.2 
Ipilimumab 
 
2.2.1 Mechanism of Action 
 
Ipilimumab has specificity and high affinity for human CTLA-4. Ipilimumab completely blocked 
binding of B7.1 and B7.2 to human CTLA-4 at concentrations higher than 6 ug/mL and 1 ug/mL, 
respectively. Data suggests that treatment with ipilimumab has a low ability to elicit effector 
functions able to deplete activated T cells in vivo. 
 
2.2.2 Non-clinical Pharmacology 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
7 
The half-life of ipilimumab in cynomolgus monkeys was long (203 ± 62.8 to 339 ± 112 hours). 
Consistent with the long half-life, the total plasma clearance after a single dose of ipilimumab 
was low (0.196  ± 0.037 mL/h/kg). The steady state volume of distribution, 44.1 ± 6.05 mL/kg, 
was similar to the reported plasma volume of monkeys, suggesting that ipilimumab remained in 
the vascular system. 
 
In accordance with regulatory guidelines for biotechnology-derived pharmaceuticals, no tissue 
distribution studies with ipilimumab have been conducted in animals. However, the low volume 
of distribution in cynomolgus monkeys (0.046 to 0.060 L/kg) for each study drug indicates that 
there is little extravascular distribution of the drug. The expected in vivo degradation of mAbs is 
to small peptides and amino acids via biochemical pathways that are independent of cytochrome 
P450 enzymes.  
 
2.2.3 Clinical Pharmacology 
 
Ipilimumab has a terminal half-life of approximately 15.4 days. A population PK analysis of 
ipilimumab (n=785) demonstrated that the PK of ipilimumab is linear and exposures are dose 
proportional across the tested dose range of 0.3 to 10 mg/kg. Upon repeated dosing of 
ipilimumab, administered every three weeks, minimal systemic accumulation was observed by 
an accumulation index of 1.5-fold or less and ipilimumab steady-state concentrations were 
achieved by the third dose. 
 
The effects of various covariates on the PK of ipilimumab were assessed in population PK 
analyses. The clearance of ipilimumab increased with increasing body weight supporting the 
recommended body weight (mg/kg) based dosing. The following factors had no clinically 
important effect on the clearance of ipilimumab: age (range: 23 to 88 years), sex, performance 
status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate 
dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available 
in non-Caucasian ethnic groups.  
 
Renal Impairment: The effect of renal impairment on the clearance of ipilimumab was evaluated 
in patients with mild, moderate, and severe renal impairment compared to patients with normal 
renal function in population PK analyses. No clinically important differences in the clearance of 
ipilimumab were found between patients with renal impairment and patients with normal renal 
function  
 
Hepatic Impairment: The effect of hepatic impairment on the clearance of ipilimumab was 
evaluated in patients with mild hepatic impairment (n=76) compared to patients with normal 
hepatic function (n=708) in the population PK analyses, and no clinically important differences 
in the clearance of ipilimumab were found. Ipilimumab has not been studied in patients with 
moderate or severe hepatic impairment. 
 
2.2.4 Safety and clinical activity 
 
The overall safety experience with ipilimumab, as a monotherapy or in combination with other 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
8 
therapeutics, is based on experience in dozens of clinical trials and post-approval safety 
monitoring. For monotherapy, the safety profile is similar across tumor types. In Phase 3 
controlled studies, the safety profile of ipilimumab monotherapy is acceptable in the context of 
the observed clinical efficacy, and manageable using established safety guidelines. Clinically 
relevant AEs typical of stimulation of the immune system were manageable by delaying or 
stopping ipilimumab treatment and timely immunosuppressive therapy or other supportive care. 
 
Several small studies have tested ipilimumab as a single agent in patients with cHL (see section 
2.3). More extensive information regarding safety and clinical activity is available for other 
cancer histologies, in particular, melanoma. The safety and efficacy of adjuvant ipilimumab 
therapy was tested in randomized phase III trial among patients with resected stage III cutaneous 
melanoma (NCT00636168). Patients were randomized to receive ipilimumab 10 mg/kg or 
placebo as an intravenous infusion every 3 weeks for 4 doses, followed by ipilimumab 10 mg/kg 
or placebo every 12 weeks from Week 24 to Week 156 (3 years) or until documented disease 
recurrence or unacceptable toxicity. Ipilimumab treatment was associated with an improvement 
both recurrence-free survival (HR 0.75, p<0.002) and overall survival (0.72, p<0.002). Among 
the patients treated with ipilimumab, the most frequent adverse events included pruritus (41%), 
diarrhea (39%), fatigue (38%), rash (38%), headache (31%), weight loss (31%), nausea (24%), 
ALT elevation (16%), abdominal pain (14%), pyrexia (14%), cough (14%), decreased appetite 
(14%), AST elevation (12%), hypophysitis (13%), and vomiting (12%). Grade 3+ adverse events 
occurring in more than 1% of patients included: diarrhea (10%), colitis (7%), hypophysitis (5%), 
ALT elevation (5%), AST elevation (4%), pruritus (2%), fatigue (2%), rash (1%), nausea (1%), 
and pyrexia (1%)(6). Rates of irAEs and treatment discontinuation are lower when ipilimumab is 
dose at 3 mg/kg (7). 
 
2.3 
Nivolumab 
 
2.3.1 Mechanism of Action 
 
Nivolumab is an IgG4 antibody which binds to PD-1 (Programmed cell death protein 1; CD279) 
with nanomolar affinity and shows a high degree of specificity for PD-1 – blocking binding of 
PD-1 to PD-L1 and PD-L2. Nivolumab binds to human PD-1 and not to other members of the 
CD28 family, such as ICOS, CTLA-4 or BTLA. 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.  
 
2.3.2 Non-clinical Pharmacology 
 
Cynomolgus monkeys received single IV doses of nivolumab at 1 mg/kg (3 males and 3 females) 
and 10 mg/kg (3 males). Nivolumab was immunogenic in this study: 5 of 6 animals administered 
doses of 1 mg/kg and 2 of 3 animals administered doses of 10 mg/kg tested positive for anti-
nivolumab antibodies (determined to be neutralizing antibodies) 27 days after dosing. Nivolumab 
concentrations declined in a multi-phasic manner from the maximum concentration, which was 
observed at 0.25 to 0.5 hours. Concentrations were measurable through a median time of 384 
hours for males and females at 1 mg/kg and through 648 hours for males at 10 mg/kg. The 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
9 
apparent elimination half-life estimates for males and females at 1 mg/kg were similar, at 124 
and 139 hours, respectively. The T-HALF estimate at 10 mg/kg for males was 261 hours, but the 
data were variable (SD = 200 hours). Consistent with the long half-life, total serum clearance 
was low. Systemic exposure to nivolumab increased in an approximately dose proportional 
manner. 
 
2.3.3 Clinical Pharmacology 
 
Nivolumab pharmacokinetics (PK) were assessed using a population PK approach for single-
agent nivolumab. The PK of nivolumab was studied in patients over a dose range of 0.1 mg/kg to 
20 mg/kg or as a flat dose of 240-480mg administered as a single dose or as multiple doses of 
nivolumab as a 60-minute intravenous infusion every 2 or 4 weeks. The exposure to nivolumab 
increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 
weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that 
observed with a 60-minute infusion. Steady-state concentrations of nivolumab were reached by 
12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold. 
 
Distribution: The geometric mean volume of distribution at steady state and coefficient of 
variation is 6.8 L (27.3%). 
 
Elimination: Nivolumab clearance decreases over time, with a mean maximal reduction from 
baseline values of 24.5% resulting in a geometric mean steady-state clearance of 8.2 mL/h in 
patients with metastatic tumors; the decrease in steady-state clearance is not considered clinically 
relevant. Nivolumab clearance does not decrease over time in patients with completely resected 
melanoma, as the geometric mean population clearance is 24% lower in this patient population 
compared with patients with metastatic melanoma at steady state. The geometric mean 
elimination half-life is 25 days. 
 
Specific Populations: The following factors had no clinically important effect on the clearance of 
nivolumab: age (29 to 87 years), weight (35 to 160 kg), sex, race, baseline LDH, PD-L1 
expression, solid tumor type, tumor size, renal impairment (eGFR greater than or equal to 15 
mL/min/1.73 m2), and mild (total bilirubin [TB] less than or equal to the ULN and AST greater 
than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment 
(TB greater than 1.5 to 3 times ULN and any AST). Nivolumab has not been studied in patients 
with severe hepatic impairment (TB greater than 3 times ULN and any AST). 
 
Drug Interaction Studies: When nivolumab 1 mg/kg was administered in combination with 
ipilimumab 3 mg/kg, the clearance of nivolumab was increased by 29% and the clearance of 
ipilimumab was unchanged compared to nivolumab administered alone. When nivolumab 3 
mg/kg was administered in combination with ipilimumab 1 mg/kg, the clearance of nivolumab 
and ipilimumab were unchanged. When administered in combination, the clearance of 
nivolumab increased by 20% in the presence of anti-nivolumab antibodies.    
 
2.3.4 Safety and clinical activity 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
10 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 20,200 subjects treated to date. 
For monotherapy, the safety profile is similar across tumor types. In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. Clinically relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
 
Two studies evaluated the efficacy of nivolumab as a single agent in adult patients with cHL 
after failure of autologous stem cell transplantation (ASCT). CHECKMATE-205 
(NCT02181738) was a single-arm, open-label, multicenter, multicohort trial in cHL. 
CHECKMATE-039 (NCT01592370) was an open-label, multicenter, dose escalation trial that 
included patients with cHL. Patients received nivolumab 3 mg/kg by intravenous infusion every 
2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. Efficacy 
was evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had 
relapsed or progressive cHL after ASCT. Patients had a median of 4 prior systemic regimens 
(range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior 
brentuximab vedotin. Patients received a median of 21 doses of nivolumab (range: 1 to 48) and 
achieved a best ORR of 69% and a CRR of 14%. The median PFS was 13.1 months. The median 
DOR has not yet been reached. In the larger phase II CHECKMATE-205 study, the most 
common drug-related adverse events were fatigue (23%), diarrhea (15%), infusion relation 
(14%), rash (12%), nausea (10%), and pruritus (10%). Grade 3 or higher drug-related adverse 
events occurring in at least 1% of patients included: lipase increase (5%), neutropenia (3%), ALT 
increase (3%), AST increase (2%), amylase increase (2%), pneumonia (1%)(3,8).  
 
2.3.5 Safety of combination ipilimumab and nivolumab 
 
The combination of nivolumab + ipilimumab is approved in subjects with unresectable or 
metastatic melanoma as well as metastatic renal cell carcinoma and is currently being studied in 
multiple tumors. Results to date suggest that the safety profile of nivolumab + ipilimumab 
combination therapy is consistent with the mechanisms of action of nivolumab and ipilimumab. 
The nature of the AEs is similar to that observed with either agent used as monotherapy; 
however, both frequency and severity of most AEs are increased with the combination. 
 
The combination of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) was tested in 550 patients 
with advanced stage renal cell carcinoma as part of a phase III trial. In this cohort, the most 
common treatment-related adverse events were fatigue (37%), pruritus (28%), diarrhea (27%), 
rash (22%), nausea (20%), increased lipase level (16%), decreased appetite (14%), asthenia 
(13%), and vomiting (11%). Grade 3 or higher drug-related adverse events occurring in at least 
1% of patients included: increased lipase (10%), diarrhea (4%), fatigue (4%), rash (1%), nausea 
(1%), decreased appetite (1%), and asthenia (1%)(9). This combination was also tested in 31 
patients with cHL as part of a phase 1b trial in 65 patients with relapsed hematologic 
malignancies. In this cohort, the most frequent adverse events were fatigue (26%), pyrexia 
(23%), and diarrhea (18%). In total, 19 pts (29%) had a drug-related AE of grade ≥3(10).  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
11 
2.4 
Rationale 
 
Classic Hodgkin lymphoma (cHL) is characterized by an unusual tissue architecture composed 
of rare Reed-Sternberg (RS) cells surrounded by a complex network of immune cells that are 
unable to mount an effective anti-tumor immune response. In recent years, investigators have 
uncovered mechanisms by which RS cells evade immune detection, which has enabled 
significant therapeutic breakthroughs in cHL. Nearly all patients with cHL harbor genetic 
alterations in 9p24.1, an amplicon which contains the genes for both PD-1 ligands, PD-L1 and 
PD-L2(11). The amplicon also contains the JAK2 gene and augmented JAK/STAT signaling 
generates additional production of PD-L1 and PD-L2 proteins. Together, these alterations drive 
abundant expression of PD-1 ligands on RS cells which can bind to PD-1 on infiltrating effector 
immune cells leading to inactivation and immune evasion. Based on this genetic dependency, 
patients with cHL were included as independent cohort expansions in phase I trials of PD-1 
inhibitors. These and subsequent phase II trials reported overall response rates (ORRs) of around 
70% which led to the FDA approval of two PD-1 inhibitors, nivolumab and pembrolizumab, for 
relapsed/refractory (R/R) cHL(3,4,8,12).  
 
However, even with the success of PD-1 directed mAb in cHL, significant challenges remain for 
patients with R/R disease. Approximately 10-15% of patients will progress rapidly with PD-1 
blockade and many other patients will experience limited disease control with these agents(3,4). 
In particular, patients who achieve a best response of stable disease or partial response (~70% of 
all patients) achieve more limited progression-free survival (PFS) (11.2 months and 15.1 months, 
respectively) compared to patients who achieve a complete response (22.2 months)(3). Novel 
treatment strategies are needed for patients who achieve an incomplete response or who 
experience progression on PD-1 blockade.  
 
