Clinical trial NCT02681302
Conditions: Multiple Myeloma Lymphoma
Sponsor: Hackensack Meridian Health
Start date: 2016-06-07; Completion date: 2024-05-10
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study is to determine the safety and clinical effect of combined checkpoint inhibition administered after autologous hematopoietic stem cell transplantation in each of six clinical cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of adverse events and rates of complete response and progression free survival, investigators intend to monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the time of disease progression. Investigators will also analyze the gut microbiome prior to conditioning, throughout treatment, post-transplant and at time of relapse.

Detailed description:
This is a phase Ib-IIA study of post-transplant combined check point inhibitors for patients with a high risk of relapse (\>50%) after an autologous hematopoietic stem cell transplant.

Patients will accrue to study by disease groups and followed separately by group for incidence and severity of toxicity, ability to receive intended schedule of combined check point inhibitors and for complete response and progression free survival (PFS) rates. Complete response and progression free survival rates will be compared to published standards for each disease group. Expected PFS at