While alterations in the PD-1 signaling axis are nearly universal and appear to be critical for cHL 
pathogenesis, numerous other immune checkpoint receptors and ligands are present in the cHL 
tumor microenvironment (TME) and may also play important roles in immune evasion. These 
immune checkpoints offer additional potential targets for therapeutic intervention. Patel et al. 
used multiplex immunofluorescence to analyze the expression and distribution of the inhibitory 
immune checkpoint receptor CTLA-4 and its ligand CD86 in cHL. They found frequent 
expression of CTLA-4 on intratumoral T cells and strong expression of CD86 on nearly all RS 
cells as well as on a subset of tumor-associated macrophages (TAMs). Intratumoral T cells were 
more likely to express CTLA-4 than PD-1 and both CTLA-4 and CD86 were enriched within 
PD-L1 positive clusters of RS cells and TAMS, suggesting that CTLA-4 may also be important 
for maintaining an immunosuppressive niche for RS cells. Importantly, frequent CTLA-4 and 
CD86 expression in the cHL TME was seen both before and after treatment with PD-1 
blockade(13). 
 
These results provide a strong scientific rationale for additional clinical investigation of CTLA-4 
directed therapies in cHL. Already, there are several small studies that suggest that ipilimumab 
has clinical activity among patients with R/R cHL. Two trials have investigated single-agent 
ipilimumab among patients with relapsed disease after allogeneic transplantation. Two of 
fourteen patients achieved a complete response (CR) after a single dose of ipilimumab in an 
initial study(14), and 4 of 7 patients achieved a reduction in tumor burden (including 1 partial 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
12 
response) in a subsequent study that employed repeated dosing of ipilimumab(15). Despite its 
use after allogeneic transplantation (where the risk of immune-related complications including 
graft-versus-host disease is high), the safety profile of single agent ipilimumab was manageable. 
The largest experience with CTLA-4 blockade in cHL comes from a trial combining ipilimumab 
(1 mg/kg) with nivolumab (3mg/kg) in patients with R/R hematologic malignancies. In this trial, 
31 patients with HL received 4 cycles of combination therapy followed by nivolumab 
monotherapy every 2 weeks for up to 2 years. Response rates with the combination (ORR 74%, 
CRR 19%) were similar to PD-1 blockade monotherapy, but longer-term follow-up suggests that 
combination therapy may be associated with more durable remissions(10). The 18-month PFS 
with combination ipilimumab and nivolumab (~65%) which compares favorably to that observed 
with nivolumab monotherapy in the phase II CHECKMATE 205 trial (median PFS of 14.7 
months). Higher rates of immune-related adverse events (irAEs) were observed with ipilimumab 
and nivolumab compared to nivolumab monotherapy, however, most irAEs were manageable. 
The rate of treatment discontinuation due to adverse events with combination therapy was 
similar to that observed in phase II trials of PD-1 mAb monotherapy (8% vs 4-6%)(3,4,10). 
Ipilimumab (1 mg/kg every 12 weeks) has also been tested in R/R cHL as part of a triplet therapy 
with nivolumab (3mg/kg every 3 weeks) and BV (1.8 mg/kg every 3 weeks). Among 22 patients, 
the ORR and CRR were 82% and 72%, respectively. Frequent adverse events were observed and 
while these were typically manageable, 3 patients (14%) discontinued therapy after one 
cycle(16). 
 
The frequent expression of CTLA-4 and its ligand CD86 within the cHL TME provide a strong 
biologic rationale for CTLA-4 directed therapies in cHL. In addition, available clinical data 
suggests that ipilimumab has clinical activity and a tolerable risk profile when used as 
monotherapy or in combination with nivolumab. We have designed a phase II trial that targets 
the use of ipilimumab to those patients who derive less benefit from PD-1 blockade with the goal 
of limiting overall toxicity exposure. The trial will utilize a response-adapted design among 
patients who failed PD-1 mAb therapy. Patients will begin with ipilimumab monotherapy and 
then undergo a restaging PET/CT. Patients achieving an objective response will continue 
treatment with ipilimumab maintenance, while non-responders will receive ipilimumab and 
nivolumab re-induction therapy for 4 cycles followed by ipilimumab maintenance treatment. 
Given the key role of the PD-1 axis, we hypothesize that some patients may benefit from the 
addition of nivolumab to CTLA-4 blockade even after they have progressed following treatment 
with both treatments alone. Observation of objective responses to combination therapy with 
nivolumab and ipilimumab in this setting would provide strong evidence of synergy with 
combined PD-1 and CTLA-4 blockade. 
 
2.5 
Correlative Studies Background 
 
2.5.1 Multiplex immunofluorescence (MIF): 
 
This study will incorporate a laboratory technique known as MIF, which is used to examine the 
expression and distribution of up to 6 antigens of interest within formalin-fixed paraffin 
embedded (FFPE) tissue. The technique allows for examination of co-localization of proteins of 
interest and protein-protein interaction. MIF has been used successfully to interrogate the TME 
of multiple subtypes of lymphoma, including Hodgkin lymphoma, where it clarified the critical 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
13 
roles of the PD-1 and CTLA-4 in maintaining an immunosuppressive microenvironment(13,17). 
We aim to use MIF to characterize the expression of immune checkpoint proteins (CTLA-4, 
CD86, PD-1, PD-L1, and others) and to describe the distribution of immune cells, including 
CD8+ T cells, CD4+ T cells, T regulatory cells, NK cells, and tumor-associated macrophages 
(TAMs). In addition, using on-treatment and post-progression tumor samples we will describe 
alterations following treatment with ipilimumab +/- nivolumab. We hypothesize that there may 
be baseline TME features that predicts response to ipilimumab +/- nivolumab therapy. In 
addition, post-progression biopsies may suggest mechanisms of resistance that could be explored 
further in subsequent studies.  
 
2.5.2 Multiplex Ion Beam Imaging (MIBI): 
 
Simultaneous detection of multiple targets is limited by spectral overlap of the fluorophores used 
to tag individual antibodies. Due to this technical limitation, MIF typically cannot assess more 
than 6 antigens at a time. Multiplex Ion Beam Imaging (MIBI) uses secondary ion mass 
spectrometry to image antibodies carrying metal isotopes. As a result, MIBI is capable of 
analyzing samples stained simultaneously with more than 40 metal-isotope labelled 
antibodies(18). This technique will be used in conjunction with MIF to analyze the TME of cHL, 
characterize the expression of immune checkpoint proteins, and describe the distribution of 
immune cells. In addition, using on-treatment and post-progression tumor samples we will 
describe alterations following treatment with ipilimumab +/- nivolumab. 
 
2.5.3 Circulating tumor DNA (ctDNA): 
 
Plasma is a source of circulating tumor DNA (ctDNA) which can be used for to identify tumor 
genotypes, copy number abnormalities, immunoglobulin gene rearrangements, and single gene 
mutations. In addition, serially collected plasma samples can be used to track the level of ctDNA 
over time in response to therapy. In multiple tumor lymphoma subtypes, including diffuse large 
B-cell lymphoma (DLBCL) and cHL, an early drop in level of ctDNA (i.e. 2 log reduction) after 
2 cycles of induction chemotherapy has been associated with a significant improvement in 
PFS(19,20). Early data suggests that changes in levels of ctDNA may also hold predictive value 
for patients with lymphoma receiving immune-based therapies(21,22). We plan to collect serial 
plasma samples for analysis of ctDNA. Our group is currently developing an assay for ctDNA 
evaluation in cHL. We will quantify circulating tumor DNA at different timepoints and analyze 
changes in copy number abnormalities and relevant pathogenic gene. We hypothesize that an 
early reduction in ctDNA will be associated with clinical response and improved PFS. We will 
also use serial samples to characterize the genetic bases of immune evasion and correlate these 
alterations with responses to therapy 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
14 
3. 
PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Patients must have histologically determined classic Hodgkin lymphoma with pathologic 
review at the participating institution.  
3.1.2 Participants must have measurable disease, defined as a lymph node or tumor mass ≥1.5 
cm in at least one dimension by CT, PET/CT, or MR. Imaging must have been completed 
no greater than 6 weeks prior to study enrollment. Measurable disease that has previously 
been irradiated is permissible only if there has been evidence of progression since the 
radiation.  
3.1.3 Patients must have progressed after two or more lines of systemic treatment, including 
autologous stem cell transplantation, if eligible.  
3.1.4 Progression of disease or relapse following treatment with nivolumab or pembrolizumab. 
Intervening treatments with between PD-1 mAb therapy and the trial are permitted. 
3.1.5 Patients may have had a prior autologous stem cell transplant and may have been treated 
with chimeric antigen receptor T-cells (CAR T-cells). 
3.1.6 Age ≥18 years.   
3.1.7 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)  
3.1.8 Adequate hematologic and organ function as defined below: 
• Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by 
lymphoma in which case ANC must be >0.75x109/L. Growth factor support is 
allowed provided it is received at least 5 days prior to enrollment labs.  
• Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which case 
platelets must be >50 x109/L 
• Estimated GFR (by Cockroft-Gault equation) > 40ml/min 
• Total bilirubin < 1.5 X ULN 
• AST/ALT < 2.5 X ULN 
3.1.9 Ability to understand and the willingness to sign a written informed consent document.  
3.1.10 Willingness to provide pre-treatment tumor sample by core needle or excisional surgical 
biopsy. An archival sample is acceptable in the following situations: the sample was 
acquired within 90 days of initiation of PD-1 therapy AND the following provisions are 
met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) 
tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, 
sections from this block should be provided that are freshly cut and mounted on 
positively-charged glass slides (SuperFrost Plus are recommended).  Preferably, 25 slides 
should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this 
criterion may be made with approval of the Study Chair. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
15 
3.1.11 Willingness to use contraception during and after study treatment. Women of child-
baring potential (WOCBP) will be instructed to adhere to contraception for a period of 5 
months following last dose of nivolumab and 6 months following the last dose of 
ipilimumab. Men receiving nivolumab and who are sexually active with WOCBP will be 
instructed to adhere to contraception for a period of 7 months after last dose of nivolumab 
and 6 months after the last dose of ipilimumab.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
16 
3.2 
Exclusion Criteria 
3.2.1 Patients currently receiving anticancer therapies or who have received anticancer 
therapies within 28 days of the start of study drug (including chemotherapy, radiation 
therapy, antibody-based therapy, etc.), or 56 days for radioimmunotherapy. Steroids for 
symptom palliation are allowed but must be either discontinued or on stable doses of < 
10mg daily of prednisone (or the equivalent) at the time of initiation of protocol therapy. 
3.2.2 Patients may not be receiving any other investigational agents or have received 
investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of beginning 
treatment. 
3.2.3 History of severe allergic or anaphylactic reactions to monoclonal antibody therapy 
unless in consultation with an allergy specialist they are deemed eligible for retreatment 
with desensitization. 
3.2.4 Patients who have undergone prior allogeneic stem cell transplantation 
3.2.5 Patients with a history of or active autoimmune disease (except controlled asthma, 
Hashimoto thyroiditis, atopic dermatitis, or vitiligo), or requiring systemic corticosteroids 
at a dose of 10mg prednisone equivalent daily.  Patients with a history of autoimmune 
disease who never required corticosteroids and with no evidence of disease activity, and 
in whom the risk of reactivation is felt not to be serious, may be enrolled after discussion 
with the overall study chair.  Exceptions to this are patients with a history of 
inflammatory bowel disease (ulcerative colitis and Crohn’s disease).  These patients are 
excluded regardless of whether their disease is active or inactive. 
3.2.6 Patients who experienced grade 4 immune-related adverse events (irAEs) during 
treatment with a PD-1 mAb. 
3.2.7 Patients with active pneumonitis or colitis, or patients with cirrhosis. 
3.2.8 Patients, who have had a major surgery or significant traumatic injury within 4 weeks of 
start of study drug, patients who have not recovered from the side effects of any major 
surgery (defined as requiring general anesthesia). 
3.2.9 Patients with known HIV infection or hepatitis B or C infection.  Testing for HIV is 
optional.  Testing for hepatitis B and C is mandatory.  Patients with hepatitis B core Ab 
positivity but negative surface antigen and negative viral load may be enrolled if they can 
be treated with a prophylactic agent (eg, entecavir); patients with hepatitis C 
seropositivity who have a negative viral load can also be enrolled. 
3.2.10 Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined 
as exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment). 
3.2.11 Prior history of another malignancy (except for non-melanoma skin cancer or in situ 
cervical or breast cancer) unless disease free for at least 2 years. Patients with prostate 
cancer are allowed if PSA is less than 1. 
3.2.12 Patients should not have received immunization with attenuated live vaccine within one 
week of study entry or during study period. 
3.2.13 History of noncompliance to medical regimens. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
17 
3.2.14 Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study. 
3.2.15 Patients with any one of the following currently on or in the previous 6 months will be 
excluded:  myocardial infarction, congenital long QT syndrome, torsade de pointes, left 
anterior hemiblock, unstable angina, coronary/peripheral artery bypass graft, or 
cerebrovascular accident. 
3.2.16 Other uncontrolled intercurrent illness that would limit adherence to study requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) 
of the registering site. If the subject does not receive protocol therapy following registration, the 
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager.  All sites should call the Project Manager at 617-632-2328 to verify dose level 
availabilities.   
 
Following registration, participants should begin protocol therapy within 5 days. Issues that 
would cause treatment delays should be discussed with the Sponsor-Investigator.  If the subject 
does not receive protocol therapy following registration, the subject must be taken off study in 
the CTMS (OnCore) with an appropriate date and reason entered.   

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
18 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by participating site and 
e-mailed to the DFCI Project Manager.  
• Copy of required assessments that support eligibility 
• Signed informed consent document 
• HIPAA authorization form (if applicable) 
• Completed DFCI eligibility checklist 
 
The participating site will e-mail the DFCI Project Manager to verify eligibility.  The DFCI 
Project Manager will follow DF/HCC policy (REGIST-101) and register the participant on the 
protocol.  The DFCI Project Manager will email the participant study number, and if applicable 
the dose treatment level, to the participating site.  The DFCI Project Manager may also contact 
the participating site and verbally confirm registration.  
 
 
5. TREATMENT PLAN 
 
Figure 1 Trial Schema 
 
   
 
 
Patients with R/R cHL who have previously failed a PD-1 mAb will be enrolled. For details 
regarding dosing, see section 5.1. Study therapy is expected to be administered on an outpatient 
basis. Patients will receive 4 doses of ipilimumab therapy dosed every 3 weeks (12 weeks), 
followed by a restaging PET/CT scan. Patients achieving an objective response to ipilimumab 
monotherapy will receive up to 8 doses of maintenance ipilimumab dosed every 12 weeks (96 
weeks), for a total of 108 weeks of study therapy. Patients with SD or PD following ipilimumab 
monotherapy (who are clinically stable) will receive 4 cycles of combination ipilimumab and 
nivolumab therapy dosed every 3 weeks (12 weeks), followed by up to 7 doses of maintenance 
ipilimumab dosed every 12 weeks (84 weeks), for a total of up to 108 weeks of study therapy. 
Patients who have progressive disease after fewer than 4 cycles of ipilimumab are eligible to 
proceed to combination therapy with nivolumab and ipilimumab if they are clinically stable. 
Therapy will be stopped sooner for unacceptable toxicity, patient withdrawal, disease 
progression, physician decision, or death. Patients achieving a complete response for ≥ 6 months 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
19 
can elect to stop study therapy.  
 
Patients will be evaluated with PET/CT scans at baseline and again after 4 doses of ipilimumab 
monotherapy (week 12) (or earlier if there is clinical concern for progression). Among 
ipilimumab responders, restaging scans will occur prior to ipilimumab maintenance cycle 2 
(week 24), cycle 3 (week 36), cycle 5 (week 60), and cycle 7 (week 84). Among ipilimumab 
non-responders, restaging scans will occur after 4 cycles of ipilimumab + nivolumab 
combination therapy (week 24) and prior to ipilimumab maintenance cycle 2 (week 36), cycle 4 
(week 60), and cycle 6 (week 84). The end-of-treatment assessment will occur 4-12 weeks after 
the last doses of study therapy (i.e. weeks 112-120 for patients who complete all planned study 
therapy). Afterwards, patients will be re-imaged every 24 weeks. Patients in CR at any time point 
may have CT imaging only at subsequent time points.  
 
Toxicity will be continuously monitored and recorded using CTCAE 5 criteria, up to 30 days 
following the last dose of the study treatment or until resolution of toxicity to grade 1 or baseline, 
whichever occurs last.   
 
Tumor biopsies (pre-treatment, on-treatment, and post-progression) and serial peripheral blood 
samples will be used to identify possible genetic or immune biomarkers of response. When 
safely feasible, tumor biopsy (excisional or core needle) will be obtained at baseline (unless an 
archival sample within 90 days and without intervening treatment is available with at least 15 
unstained slides). In addition, patients will undergo an optional core needle biopsy between day 
14 and 21 of cycle 1 of therapy. When feasible, a core needle biopsy will also be obtained at the 
time of progression. Serial peripheral blood will be collected for research purposes (see Section 
9).   
 
5.1 
Treatment Regimen 
 
Table 1 Treatment regimen 
Induction 
treatment 
Ipilimumab 3 mg/kg 
every 3 weeks for 4 
doses  
Ipilimumab 3 mg/kg 
every 3 weeks for 4 
doses  
Re-induction Ipilimumab responders: 
Not applicable 
Ipilimumab non-
responders: 
Nivolumab 3mg/kg + 
Ipilimumab 1 mg/kg 
every 3 weeks for 4 
doses (i.e. on day 1 of 
each 3-week cycle) 
Maintenance 
treatment 
Ipilimumab 3 mg/kg 
every 12 weeks (for up to 
8 doses) 
Ipilimumab 3 mg/kg 
every 12 weeks (for up 
to 7 doses) 
 
Patients will receive ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by a restaging 
PET/CT scan. Patients achieving an objective response to ipilimumab monotherapy will receive 
up to 8 doses of maintenance ipilimumab dosed at 3mg/kg every 12 weeks (96 weeks), for a total 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
20 
of 108 weeks of study therapy. Patients with SD or PD after ipilimumab monotherapy, (who are 
clinically stable) will receive 4 cycles of combination ipilimumab 1 mg/kg and nivolumab 3 
mg/kg dosed every 3 weeks (12 weeks), followed by up to 7 doses of maintenance ipilimumab 
dosed at 3 mg/kg every 12 weeks (96 weeks), for a total of up to 108 weeks of study therapy. 
Patients who have progressive disease after fewer than 4 cycles of ipilimumab are eligible to 
proceed to combination therapy with nivolumab and ipilimumab if they are clinically stable. 
Patients will continue study therapy until PD* or unacceptable toxicity. Patients achieving a 
complete response for ≥ 6 months can elect to stop ipilimumab therapy.  
 
Patients can opt to continue trial therapy beyond progression if they meet the conditions 
described in Section 5.6. 
 
5.2 
Pre-Treatment Criteria 
 
The following treatment parameters must be met at visits when each new cycle is being started: 
• ANC must be ≥ 500/mm3,  
• Platelet count must be ≥ 50 x 109/L, All non-hematologic toxicities have improved 
sufficiently to restart treatment per Table 6. 
 
5.3 
Agent Administration 
 
5.3.1 Ipilimumab 
 
Ipilimumab will be administered intravenously as a 90-minute infusion (+/- 15 minutes) on day 1 
of each cycle at a dose of 1 mg/kg when administered in combination with nivolumab and at a 
dose of 3 mg/kg when administered alone. Maintenance ipilimumab (3 mg/kg) will be 
administered once every 12 weeks. Dosing of ipilimumab will be based on actual body weight. 
When both study drugs are to be administered on the same day, separate infusion bags and filters 
must be used for each infusion. Nivolumab is to be administered first. The nivolumab infusion 
must be promptly followed by a saline flush to clear the line of nivolumab before starting the 
ipilimumab infusion. The second infusion will always be ipilimumab and will start no sooner 
than 30 minutes after completion of the nivolumab infusion. For management of infusion 
reactions, see section 6.6.   
 
5.3.2 Nivolumab 
 
Nivolumab will be administered intravenously as a 30-minute infusion (+/- 10 minutes) on day 1 
of relevant treatment cycles at a dose of 3 mg/kg. When both study drugs are to be administered 
on the same day, separate infusion bags and filters must be used for each infusion. Nivolumab is 
to be administered first. The nivolumab infusion must be promptly followed by a saline flush to 
clear the line of nivolumab before starting the ipilimumab infusion. The second infusion will 
always be ipilimumab and will start no sooner than 30 minutes after completion of the 
nivolumab infusion. For management of infusion reactions, see section 6.6.   
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
21 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed 
during the active treatment period, except for administration of inactivated vaccines (for 
example, inactivated influenza vaccine).  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, permanent discontinuation 
from study therapy may be required.  The Investigator should consult with the Principal 
investigator about individual cases.  The final decision on any supportive therapy or vaccination 
rests with the Investigator and/or the patient’s primary physician.  However, the decision to 
continue the patient on study therapy or medication/vaccination schedule requires the mutual 
agreement of the Investigator, the Principal investigator, and the patient. Prior/concomitant 
treatment considered necessary for the patient’s well-being may be given at discretion of the 
treating physician. 
 
Concomitant medications and treatments, including herbal supplements, will be recorded from 
28 days prior to the start of study treatment and up to 90 days after the last dose of study 
treatment (at Days 30, 60, and 90 post-treatment +3 days).  All concomitant medications and 
Non-Drug Supportive Interventions should be recorded in the CRF including supportive care 
drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat adverse events or 
chronic diseases, and non-drug supportive interventions (eg, transfusions). 
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol acetate for 
anorexia) are allowed. 
5.4.1 Pre-medications 
 
No pre-medications are required with this regimen, unless the patient experiences an infusion-
related reaction (see Section 6.4). 
 
5.4.2 Antibiotics 
 
Infectious prophylaxis is not required while on study. 
 
5.4.3 Hydration 
 
No pre-hydration or hydration is required with this regimen. 
 
5.4.4 Other supportive treatments 
 
Growth factors, blood product transfusions, and the use of bisphosphonates are permitted at the 
discretion of the treating physician. 
 
5.4.5 Other Prohibited Concomitant Medications and Treatments 
 
Patients are prohibited from receiving the following therapies during the treatment phase of this 
trial:  
• Anti-cancer systemic chemotherapy or biological therapy. 
• Immunotherapy not specified in this protocol.  

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
22 
• Investigational agents other than ipilimumab +/- nivolumab.  
• Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see 
Clarification About Steroid Use below), or for treatment of issues unrelated to study drug 
after consultation with study chair. 
• Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period; however, the administration of inactivated 
vaccines (eg, influenza vaccine) is allowed during the study. 
• Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known to 
potentially interfere with major organ function (eg, hypericin). 
• Daily intake over 2 grams acetaminophen/paracetamol. 
• Radiation therapy can be considered for treatment of isolated symptomatic site(s) after 
discussion with the study chair. 
 
Clarifications About Steroid Use with ipilimumab +/- nivolumab: Data have indicated that 
corticosteroids have an adverse effect on T-cell function and that they inhibit and damage 
lymphocytes(24).  Furthermore, as with all immunotherapies intended to augment cell mediated 
immunity, there is a risk that concomitant immunosuppressive therapies, such as steroids, will 
counteract the intended benefit of the proposed study treatment.  However, studies with 
anti-CTLA-4 compounds have indicated that short-term use of steroids may be employed 
without compromising clinical outcomes(24).  Therefore, the use of steroids during this trial is 
restricted as follows: 
• Therapeutic use: for the treatment of infusion related reactions and treatment of irAEs, 
steroids are permitted according to the modalities indicated in Table 2: Management of 
Immune-Related Adverse Events.  
• Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable. 
• Other uses should be first discussed with the Study Chair 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), maintenance therapy may 
continue per Section 5.1 or until one of the following criteria applies: 
 
• 
Disease progression. (Note: patients who have PD after ipilimumab may continue trial 
therapy with ipilimumab + nivolumab if they are clinically stable. Patients experience 
progressive disease at other time points may continue trial therapy beyond 
progression if they meet the criteria described in section 5.6). 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
23 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
5.6 
Continuation of Treatment Beyond Progression 
 
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses follows delayed kinetics of weeks or months and can be 
preceded by initial apparent radiological progression or appearance of new lesions or some 
enlarging lesions while certain target lesions are regressing (“mixed response”). It may thus 
reasonable to allow for these possibilities and continue to treat the subject until progression is 
confirmed at the next imaging assessment. These considerations should be balanced by clinical 
judgment as to whether the subject is clinically deteriorating and unlikely to receive any benefit 
from continued treatment. Such deterioration will be assessed to have occurred after a clinical 
event that, in the Investigator’s opinion, is attributable to disease progression, is unlikely to 
reverse with continued study treatment and therefore indicates that the subject is not benefiting 
from study treatment and cannot be managed by the addition of supportive care.  
 
The following criteria must be met for a patient to receive study treatment beyond progression: 
 
1. The treating physician feels that the patient is deriving clinical benefit from treatment 
2. Restaging scan meets criteria for an indeterminate response based on the lymphoma 
response to immunomodulatory therapy criteria (LYRIC criteria) (23) (see Appendix C) 
a. Indeterminate response 1 (IR1) - Increase in overall tumor burden (as assessed by 
sum of the product of the diameters [SPD]) of ≥50% of up to 6 measurable lesions 
in the first 12 weeks of therapy, without clinical deterioration 
b. Indeterminate response 2 (IR2) - Appearance of new lesions or growth of one or 
more existing lesion(s) ≥50% at any time during treatment; occurring in the 
context of lack of overall progression (<50% increase) of overall tumor burden, as 
measured by SPD of up to 6 lesions at any time during the treatment 
a. Indeterminate response 3 (IR3) Increase in FDG uptake of 1 or more lesion(s) 
without a concomitant increase in lesion size or number. 
3. Stable performance status 
4. Tolerance of study therapy 
5. Approval is granted by the study chair. 
 
5.7 
Duration of Follow Up 
 
Participants will be followed for up to 10 years after removal from protocol therapy or until 
death, whichever occurs first.  Participants removed from protocol therapy for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
24 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Completion of all study activities 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Every effort should be made to administer study drugs according to the planned dose and 
schedule.  
Patients whose treatment is delayed due to adverse events should be evaluated at intervals of one 
week or less until adequate recovery has been documented or no further improvement is 
expected. Dose delays will be made as indicated in the following table(s). In the event of 
multiple toxicities, dose modifications should be based on the worst observed toxicity. Patients 
must be instructed to notify Investigators at the first occurrence of any adverse symptom/s. 
Treatment modification recommendations should be followed unless previously discussed with 
and agreed by the study chair.  All dose modifications/adjustments must be clearly documented 
in the patient's notes and in the CRF. The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
dose delays and dose modifications. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
6.1 
Management of Adverse Events 
 
Both ipilimumab and nivolumab stimulate the immune system and can result in immune-related 
adverse events (irAEs).  Any event suspected to be immune-related should be managed 
according to the guidance for management of immune-related adverse events in this section and 
in Table 2. Adverse events that are felt to be non-immune-related should be managed based on 
Tables 3 or 4.  
6.2 
Immune Related Adverse Events (irAEs) 
 
Immune-related adverse events described with these drugs include: pneumonitis, colitis, 
hepatitis, endocrinopathies (including thyroid disorders, adrenal insufficiency, hypophysitis, and 
diabetes mellitus or hyperglycemia), rash, nephritis and renal dysfunction, encephalitis, eye 
disorders (including uveitis, iritis), and other immune-mediated reactions including myositis and 
myocarditis. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
25 
Any adverse event which may have an underlying immune-mediated mechanism including those 
described above, and without other confirmed etiologies, should be considered immune-related. 
Treatment of irAEs should be based on the guidelines outlined in Table 2 but can be superseded 
by the judgment of the treating physician.   

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
26 
Table 2 Management of Immune-Related Adverse Events 
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue immunotherapy 
agent(s) 
 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3/4.  
Grade 2  
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold all 
immunotherapy agents 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume immunotherapy agents 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; 
IV fluids ≥ 24 h; interfering with 
ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, 
perforation 
Withhold all 
immunotherapy agents for 
Grade 3. 
Permanently discontinue 
immunotherapy agents 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, 
then taper over at least 1 month;  
 
If worsens, persists > 3 to 5 days, 
or recurs after improvement: 
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis.  

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
27 
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area or >30% of body surface 
area with mild symptoms only 
Continue immunotherapy 
agent(s) 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold all immunotherapy agents  
Consider skin biopsy  
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume immunotherapy agents 
following steroids taper. 
 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area with moderate to 
severe symptoms;  
Grade 4: Life threatening 
consequences  
Withhold all 
immunotherapy agents. 
Permanently discontinue for 
Stevens-Johnson syndrome 
(SJS), toxic epidermal 
necrolysis (TEN) or Grade 4 
rashes.  
Consider skin biopsy and 
dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month; resume immunotherapy 
agents following steroids taper (for 
Grade 3 only). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding all 
immunotherapy agent(s)  
Monitor for symptoms 
every 2 to 3 days  
Re-assess at least every 3 weeks 
 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
28 
Grade 2 
Mild to moderate new symptoms  
Withhold all 
immunotherapy agents 
Consider Pulmonary and 
Infectious Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding 
prophylactic antibiotics for 
opportunistic infections  
Re-assess every 1 to 3 days  
 
If improves:  
When symptoms return to Grade ≤ 
1, taper steroids over at least 1 
month, and then resume all 
immunotherapy agents following 
steroids taper  
 
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue all 
immunotherapy agents. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month.  
 
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or mycophenolate 
mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN  
Continue immunotherapy 
agent(s) 
Continue liver function monitoring  
 
If worsens:  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 
x ULN  
Withhold all 
immunotherapy agents 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
immunotherapy agents. 
 
If elevation persists > 5 to 7 days or 
worsens:  
Treat as Grade 3 to 4. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
29 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN  
Permanently discontinue all 
immunotherapy agents  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
(Use 2.0 mg/kg for grade 4 
hepatic irAEs) 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver 
biopsy if clinically 
warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 
month.  
 
If does not improve in > 3 to 5 
days, worsens or rebounds:  
Add mycophenolate mofetil 1 gram 
(g) twice daily  
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue immunotherapy 
agent(s) 
Continue renal function 
monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
 
 
 
 
 
Withhold all immunotherapy 
agents 
Increase frequency of monitoring 
to every 3 days 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month, and resume 
immunotherapy agents following 
steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
Permanently discontinue all 
immunotherapy agents 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent. 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
30 
 
 
 
 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold all immunotherapy 
agents. 
Consider hospitalization. 
In the presence of life-
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management. 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If 
symptoms 
improve 
and 
immune-mediated etiology is 
ruled 
out, 
re-start 
immunotherapy agents. 
 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue all 
immunotherapy agents. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or 
worsening, consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
31 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue immunotherapy 
agent(s) 
 
Endocrinology consult if 
needed 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
 
For any symptomatic endocrine 
reactions lasting > 6 weeks, 
permanently discontinue both 
immunotherapy agents. 
 
Grade 3 or Grade 4 thyroid 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism)  
 
Grade 3 (diabetes 
mellitus/hyperglycemia) 
Withhold all immunotherapy 
agents 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), or insulin 
(for type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
Resume all immunotherapy 
agents once symptoms and/or 
laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.  
 
For any symptomatic endocrine 
reactions lasting > 6 weeks, 
permanently discontinue both 
immunotherapy agents. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
32 
hypophysitis) 
 
Grade 3 or Grade 4 adrenal 
insufficiency 
 
Grade 4 diabetes 
mellitus/hyperglycemia 
Permanently discontinue all 
immunotherapy agents. 
 
Consider hospitalization 
Endocrinology consult 
 
Start corticosteroid 
replacement (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / 
hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
Grade 1-3 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol with 
inappropriately low ACTH) : 
• Refer to 
endocrinologist for 
dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women)  
• Hormone 
replacement/suppressiv
e therapy as 
appropriate  
• Perform pituitary MRI 
and visual field 
examination as 
indicated 
 
If hypophysitis confirmed: 
Resume all immunotherapy 
agents once symptoms and 
hormone tests improve to 
Grade ≤ 1 (with or without 
hormone replacement). 
 
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented.  
 
Continue hormone 
replacement/suppression 
therapy as appropriate. 
 
For any symptomatic endocrine 
reactions lasting > 6 weeks, 
permanently discontinue both 
immunotherapy agents. 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
33 
• Continue all 
immunotherapy agents if 
mild symptoms with 
normal MRI. Repeat the 
MRI in 1 month 
• Withhold all 
immunotherapy agents if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper 
during at least 1 month. 
• Add prophylactic 
antibiotics for 
opportunistic infections. 
Grade 4 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
Permanently discontinue all 
immunotherapy agents. 
 
See additional 
recommendations for grade 1-
3 hypophysitis above. 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
Ophthalmic irAEs 
Grade (NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
 
Continue immunotherapy 
agent(s) 
 
Continue monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 4 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
 
 
 
 
 
Withhold all immunotherapy 
agents 
Increase frequency of 
monitoring to every 3 days 
 
Initiate topical therapy and/or  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics 
for opportunistic infections 
If returns to Grade ≤1 within 
two weeks: 
Taper steroids over at least 1 
month, and resume 
immunotherapy agents 
following steroids taper. 
 
If does not return to Grade ≤1 
within two weeks: permanently 
discontinue all immunotherapy 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
34 
 
agents 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Withhold all immunotherapy 
agents pending clinical 
investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-
starting all immunotherapy 
agents 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold all immunotherapy 
agents 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent   
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult as 
appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month and resume all 
immunotherapy agents 
following steroid taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue all 
immunotherapy agents. to 2.0 
mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult as 
appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Re-treatment can be considered 
(if deemed beneficial by the 
patient’s treating physician) 
after discussion with the study 
chair.  
Grade 4  
 
Permanently discontinue all 
immunotherapy agents 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics 
for opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month 
Requirement for 7.5 mg per 
day or greater prednisone or 
equivalent for more than 6 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
Permanently discontinue all 
immunotherapy agents 
Specialty consult 
If a steroid course of greater 
than 6 weeks is required, but a 
patient is later successfully 
weaned to a dose of less than 
7.5 mg per day, study treatment 
may be resumed in select cases 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
35 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
depending on the clinical 
benefit, the severity of the AE, 
in consultation with study chair. 
 
 
 
6.3 
Non-Immune Related Adverse Events  
 
Dose delays for drug-related non-immune related toxicities related to ipilimumab and nivolumab 
are detailed in Table 2 and Table 3. The treatment modifications detailed in these tables should 
be followed for both ipilimumab and nivolumab.   
Table 3 Treatment Modifications for Non-Immune Treatment-Related Hematologic 
Toxicities 
 
 
Treatment modification 
Grade 1 
Continue per schedule 
Grade 2 
Continue per schedule 
Grade 3 
Thrombocytopenia 
Withhold study treatment and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; if returns to 
grade 2 or less within 7 days, resume study treatment (first occurrence 
only). If the AE does not return to grade 2 or baseline level in 7 days or 
recurs after re-initiation of study therapy, we recommend a diligent 
search for alternative causes and consideration of discontinuation in 
consultation with study chair. 
Other Grade 3 
Cytopenias 
Continue per schedule 
Grade 4 
Withhold study treatment and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; if returns to 
grade 2 or less within 7 days, resume study treatment (first occurrence 
only). If the AE does not return to grade 2 or baseline level in 7 days or 
recurs after re-initiation of study therapy, we recommend a diligent 
search for alternative causes and consideration of discontinuation in 
consultation with study chair. 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
36 
Table 4 Treatment Modifications for Treatment-Related Non-Hematologic Toxicities 
 
Non-Hematologic 
Toxicity 
Treatment modification 
Grade 1 
Continue per schedule 
Grade 2 
Continue per schedule 
Grade 3 
First occurrence: Withhold until return to grade 1 or baseline level; re-
initiate therapy (after discussion with study chair). For recurrent grade 3 
AEs, permanently discontinue both immunotherapy agents  
Other-Grade 4 
Permanently discontinue* 
irAEs 
See Table 2 
Infusion-related 
reactions 
See Section 6.6 
*For asymptomatic grade 4 laboratory abnormalities including lipase, amylase, CK elevations, 
the subject may be restarted on treatment if the abnormality resolves to grade 1 or baseline, in 
cases where the investigator judges that the benefit of resuming treatment outweighs the risk, and 
after discussion with the Study Chair. 
6.4 
Treatment Delays 
 
Treatment should be delayed per Tables 2-4 or based on any adverse event, laboratory 
abnormality, or condition that, in the judgment of the investigator, warrants delaying the dose of 
study medication. If a dose delay is necessary, all study drugs must be delayed until treatment 
can resume.  
 
Subjects should resume treatment per Tables 2-4. Subjects must be re-treated within 6 weeks 
from the previous dose. Treatment may be resumed after 6 weeks after discussion with the Study 
Chair if the benefit/risk justify continuing study therapy. At least 19 days must elapse between 
the replacement dose of study therapy and administration of the subsequent dose of study 
therapy. In the case of endocrine-related AEs, hormone replacement therapy may be utilized to 
restore physiologic function and to permit retreatment with study drug. If this is not possible the 
subject must be discontinued from study therapy. 
 
6.5 
Dose Reductions 
 
No dose reductions are permitted for ipilimumab or nivolumab.  
 
6.6 
Management of Infusion-Related Reactions 
 
Infusion reactions with ipilimumab and nivolumab are rare and no empiric premedication is 
recommended.  If an infusion related reaction occurs following infusion, managed guidelines are 
outlined in Table 5. Symptoms may include one or more of the following: fever, chills, rigors, 
diaphoresis, and headache.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
37 
Once the infusion rate has been decreased by 50% due to an infusion-related reaction, the same 
decreased infusion rate must be used for all subsequent infusions.  
 
Table 5 Treatment Modifications for Symptoms of Infusion Related Reactions 
 
NCI-CTCAE Grade  
Treatment Modification for ipilimumab 
and/or nivolumab 
Grade 1 – mild 
• Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated 
 
• Decrease the infusion rate by 50% and 
monitor closely for any worsening  
Grade 2 – moderate 
• Therapy or infusion interruption indicated 
but responds promptly to symptomatic 
treatment (for example, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for  
24h 
 
• Temporarily discontinue infusion 
• Resume infusion at 50% of previous rate 
once infusion-related reaction has resolved 
or decreased to at least Grade 1 in 
severity, and monitor closely for any 
worsening  
Grade 3 or Grade 4 – severe or 
life-threatening 
• Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae 
• Grade 4: Life-threatening consequences; 
urgent intervention indicated 
 
• Stop the infusion immediately and 
disconnect infusion tubing from the 
subject 
• Subjects cannot receive any further 
treatment with the offending agent.   
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs: nonsteroidal anti-inflammatory drugs. 
 
6.6.1 Additional Treatment Modifications for Patients with Grade 2 Infusion-Related Reactions 
 
In the event of a Grade 2 infusion-related reaction that does not improve or that worsens 
following implementation of the modifications indicated in Table 5 (including reducing the 
infusion rate by 50%), the Investigator may consider treatment with corticosteroids per local 
guidelines, and the infusion should be stopped for that day.  At the time of the next cycle, the 
following prophylactic pre-medications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional study drug administrations. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
38 
 
6.6.2 Management of Severe Hypersensitivity Reactions and Flu-Like Symptoms 
 
Symptoms of hypersensitivity may include impaired airway, decreased oxygen saturation 
(<92%), confusion, lethargy, hypotension, pale or clammy skin, and cyanosis.  These symptoms 
may, if necessary, be managed with epinephrine and dexamethasone.  Oxygen therapy should be 
administered as appropriate.  Patients should be monitored per institutional standards. 
6.7 
Discontinuation of One Study Drug 
 
Patients receiving combination therapy with both ipilimumab and nivolumab may experience a 
severe adverse event that is felt to be primarily attributable to only one of the study drugs (i.e. an 
infusion-related reaction during nivolumab or an irAE more commonly observed with 
ipilimumab, etc). If a patient experiences an AE that would result in study treatment 
discontinuation per protocol that is felt to be primarily related to a single study drug, the patient 
may continue receiving the other agent on protocol, if approved by the principal investigator.  
6.8 
Study-wide early stopping rules 
 
Observation of >1 treatment-related grade 5 event would pause accrual and initiate a study-wide 
review.  
 
Excessive toxicity will be defined as grade 4 AEs or grade 3 AEs lasting > 72 hours (excluding 
asymptomatic laboratory AEs). Observation of excessive toxicity in >3 patients would pause 
accrual and initiate a study-wide review.  
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Events List(s) 
 
7.1.1.1 Ipilimumab 
 
Common (>20% incidence) 
• 
Diarrhea, nausea 
• 
Fatigue 
• 
Immune-related adverse events including the following: 
o Dermatitis  
 
Occasional (4-20% incidence) 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
39 
• 
Abnormal heartbeat 
• 
Hearing loss 
• 
Swelling and redness of the eye 
• 
Pain 
• 
Difficulty swallowing, eating 
• 
Constipation, vomiting 
• 
Weight loss, loss of appetite 
• 
Fever 
• 
Dehydration 
• 
Pain or swelling of the joints 
• 
Infusion reaction during or following a drug infusion 
• 
Immune-related adverse events including the following: 
o Pneumonitis 
o Colitis 
o Kidney problems, including nephritis and kidney failure requiring dialysis 
o Myositis 
o Neuritis 
o Endocrine gland problems (especially the thyroid, pituitary and adrenal glands, 
and pancreas 
 
Rare (<3% incidence) 
• 
Bleeding 
• 
Bowel obstruction 
• 
Fluid around heart 
• 
Severe illness with multiorgan failure 
• 
Swelling of the brain which may cause headache, blurred vision, stiff neck, and/or 
confusion 
• 
Immune-related adverse events including the following: 
o Hyperglycemia 
o Myocarditis, including swelling and heart failure.  
• 
Complications associated with stem cell transplant using donor stem cells 
 
7.1.1.2 Nivoluamb 
 
Frequent (>10% incidence) 
• 
Diarrhea 
• 
Fatigue 
• 
Itching 
• 
Rash 
 
Occasional (1-10% incidence) 
• 
Allergic reaction (hypersensitivity).  
• 
Abdominal pain 
• 
Increased alkaline phosphatase, aspartate aminotransferase, bilirubin or alanine 
aminotransferase.  
• 
Increased amylase or lipase 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
40 
• 
Chills 
• 
Constipation 
• 
Cough 
• 
Increased blood level of creatinine 
• 
Decreased appetite 
• 
Dizziness 
• 
Dry mouth 
• 
Dry skin 
• 
Fever 
• 
Headache 
• 
Hyperglycemia 
• 
Colitis 
• 
Mucositis 
• 
Infusion reaction   
• 
Loss of color (pigment) from areas of skin 
• 
Pneumonitis 
• 
Muscle and/or bone pain 
• 
Nausea 
• 
Hyponatremia 
• 
Swelling, including face, arms, and legs 
• 
Hypothyroidism or hyperthyroidism 
• 
Neuropathy 
• 
Vomiting 
 
Rare (0.1%-1% incidence) 
• 
Hypophysitis 
• 
Lung inflammation (bronchitis) 
• 
Cranial nerve disorder, which may cause facial pain or twitching, dizziness, hearing loss, 
weakness, and/or paralysis. 
• 
Dehydration 
• 
Diabetes complications resulting in excessive blood acids 
• 
Double Vision 
• 
Dry eye 
• 
Erythema Multiforme 
• 
Hair loss 
• 
Tachycardia or heart arrhythmias 
• 
Hypertension 
• 
Irregular heartbeat 
• 
Hives  
• 
Inflammation of the eye 
• 
Nephritis 
• 
Inflammation of the pancreas, causing pain in the upper abdomen. 
• 
Inflammation of the pituitary gland, which may cause headaches, change in eyesight, few 
to no menstrual cycles (for women), increased thirst, and increased frequency passing 
urine.  
• 
Gastritis 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
41 
• 
Thyroiditis 
• 
Hepatitis 
• 
Joint pain or stiffness 
• 
Low blood pressure 
• 
Pemphigoid 
• 
Pituitary gland function decreased 
• 
Psoriasis 
• 
Kidney failure 
• 
Myositis (an infection of the muscle).  
• 
Infection in the upper respiratory tract 
• 
Vision blurred 
 
Very rare (< 0.1% incidence) 
• 
Life-threatening allergic reaction  
• 
Damage to the protective covering of the nerves in the brain and spinal cord 
• 
Disease caused by the body’s immune system attacking healthy organs 
• 
Drug induced liver injury 
• 
A disorder called Guillain-Barré syndrome in which the body’s immune system attacks 
part of the peripheral nervous system.  
• 
Inflammation of blood vessels that can lead to damage of different organs 
• 
Inflammation of the brain, potentially life-threatening or fatal Inflammation of the heart 
muscle.  
• 
Inflammation of the lining of the brain and spinal cord 
• 
Lung infiltrates, associated with infection or inflammation 
• 
A neurologic syndrome characterized by muscle weakness called myasthenic syndrome, 
including myasthenia gravis  
• 
Polymyalgia rheumatic 
• 
Rupture of the intestine/hole in the intestine 
• 
Sarcoidosis  
• 
Stevens Johnson syndrome or Toxic Epidermal Necrolysis 
• 
A disorder of the lymph nodes called histiocytic necrotizing lymphadenitis or Kikuchi 
lymphadenitis 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version  5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity, or frequency from the expected toxicity information which 
is provided. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
42 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
• A serious adverse event (SAE) is an AE that meets any of the following criteria: 
− 
Results in death (i.e., the AE actually causes or leads to death) 
− 
Is life-threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.) 
− 
Requires or prolongs inpatient hospitalization 
− 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
− 
Results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to ipilimumab and/or nivolumab  
− 
Important medical events that may not result in death, are not immediately life-
threatening, or do not require hospitalization may be considered SAEs when, based 
on appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
7.3 
Adverse Event Reporting  
 
7.3.1 In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the PI. 
 
7.3.2 Investigators must report to the PI any adverse event (AE) that occurs after the initial 
dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
on the local institutional SAE form.  
 
7.3.3 Adverse Event Reporting Guidelines 
 
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC requirements, and 
the IRB of record for each site as applicable per IRB policies. The table below indicates which 
events must be reported to the DF/HCC Sponsor-Investigator. 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
43 
 
 
 
 
Attribution 
Table 6 DF/HCC Reportable Adverse Events (AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
10 working 
days# 
10 working 
days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
10 working 
days 
10 working 
days# 
10 working 
days 
 
24 hours* 
# If listed in protocol or informed consent document as expected event does not need to be reported 
(except through routine reporting mechanisms) 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of 
the last intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
 
7.4 
Reporting to Bristol-Myers Squibb 
 
Bristol-Myers Squibb (BMS) will also be informed of any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment. Any SAE occurring after the reporting period must be promptly reported if a 
causal relationship in the investigational drug is suspected. Participant or partner pregnancy 
while on treatment or within 30 days of the last dose of treatment is also required to be reported 
to BMS via expedited reporting procedures.  
 
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-
threatening), the study team will report to BMS by email (Worldwide.Safety@bms.com) any 
Serious Adverse Event (“SAE,” as defined below) for which reporting is required under this 
provision (as described below).  Such SAEs are to be reported for study subjects or individuals 
otherwise exposed to study drugs as described below.  The study teams should report SAEs as 
soon as they are determined to meet the definition, even if complete information is not yet 
available. 
 
SAEs to BMS will be reported on a SAE report form supplied by BMS and sent to the Sponsor-
Investigator to review and report to Worldwide.Safety@bms.com on behalf of the reporting 
external site. Submissions should be made within 24 hours of the site’s knowledge of the event.  
 
7.4.1 SAE Definition for Reporting to BMS   
 
An SAE is any adverse event, without regard to causality, that is life-threatening (i.e., causes an 
immediate risk of death) or that results in any of the following outcomes: death; in-patient 
hospitalization or prolongation of existing hospitalization; persistent or significant disability or 
incapacity (i.e. substantial disruption of the ability to conduct normal life functions); or a 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
44 
congenital anomaly or birth defect.  Any other medical event that, in the medical judgment of the 
Principal Investigator, may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the outcomes listed above is also considered an SAE.  A planned medical or 
surgical procedure is not, in itself, an SAE.   
 
7.4.2 Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure  
 
Even though there may not be an associated SAE, occupational exposure to ipilimumab +/- 
nivolumab or exposure during pregnancy or lactation is reportable to BMS.   
 
7.4.3 Exclusions from SAE Reporting Requirements 
 
Specifically excluded from the reporting requirements for SAEs under this provision is any SAE 
identified in the Protocol as anticipated to occur in the Study population at some frequency 
independent of drug exposure, unless the Principal Investigator assesses such an event as related 
to study medication.  Also, specifically excluded from the reporting requirements is any SAE 
judged by the Overall Investigator to represent progression of the malignancy under study, unless 
it results in death within the SAE Reporting Period.   
 
7.4.4 SAE Reporting Period 
 
The SAEs that are subject to this reporting provision are those that occur from after the first dose 
of study medication(s) through 30 calendar days after the last administration of the study 
medication(s). In addition, if a Sponsor-Investigator becomes aware of an SAE occurring within 
30 days of last dose of study medication the Sponsor-Investigator should report that SAE to 
BMS if the Sponsor-Investigator suspects a causal relationship between the study drug and the 
SAE.  In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents.  
 
7.5 
Reporting to the Food and Drug Administration (FDA) 
 
The Sponsor-Investigator will be responsible for all communications with the FDA. The 
Sponsor-Investigator will report to the FDA, regardless of the site of occurrence, any serious 
adverse event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA. 
 
7.6 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity 
case report forms.  AEs reported through expedited processes (e.g., reported to the IRB, 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
45 
FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Ipilimumab 
 
8.1.1 Description 
 
Ipilimumab is a fully human monoclonal immunoglobulin that binds to CTLA-4 and inhibits its 
interaction with ligands on antigen presenting cells. Ipilimumab has a terminal half-life of 
approximately 15.4 days. A population PK analysis of ipilimumab (n=785) demonstrated that the 
PK of ipilimumab is linear and exposures are dose proportional across the tested dose range of 
0.3 to 10 mg/kg.   
 
8.1.2 Form 
 
Injection: 50 mg/10 mL (5 mg/mL) as a clear to slightly opalescent, colorless to pale-yellow 
solution in a single-use vial. 
 
8.1.3 Storage and Stability 
 
Ipilimumab should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light 
by storing in the original carton until time of use. Do not freeze or shake. 
 
8.1.4 Compatibility 
 
When both ipilimumab and nivolumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the ipilimumab infusion. The second infusion will always be ipilimumab and will 
start no sooner than 30 minutes after completion of the nivolumab infusion. 
 
8.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
46 
 
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
 
Please refer to the current IB/pharmacy reference sheets for storage, handling and preparation 
instructions. 
 
8.1.6 Availability 
 
Ipilimumab will be provided by BMS from investigational supply. 
 
8.1.7 Preparation 
 
Please refer to the current IB/pharmacy reference sheets for preparation instructions. Study 
product should be prepared and dispensed by an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, practitioner, pharmacist, or medical 
assistant) as allowed by local, state, and institutional guidance.  Only qualified personnel who are 
familiar with procedures that minimize undue exposure to them and to the environment should 
undertake the preparation, handling, and safe disposal of biologic agents. 
 
Dosing of ipilimumab will be based on the patient’s weight in kilograms (kgs).  All patients 
should be weighed within 3 days prior to dosing for every cycle to ensure they did not 
experience either a weight loss or gain >10% from the weight used for the last dose calculation.  
If the patient experienced either a weight loss or gain >10% compared to the weight used for the 
last dose calculation, the amount of study drug must be recalculated. 
Vials are for single use only.  Any unused portion of the solution must be discarded in a 
biohazard waste disposal container with final disposal according to accepted local and national 
standards of incineration. 
8.1.8 Administration 
 
Ipilimumab is to be administered as a 90-minute infusion. When both study drugs are to be 
administered on the same day, separate infusion bags and filters must be used for each infusion. 
Nivolumab is to be administered first. The nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab before starting the ipilimumab infusion. The second 
infusion will always be ipilimumab and will start no sooner than 30 minutes after completion of 
the nivolumab infusion. 
 
8.1.9 Ordering 
 
Ipilimumab will be supplied by BMS.  No patients or third-party payers will be charged.  Use the 
Drug Supply Request Form provided to order ipilimumab.  For all inquiries regarding 
ipilimumab supplies, please contact: Distribution.allentown@thermofisher.com. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
47 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the inventory and disposition of ipilimumab using a drug accountability form 
that is compliant with local and federal guidelines.  
 
Additionally, a designated study team member will complete drug accountability/reconciliation 
based on the participant actual drug return versus the anticipated drug return and document the 
findings according to local and federal regulations and guidance.  
 
8.1.11 Destruction and Return 
 
After full drug accountability and reconciliation, all unused ipilimumab will be destroyed 
according to site procedures. Destruction will be documented in the Drug Accountability Record 
Form. If any study drug is lost or damaged, the disposition of the study drug should be 
documented.  
 
8.2 
Nivolumab 
 
8.2.1 Description 
 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds to PD-1. Following single 
dose, maximum concentration (Cmax), and area under the curve (AUCinf) of nivolumab were 
found to be dose proportional within the studied dose range of 0.3-10 mg/kg. The terminal half-
life of nivolumab from single dose was 17-25 days in patients with multiple tumor types. 
Following multiple doses of 0.1 to 10 mg/kg administered every 2 weeks, Cmax and AUC of 
nivolumab were found dose proportional. The steady-state is expected to be achieved by the 
sixth dose. 
 
8.2.2 Form 
 
Injection: 100 mg/10 mL (5 mg/mL) as a clear, colorless to pale yellow liquid in a single-use 
vial. 
 
8.2.3 Storage and Stability 
 
Nivolumab should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light 
by storing in the original carton until time of use. Do not freeze or shake. 
 
8.2.4 Compatibility 
 
When both nivolumab and ipilimumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the ipilimumab infusion. The second infusion will always be ipilimumab and will 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
48 
start no sooner than 30 minutes after completion of the nivolumab infusion. 
 
8.2.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately. 
 
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
 
Please refer to the current IB/pharmacy reference sheets for storage, handling and preparation 
instructions. 
 
8.2.6 Availability 
 
Nivolumab will be provided by BMS from investigational supply. 
 
8.2.7 Preparation 
 
Please refer to the current IB/pharmacy reference sheets for preparation instructions. Study 
product should be prepared and dispensed by an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, practitioner, pharmacist, or medical 
assistant) as allowed by local, state, and institutional guidance.  Only qualified personnel who are 
familiar with procedures that minimize undue exposure to them and to the environment should 
undertake the preparation, handling, and safe disposal of biologic agents. 
 
During the first 4 cycles, dosing of nivolumab will be based on the patient’s weight in kilograms 
(kgs), whereas maintenance nivolumab will be administered at a flat dose of 480 mg. All patients 
should be weighed within 3 days prior to dosing for cycles 1-4 to ensure they did not experience 
either a weight loss or gain >10% from the weight used for the last dose calculation.  If the 
patient experienced either a weight loss or gain >10% compared to the weight used for the last 
dose calculation, the amount of study drug must be recalculated. 
Vials are for single use only.  Any unused portion of the solution must be discarded in a 
biohazard waste disposal container with final disposal according to accepted local and national 
standards of incineration. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
49 
8.2.8 Administration 
 
Nivolumab is to be administered as a 30-minute infusion. When both study drugs are to be 
administered on the same day, separate infusion bags and filters must be used for each infusion. 
Nivolumab is to be administered first. The nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab before starting the ipilimumab infusion. The second 
infusion will always be ipilimumab and will start no sooner than 30 minutes after completion of 
the nivolumab infusion. 
 
8.2.9 Ordering 
 
Nivolumab will be supplied by BMS.  No patients or third-party payers will be charged.  Use the 
Drug Supply Request Form provided to order nivolumab.  For all inquiries regarding nivolumab 
supplies, please contact: Distribution.allentown@thermofisher.com. 
8.2.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the inventory and disposition of nivolumab using a drug accountability form 
that is compliant with local and federal guidelines.  
 
Additionally, a designated study team member will complete drug accountability/reconciliation 
based on the participant actual drug return versus the anticipated drug return and document the 
findings according to local and federal regulations and guidance.  
 
8.2.11 Destruction and Return 
 
After full drug accountability and reconciliation, all unused nivolumab will be destroyed 
according to site procedures. Destruction will be documented in the Drug Accountability Record 
Form. If any study drug is lost or damaged, the disposition of the study drug should be 
documented.  
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
The biomarkers for the trial include measurements from tumor tissues and analyses of blood 
samples to explore molecular, cellular, and soluble markers that may be relevant to the 
mechanism of action of the drug(s) or response/resistance to the drug(s). The correlative studies 
are best described as ancillary. While the goal of the correlative studies is to provide supportive 
data for the clinical study, there may be circumstances when a decision is made to stop a 
collection, not perform, or discontinue an analysis due to practical reasons (e.g., inadequate 
sample number), issues related to the quality of the sample, or issues related to the assay that 
preclude analysis, etc). Therefore, depending on the results obtained during the study, sample 
collection/analysis may be omitted at the discretion of the PI. 
 
A cheek swab/saliva sample will be collected prior to treatment. In addition, peripheral blood 
will be collected for research at baseline, and after 3, 6, 12, 24, and 48 weeks of therapy. In 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
50 
addition, peripheral blood samples will be collected at the time of progression (when feasible).  
Analyses of these samples may include investigation of ctDNA, such as quantification of ctDNA 
at different timepoints and examination of changes in copy number abnormalities and relevant 
pathogenic genes.  
 
When safely feasible, tumor biopsies (excisional or core needle) will be obtained at baseline, 
between day 14 and 21 of cycle 1 of therapy (optional), and at the time of progression (optional). 
An archival sample within 90 days and without intervening treatment is acceptable as the pre-
treatment biopsy assuming that the following provisions are met: 1) Priority: tumor containing 
formalin-fixed, paraffin-embedded (FFPE) tissue block; 2) Priority: if the tumor containing 
FFPE tissue block cannot be provided in total, sections from this block should be provided that 
are freshly cut and mounted on positively-charged glass slides (SuperFrost Plus are 
recommended).  Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides 
is required.  
 
These may be obtained by excisional or core needle biopsy.  Biopsies may be analyzed for tumor 
and microenvironmental expression of checkpoint markers and for immune architecture by a 
combination of immunohistochemistry and multiparameter spectral imaging.  Ideally, 5-6 core 
needle biopsies will be collected.   
Analysis of tumor samples may include interrogation of the TME using multiplex 
immunofluorescence (MIF) with a specific interest in the frequency and distribution of immune 
cells (CD4+ T cells, CD8+ T cells, Tregs, NK cells, tumor-associated macrophages) and relevant 
immune checkpoint pathways (CTLA-4/CD86, PD-1/PD-L1). Findings may be validated and 
explored further using multiplexed ion beam imaging (MIBI).  
 
Banked biospecimens will be handled in a manner that protects each subject’s privacy and 
confidentiality.  Banked biospecimens will be assigned the subject’s study identification code 
(ID) at the site.  The data generated from these banked biospecimens will also be indexed by this 
ID.  Biospecimens will be kept until destruction in facilities with access limited to authorized 
personnel, and biospecimen-derived data will be stored on password-protected computer 
systems.  The key between the subject’s ID and the subject’s direct personally identifying 
information (eg, name, address) will be held at the study site.  Biospecimens will be used only 
for the purposes described in the protocol and informed consent document; any other uses 
require additional ethical approval.  Unless a time limitation is required by local regulations or 
ethical requirements, biospecimens will be stored for many years (no time limit) to allow for 
research in the future, including research conducted during the lengthy drug-development 
process and also postmarketing research.  Subjects may withdraw their consent for the use of 
their banked biospecimens at any time by making a request to the investigator; in this case, any 
remaining biospecimens will be destroyed, but data already generated from the biospecimens 
will continue to be available to protect the integrity of existing analyses.  Unless prohibited by 
local regulations or ethics committee decision, a 4-mL blood genomic banked biospecimen Prep 
D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] [K2EDTA] whole-blood collection 
optimized for DNA analysis) will be collected at the time specified in the Study Calendar section 
of the protocol to be retained for potential pharmacogenomic/genomic/biomarker analyses 
related to drug response and disease/condition under study.  For example, putative safety 
biomarkers, drug-metabolizing enzyme genes, drug-transport protein genes, or genes thought to 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
51 
be related to the mechanism of drug action may be examined.  The primary purpose is to 
examine DNA; however, the biospecimen may also be used to study other molecules (eg, RNA, 
proteins, and metabolites). 
Details of time points and sampling are provided in the Study Calendar.  Reference the 
laboratory manual for specimen collection, processing, and shipment instructions. 
In order to complete all the assessments on tumor materials and blood samples, the Principal 
Investigator will provide instructions and necessary supplies to the site, including shipping 
materials and prepaid mailers.  The panel of biomarkers might be adjusted based on results from 
ongoing research and/or safety; therefore, each patient will also be asked whether any remaining 
tumor tissue and/or blood-derived samples can be stored at a central repository (until such time 
as these samples cannot support any further analysis) and can be used for future exploratory 
research on the drug(s) and / or disease-related aspects.  Biomarker analyses may be conducted 
after the conclusion of this study and may be based on samples derived from multiple studies. 
 
 
10. STUDY CALENDAR 
 
A study calendar is below (Table 7). 
 
10.1 Required Data for Study Screening 
The following must be obtained within 28 days prior to the 1st day of treatment: 
• Medical history, medication review, physical exam, vital signs, height and weight, ECOG 
performance status (see Appendix A) 
• CBC with manual differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, LDH, TSH, creatinine kinase, lipase, triglycerides, 
PT/INR, PTT, hepatitis C antibody, hepatitis B surface antigen and hepatitis B core 
antibody.  Urine studies to include a urine dipstick for blood and protein and if positive 
(2+ or greater for protein) a microscopic urinalysis and 24-hour urine collection (for 
protein).    
• Serum or urine β-HCG for females of childbearing potential 
• Tumor restaging (within 6 weeks).  This will consist of PET/CT scans (including neck, 
chest, abdomen/pelvis).   
• Peripheral blood sample for biomarker studies (Section 9). 
• Tumor biopsy for biomarker studies (Section 9). An archival sample may be acceptable 
(see Section 3.1). 
• 12-Lead Electrocardiogram (EKG).  
 
10.2 Required Data During Study 
The following must be obtained during the study: 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
52 
• Medical history, medication review, physical exam, vital signs, and weight, ECOG 
performance status (see Appendix A) 
• Toxicity assessment 
• CBC with manual differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium. These are required at each planned study visit -- day 1 of cycles 
1-4, day 1 all maintenance cycles, day 43 of maintenance cycles.  
• TSH, creatinine kinase, lipase, and triglycerides, as well as urine studies to include a 
urinalysis (and if urine protein positive >=2+, a 24-hour urine collection to quantify 
proteinuria). These are required at each planned study visit -- day 1 of cycles 1-4, day 1 
all maintenance cycles, day 43 of maintenance cycles. Patients do need to meet 
laboratory eligibility criteria on C1D1 (see section 5.2). 
• Pregnancy test at screening and D1 of each cycle (for women of childbearing age only). 
• Peripheral blood sample for biomarker studies will be collected for research (see Section 
9) 
• Tumor restaging: PET/CT scans will be performed at baseline and after 4 doses of 
ipilimumab monotherapy (week 12). Among ipilimumab responders, restaging scans will 
occur prior to ipilimumab maintenance cycle 2 (week 24), cycle 3 (week 36), cycle 5 
(week 60), and cycle 7 (week 84). Among ipilimumab non-responders, restaging scans 
will occur after 4 cycles of ipilimumab + nivolumab combination therapy (week 24) and 
prior to ipilimumab maintenance cycle 2 (week 36), cycle 4 (week 60), and cycle 6 (week 
84). The end-of-treatment assessment will occur 4-12 weeks after the last doses of study 
therapy (i.e. weeks 112-120 for patients who complete all planned study therapy). 
Afterwards patients will be re-imaged every 24 weeks. 
 
10.3 Required at Progression or Treatment Discontinuation and Follow-Up 
 
• Medication review, physical exam, vital signs, ECOG performance status (see Appendix 
A) 
• Toxicity assessment 
• CBC with manual differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, LDH, TSH, creatinine kinase, lipase, triglycerides.  
Urine studies to include a urine dipstick for blood and protein and if positive a 
microscopic urinalysis and 24-hour urine collection (for protein).    
• Peripheral blood sample for biomarker studies at the time of progression (if feasible) 
• Core-needle tumor biopsy at the time of progression (optional) 
• Tumor restaging will be performed for patients in long-term follow-up who remain in 
remission. Patients who progress or receive other therapy for their lymphoma (for 
example, consolidation with transplantation or an alternative treatment) will only be 
followed for relapse and survival). Surveillance imaging will consist of PET/CT scans 
(including neck, chest, abdomen/pelvis) every 24 weeks for up to 2 years after initiation 
of study therapy.   

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
53 
• Patients in remission will be followed every 3 months for 2 years, then every 6 months 
for 3 years. Patients who progress or receive other therapy (for example consolidation 
with transplantation or an alternative treatment) will only be followed for relapse and 
survival.   
• After 5 years of active follow up (for patients who remain in remission and do not receive 
additional treatment), patients will be followed only for relapse and survival with follow 
up by phone call with the patient or the local physician every 6 months for up to 5 years. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
54 
 
Table 7 - Study Calendar 
 
Baseline 
Cycle 1a 
Cycle 2 
Cycle 3 
Cycle 4 
Re-
induction 
cycles 1-4b 
Maintenance 
Cyclesc 
EOT 
Follow-
Upd, j 
EDC 
Timepoints 
 
Day-28 to 
Day 0 
Day 1 
Day 14-
21 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 43 
4-12 
weeks 
from last 
study 
treatment 
 
 
 
 
±3 days 
± 7 days 
±2 weeks 
 
Ipilimumab 
 
X 
 
X 
X 
X 
(X) 
X 
 
 
 
Day 1 of 
induction and 
re-induction 
cycles and 
each 
maintenance 
cycle 
Nivolumab 
 
 
 
 
 
 
(X) 
 
 
 
 
Day 1 of re-
induction 
cycles 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
N/A 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
B-HCGe 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Baseline 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
Hepatitis B and 
C serologiesf 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
Concurrent 
Medications 
X 
X 
 
X--------------------------------------------------------------------------------------------------X 
N/A 
Physical exam 
X 
X 
 
X 
X 
X 
(X) 
X 
X 
X 
X 
At each 
study visit 
Vital signs 
X 
X 
 
X 
X 
X 
(X) 
X 
X 
X 
X 
At each 
study visit 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Baseline 
Weight 
X 
X 
 
X 
X 
X 
(X) 
X 
 
 
 
Baseline, day 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
55 
1 induction 
and re-
induction 
cycles and 
day 1 of each 
maintenance 
cycle 
Performance 
status (Appendix 
A) 
X 
X 
 
X 
X 
X 
(X) 
X 
X 
X 
X 
A each study 
visit 
CBC w/diff, 
serum chemistryg 
X 
X 
 
X 
X 
X 
(X) 
X 
X 
X 
X 
At each 
study visitg 
TSH, creatinine 
kinase, lipase, 
triglycerides, 
urine dipstick 
for blood and 
proteinh 
X 
X 
 
X 
X 
X 
(X) 
X 
X 
X 
X 
At each 
study visith 
Cheek 
swab/saliva 
sample 
 
X 
 
 
 
 
 
 
 
 
 
On Cycle 1 
Day1 
Peripheral blood 
collection for 
biomarker 
studiesi 
 
X 
 
X 
X 
 
(X) 
Xi 
X 
X 
 
See footnote 
Tumor biopsiesk 
X k 
 
(X) k 
 
 
 
 
 
 
(X) k 
 
See footnote 
Radiologic 
Evaluationl 
X 
 
 
 
 
 
(X) 
Xl 
 
X 
X 
See footnote 
Adverse Event 
Evaluation 
 
 
X---------------------------------------------------------------------------------------------------------------X 
At each 
study visit 
a: 
Cycles 1-4 are 21 days 
b: Patients who achieve an objective response after 4 cycles of ipilimumab therapy will proceed to maintenance ipilimumab treatment. Ipilimumab non-
responders (who are clinically stable) will receive re-induction with ipilimumab and nivolumab. 
c:    Maintenance cycles are 12 weeks (84 days). (see section 5.1) 
d: Follow-up evaluation. Patients will continue on treatment until disease progression, withdrawal of consent, adverse events preventing additional therapy, or 
completion of study therapy. After completing treatment, patients will have every 3-month visits for 2 years or until progressive disease, then every 6-month 
visits for 3 years. Survival follow-up will then continue to be captured every 6 months for 5 years or until participant withdrawal, death, or removal from 
study. Patient who receive subsequent anti-cancer therapy will be followed for relapse and survival (but will not require active follow-up and surveillance 
imaging on trial). 
e: 
Pregnancy testing at screening and on D1 of each cycle (for women of childbearing age only) 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
56 
f:      Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
g: See Sections 10.1 and 10.2. All tests will be required at screening. 
h: See Sections 10.1 and 10.2. 
i: 
Peripheral blood sample(s) will be collected for correlative studies per section 9 
j:     See Section 10.3. 
k: All patients are required to provide a pre-treatment core needle or excisional biopsy or an archival sample provided it was obtained within 90 days of trial 
initiation (see section 3.1). In addition, optional core needle biopsies may be collected during cycle 1 (between day 14-21) and at the time of progression. 
l: 
PET/CT scans will be performed at baseline and after 4 doses of ipilimumab monotherapy (week 12). Among ipilimumab responders, restaging scans will 
occur prior to ipilimumab maintenance cycle 2 (week 24), cycle 3 (week 36), cycle 5 (week 60), and cycle 7 (week 84)  . Among ipilimumab non-responders, 
restaging scans will occur after 4 cycles of ipilimumab + nivolumab combination therapy (week 24) and prior to ipilimumab maintenance cycle 2 (week 36), 
cycle 4 (week 60), and cycle 6 (week 84).. The end-of-treatment assessment will occur 4-12 weeks after the last doses of study therapy (i.e. weeks 112-120 
for patients who complete all planned study therapy). Afterwards patients will be re-imaged every 24 weeks. 
 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
57 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect  
 
18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) imaging will be used 
in conjunction with Computerized Tomography (CT) imaging to confirm a disease assessment of 
CR at the end of treatment.  The screening 18F-FDG PET-CT imaging will be used to determine 
evaluable index lesions for each patient.  For 18F-FDG PET-CT, tumor background ratios and 
development of new sites of abnormality will be recorded. 
Results of the 18F-FDG PET studies will be scored according to methods developed by the 
American College of Radiology Imaging Network.  All centers participating in the study will use 
the same 18F-FDG PET methodologies and measures, to the extent possible, and one center will 
be designated as the central lab to be used for final interpretation of 18F-FDG PET data. 
Anti-cancer activity will be assessed as specified in the Study Calendar (Section 10) or whenever 
disease progression is suspected (eg, symptomatic deterioration), or at the time of withdrawal 
from treatment (if not performed in the previous 6 weeks). 
If imaging is used in disease assessment, the same imaging technique (CT) used to characterize 
each identified and reported lesion at baseline will be employed in post-baseline disease 
assessments. 
Assessment of response will be made using the Lugano 2014 criteria and LyRIC (Appendix D).   
All patients’ files and radiologic images and pathology samples must be available for source 
verification and for potential peer review. 
11.1.1 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started, or death due to any 
cause. Participants without events reported are censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
58 
11.1.2 Progression-Free and Overall Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or 
registration) to progression, or censored at date of last disease evaluation for those without 
progression reported. 
 
11.1.3 Response Review 
 
For purposes of data analysis and reporting, responses on this trial will be centrally assessed 
through the Tumor Imaging Metrics Core at DF/HCC. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the Office of Data 
Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Sponsor-
Investigator and study team. 
 
The DSMC generally reviews each protocol up to four times a year with the frequency 
determined by the outcome of previous reviews. Information to be provided to the committee 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
59 
may include: up-to-date participant accrual; current dose level information; DLT information; all 
grade 2 or higher unexpected adverse events that have been reported across all sites; summary of 
all deaths occurring within 30 days of intervention for Phase I or II protocols; for gene therapy 
protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request.  
12.3 
Multi-Center Guidelines 
 
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and Participating Institutions and the procedures for auditing 
are presented in Appendix B. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is an open label phase II clinical trial of ipilimumab with or without nivolumab in patients 
with relapsed/refractory classical Hodgkin lymphoma. The trial is designed to assess the efficacy 
of ipilimumab with or without nivolumab in patients with relapsed/refractory Hodgkin 
lymphoma.  
  
13.1 
Study Design/Endpoints 
 
Primary Endpoint 
• Best ORR (Lugano criteria) 
 
Secondary Endpoints 
• Best ORR, PRR, CRR assessed by PET/CT (using Lugano criteria and LYRIC criteria) 
after ipilimumab monotherapy 
• Best ORR, PRR, CRR assessed by PET/CT (using Lugano criteria and LYRIC criteria) 
after ipilimumab and nivolumab combination therapy  
• DOR (using Lugano criteria and LYRIC criteria) for patients receiving ipilimumab 
maintenance 
• DOR (using Lugano criteria and LYRIC criteria) for patients receiving ipilimumab and 
nivolumab combination therapy 
• PFS and OS (Lugano criteria and LYRIC criteria) 
• Safety 
• Above endpoints, stratified by best response to PD-1 mAb (non-responder versus 
responder) 
 
Correlative Endpoints 
• To determine if features of the cHL TME are associated with response or resistance to 
study treatment 
• To determine if early reduction in ctDNA is associated with improved PFS.  

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
60 
• To characterize the genetic bases of immune evasion and correlate these alterations with 
responses to therapy 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
We anticipate that 13 patients will be enrolled in this phase II trial. We estimate that patients will 
be enrolled over a 30-month period. Up to 3 months of additional follow-up will be required to 
observe a participant’s response. Therefore, we anticipate analysis of primary endpoints after a 
total of 33 months. The end of the trial will occur when all patients have stopped study treatment 
(due to progression, withdrawal of consent, adverse events, etc).  
Table 8 - Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 1 
= 2 
Not Hispanic or Latino 
5 
+ 6 
= 11 
Ethnic Category: Total of all 
subjects 
6 
(A1) + 7 
(B1) = 13 
(C1) 
Racial Category 
 
American Indian or Alaskan 
Native 
0 
+ 0 
= 0 
Asian 
0 
+ 1 
= 1 
Black or African American 
1 
+ 0 
= 1 
Native Hawaiian or other Pacific 
Islander 
0 
+ 0 
= 0 
White 
6 
+ 5 
= 11 
Racial Category: Total of all 
subjects 
7 
(A2) + 6 
(B2) = 13 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 
Analysis of Primary Endpoints 
 
The desired sample size is 13 patients. We hope to demonstrate that ipilimumab monotherapy 
has significant clinical activity as a single agent, defined as an ORR of 40% or higher. The null 
hypothesis that the true ORR is 10% will be tested against a one-sided alternative (ORR 40%). 
The null hypothesis will be rejected if 4 or more patients of the 13 patients tested achieve an 
objective response. This design yields a type 1 error rate of 0.034 (one-sided) and a power of 
0.83. Analysis of re-induction with ipilimumab + nivolumab among ipilimumab non-responders 
will be descriptive in nature.  
 
13.4 
Analysis of Secondary Endpoints 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
61 
Secondary endpoints include, response assessments including ORR (defined as partial response 
and complete response), the duration of response (DOR) among patients who have achieved a 
PR or CR (defined as the time from first response to progression or last follow-up), progression 
free survival (PFS) (defined as the time from treatment start to progression, death or last follow-
up, whichever comes first), and overall survival (OS) (defined as time from treatment start to 
death or last follow-up). The safety of study will be assessed as measured by: the rate of grade 3 
or higher toxicity regardless of attribution, the rate of grade 3 or higher toxicity at least possibly 
related to study treatment, and the rate of grade 2 or higher toxicity at least probably related to 
study treatment. 
 
For patients who respond to treatment (complete or partial response), duration of response will 
be calculated from the date of response to the date of progression of disease.  Patients still 
responding at date of last follow-up will be censored. PFS will be calculated as the time from 
start of treatment to the date of progression, death or last follow-up. OS will be calculated as the 
time from the start of treatment to the date of death or last follow-up. OS, PFS and DOR will be 
calculated using Kaplan-Meier methodology. 95% confidence intervals will be calculated for all 
secondary endpoints. 
 
Correlative studies analyzing tissue samples using MIF and/or MIBI and circulating tumor DNA 
using next-generation sequencing based platforms are exploratory in nature. This testing is not 
powered to detect associations, but rather is designed to generate hypothesis for future studies. 
Completion of correlative studies will depend upon sample collection and budget considerations. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of study therapy will be evaluable for toxicity from 
the time of their first treatment. 
 
13.5.2 Evaluation of the Primary Efficacy Endpoint 
 
The primary analysis will be performed on all evaluable patients. 
 
 
14. PUBLICATION PLAN 
 
The results of this study will be submitted for presentation at national meetings and for 
publication in appropriate journals within 24 months of the completion of the study.  The first 
analysis and submission will be conducted when all patients have reached the End of Study visit 
(or been taken off study). 
 
 
 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
62 
REFERENCES 
 
1.  
Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US 
lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin 
[Internet]. 2016 Sep 12 [cited 2017 Jun 23];66(6):443–59. Available from: 
http://doi.wiley.com/10.3322/caac.21357 
2.  
Moskowitz AJ, Perales M-A, Kewalramani T, Yahalom J, Castro-Malaspina H, Zhang Z, 
et al. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem 
cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol 
[Internet]. 2009 Jul [cited 2017 Nov 3];146(2):158–63. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/19438504 
3.  
Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for 
Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous 
Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm 
Phase II CheckMate 205 Trial. J Clin Oncol [Internet]. 2018 May 10 [cited 2018 May 
29];36(14):1428–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29584546 
4.  
Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study of 
the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin 
Lymphoma. J Clin Oncol [Internet]. 2017 Jul 1 [cited 2017 Jul 23];35(19):2125–32. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/28441111 
5.  
Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a 
pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory 
Hodgkin’s lymphoma. J Clin Oncol. 2012 Jun;30(18):2183–9.  
6.  
Eggermont AMM, Chiarion-Sileni V, Grob J-J, Dummer R, Wolchok JD, Schmidt H, et 
al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III 
melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 
[Internet]. 2015 May [cited 2020 Jan 5];16(5):522–30. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/25840693 
7.  
Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, et al. United States 
Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) 
versus high-dose interferon-α2b for resected high-risk melanoma. J Clin Oncol [Internet]. 
2019 May 20 [cited 2020 Jan 16];37(15_suppl):9504–9504. Available from: 
https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.9504 
8.  
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 
Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J 
Med [Internet]. 2014 Dec 6 [cited 2014 Dec 7];372(4):311–9. Available from: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4348009&tool=pmcentrez&re
ndertype=abstract 
9.  
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. 
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl 
J Med [Internet]. 2018 Apr 5 [cited 2020 Jan 5];378(14):1277–90. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/29562145 
10.  
Ansell S, Gutierrez ME, Shipp MA, Gladstone D, Moskowitz A, Borello I, et al. A Phase 
1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory 
Hematologic Malignancies (CheckMate 039). Blood [Internet]. 2016 [cited 2017 Jul 
23];128(22). Available from: http://www.bloodjournal.org/content/128/22/183 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
63 
11.  
Roemer MGM, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 
and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict 
Outcome. J Clin Oncol [Internet]. 2016 Aug 10 [cited 2016 Oct 10];34(23):2690–7. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/27069084 
12.  
Armand P, Shipp MA, Ribrag V, Michot J-M, Zinzani PL, Kuruvilla J, et al. Programmed 
Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma 
After Brentuximab Vedotin Failure. J Clin Oncol [Internet]. 2016 Jun 27 [cited 2016 Jul 
7]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27354476 
13.  
Patel SS, Weirather JL, Lipschitz M, Lako A, Chen P-H, Griffin GK, et al. The 
microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4- positive 
T-cells that are PD-1-negative. Blood [Internet]. 2019 Oct 10 [cited 2020 Jan 
5];134(23):2059–69. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31697809 
14.  
Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, et al. CTLA4 
blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic 
cell transplantation. Blood [Internet]. 2009 Feb 12 [cited 2016 Oct 9];113(7):1581–8. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/18974373 
15.  
Davids MS, Kim HT, Costello, CL  et al. A Multicenter Phase I/Ib Study of Ipilimumab 
for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Stem Cell 
Transplantation. NEJM. 2016.  
16.  
Diefenbach C, Hong F, Ambinder RF, Cohen JB, Robertson M, David KA, et al. A Phase 
I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and 
Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial 
of the ECOG-ACRIN Research Group (E4412: Arms G-I). Blood [Internet]. 2018 Nov 21 
[cited 2019 Apr 23];132(Suppl 1):679–679. Available from: 
http://www.bloodjournal.org/content/132/Suppl_1/679 
17.  
Carey CD, Gusenleitner D, Lipschitz M, Roemer MGM, Stack EC, Gjini E, et al. 
Topological analysis reveals a PD-L1 associated microenvironmental niche for Reed-
Sternberg cells in Hodgkin lymphoma. Blood [Internet]. 2017 Sep 11 [cited 2017 Sep 
13];blood-2017-03-770719. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/28893733 
18.  
Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, et al. Multiplexed 
ion beam imaging of human breast tumors. Nat Med [Internet]. 2014 Apr 2 [cited 2020 
Jan 5];20(4):436–42. Available from: http://www.nature.com/articles/nm.3488 
19.  
Kurtz DM, Scherer F, Jin M, Soo J, Craig A, Esfahani MS, et al. Development of a 
Dynamic Model for Personalized Risk Assessment in Large B-Cell Lymphoma. Blood 
[Internet]. 2017 [cited 2018 Apr 2];130(Suppl 1). Available from: 
http://www.bloodjournal.org/content/130/Suppl_1/826 
20.  
Spina V, Khiabanian H, Messina M, Monti S, Cascione L, Bruscaggin A, et al. The 
genetics of nodal marginal zone lymphoma. Blood [Internet]. 2016 Sep 8 [cited 2018 Mar 
9];128(10):1362–73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27335277 
21.  
Sworder B. Circulating DNA for Molecular Response Prediction, Characterization of 
Resistance Mechanisms and Quantification of CAR T-Cells during Axicabtagene 
Ciloleucel Therapy [Internet]. ASH; 2019 [cited 2020 Jan 5]. Available from: 
https://ash.confex.com/ash/2019/webprogram/Paper129015.html 
22.  
Spina V, Bruscaggin A, Cuccaro A, Martini M, Di Trani M, Forestieri G, et al. Circulating 
tumor DNA reveals genetics, clonal evolution and residual disease in classical Hodgkin 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
64 
lymphoma. Blood [Internet]. 2018 Feb 15 [cited 2018 May 29];blood-2017-11-812073. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/29449275 
23.  
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, et al. Refinement of 
the Lugano Classification lymphoma response criteria in the era of immunomodulatory 
therapy. Blood [Internet]. 2016 Nov 24 [cited 2017 Jul 26];128(21):2489–96. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/27574190 
24.  
Schleimer RP, Jacques A, Shin HS, Lichtenstein LM, Plaut M. Inhibition of T cell-
mediated cytotoxicity by anti-inflammatory steroids. J Immunol [Internet]. 1984 Jan [cited 
2019 Nov 21];132(1):266–71. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/6606668 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
65 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
66 
APPENDIX B 
DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA SAFETY MONITORING PLAN 
 
 
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are 
participating in a DF/HCC clinical trial.  
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures. 
 
2 GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in addition to 
those outlined in DF/HCC Policies for Sponsor-Investigators:  
 
2.1 External Site 
 
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  The 
External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study.  
 
Each External Site is expected to comply with all applicable DF/HCC requirements stated within 
this Data and Safety Monitoring Plan and/or the protocol document. 
 
The general responsibilities for each External Site may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. For studies under a single IRB, 
the Coordinating Center with regulatory documents or source documents as requested. 
• Maintain regulatory files as per ICH GCP and federal requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as 
required. 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities when required by the sponsor. 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
67 
• Submit Serious Adverse Event (SAE) reports to the Sponsor, Coordinating Center, and 
IRB of Record as applicable.  
• Submit protocol deviations and violations to sponsor, Coordinating Center, and IRB of 
record as applicable, in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings. 
• Notify the sponsor immediately of any regulatory authority inspection of this protocol at 
the External Site. 
 
3 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC research. 
The following section will clarify DF/HCC requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Revisions and Closures 
 
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions. 
 
• Protocol revisions: External Sites will receive written notification of protocol revisions 
from the Coordinating Center. All protocol revisions must be IRB approved and 
implemented within a timely manner from receipt of the notification. 
 
• Protocol closures and temporary holds: External Sites will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds 
will be effective immediately.  In addition, the Coordinating Center, will update the 
Participating Institutions on an ongoing basis about protocol accrual data so that they will 
be aware of imminent protocol closures. 
 
3.2 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for External Sites. The External Site consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance 
Document on Model Consent Language for Investigator-Sponsored Multi-Center Trials.  This 
document will be provided separately to each External Site upon request. 
 
External Sites are to send their version of the informed consent document to the Coordinating 
Center for review and approval prior to submission to their local IRB. The approved consent 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
68 
form must also be submitted to the Coordinating Center after approval by the local IRB for all 
consent versions. 
 
The Principal Investigator (PI) at each External Site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
External Sites must follow the DF/HCC requirement that for all interventional drug, biologic, or 
device research, only attending physicians may obtain initial informed consent and any re-
consent that requires a full revised consent form.   
 
3.3 IRB Re-Approval 
 
Verification of IRB re-approval from the External Sites is required in order to continue research 
activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
3.4 DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned protocol case number (as described below) be 
used for all participant specific documents. Participant initials may be included or retained for 
cross verification of identification.  
 
3.5 Participant Registration 
 
3.5.1 Participant Registration  
 
To register a participant, the following documents should be completed by the External Site 
and e-mailed to the Coordinating Center:  
 
Celeste Carey 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Celeste_Carey@dfci.harvard.edu  
Phone: 857.215.1646 
 
• Copy of required assessments that support eligibility 
• Signed informed consent document 
• HIPAA authorization form (if applicable) 
• Completed DFCI Eligibility Checklist 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
69 
The Coordinating Center will review the submitted documents in order to verify eligibility 
and consent. To complete the registration process, the Coordinating Center will: 
• Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform the 
External Site and provide the study specific participant case number, and if applicable, 
assigned treatment and/or dose level.  
 
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number.  External Sites 
should submit all de-identified subsequent communication and documents to the Coordinating 
Center, using this case number to identify the subject.   
 
3.5.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions.  Treatment and other protocol-specific interventions may 
not be initiated until the External Site receives confirmation of the participant’s registration from 
the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations 
to this policy. 
 
3.5.3 Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process for 
requesting an eligibility exception is defined below. 
 
3.6 Data Management 
 
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms are 
designed to collect data for each study. DF/HCC provides a web based training for all eCRF 
users. 
   
3.6.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study forms 
are received with missing or questionable data, the submitting institution will receive a written or 
electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee.   
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
If study forms are not submitted on schedule, the External Site will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
70 
3.7 
Protocol Reporting Requirements 
 
3.7.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor and to the IRB of record. 
 
 
3.7.2 Reporting Procedures 
 
Requests to deviate from the protocol require approval from the IRB of record and the sponsor. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  The 
Coordinating Center will provide training for the requirements for the reporting of violations.  
 
3.7.3 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and ensure 
that all IND Safety Reports are distributed to the External Sites as required by DF/HCC Policy. 
External Sites will review/submit to the IRB according to their institutional policies and 
procedures. 
 
4 MONITORING: QUALITY CONTROL 
 
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol. 
 
4.1 Ongoing Monitoring of Protocol Compliance 
 
The External Sites may be required to submit participant source documents to the Coordinating 
Center for monitoring. External Sites may also be subject to on-site monitoring conducted by the 
Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that External 
Sites are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring practices may include but are not limited to; source data verification, and 
review and analysis of eligibility requirements, informed consent procedures, adverse events and 
all associated documentation, review of study drug administration/treatment, regulatory files, 
protocol departures reporting, pharmacy records, response assessments, and data management.  
 
External Sites will be required to participate in regular Coordinating Center initiated 
teleconferences.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
71 
Remote Monitoring: External Sites will be required to forward de-identified copies of 
participants’ medical record and source documents to the Coordinating Center to aid in source 
data verification. 
 
and/or 
 
On-Site Monitoring:  Source documentation verification (SDV) will be conducted yearly by 
having access to participants’ complete medical record and source documents. 
 
4.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at External Sites that are unable to 
comply with the protocol, DF/HCC Sponsor requirements or federal and local regulations.  
 
4.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each External Site. Accrual will be monitored for each External Site by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be 
subject to termination. 
 
5 AUDITING: QUALITY ASSURANCE 
 
5.1 DF/HCC Internal Audits 
  
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2-day period.  If violations 
which impact participant safety or the integrity of the study are found, more participant records 
may be audited.  
 
5.2 Audit Notifications 
 
It is the External Site’s responsibility to notify the Coordinating Center of all external audits or 
inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will forward a 
copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
Coordinating Center, within 12 weeks after the audit date.  
 
5.3 Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan to the 
DFCI IRB as applicable. 
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
72 
5.4 External Site Performance 
 
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed.  
 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
73 
APPENDIX C 
RESPONSE CRITERIA FOR LYMPHOMA: LUGANO 2014 AND LYRIC 
 
Criteria 
Complete Response (CR) 
Partial Response (PR) 
Stable 
Disease 
(SD) 
Progressive disease (PD) 
Lugano 
PET-CT, score 1, 2, or 3* with 
or without a residual mass on 
5PS†   
 
Or 
 
on CT, target nodes/nodal 
masses must regress to ≤ 1.5 
cm in LDi, and no 
extralymphatic sites of disease 
 
PET-CT Score 4 or 5 with reduced uptake 
compared with baseline and residual 
mass(es) of any size.   
 
Or 
 
On CT ≥ 50% decrease in SPD of up to 6 
target measurable nodes and extranodal 
sites; no increase in non-measured lesions; 
spleen if enlarged must have regressed by 
>50% in length beyond normal 
Neither 
CR, PR, 
nor PD 
PET-CT score 4 or 5 with an increase in intensity of 
uptake from baseline and/or new FDG-avid foci 
consistent with lymphoma at interim or end-of-
treatment assessment.  
 
Or 
 
On CT, an individual node/lesion must be abnormal 
with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen must increase to > 
16 cm). If no prior splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly. 
New or clear progression of preexisiting nonmeasured 
lesions.   
Regrowth of previously resolved lesions. 
A new node > 1.5 cm in any axis or a new extranodal 
site > 1.0 cm in any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must be attributable 
to lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
 
And/Or  
 
New or recurrent involvement of the bone marrow 

DF/HCC Protocol #: 21-204 
Protocol version date: v8/06 September 2023 
 
74 
 
Criteria 
Complete Response 
(CR) 
Partial Response 
(PR) 
Stable Disease (SD) 
Progressive Disease (PD) 
LYRIC 
Same as Lugano 
Same as Lugano 
Neither CR, PR, PD, 
nor IR 
As with Lugano with the following exceptions: 
Indeterminate response (IR) 
IR1: >50% increase in SPD in first 12 wks 
IR2: <50% increase in SPD with 
   a. New lesion(s), or 
   b. >50% increase in PPD of a lesion or set of lesions at any time during 
treatment 
IR(3): Increase in FDG uptake without a concomitant increase in lesion 
size meeting criteria for PD 
SPD – sum of the product of the diameters; PPD – product of the perpendicular diameters; LDi – longest diameter; SDi – short diameter; 5PS – 5-point scale; IR 
– immune response 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate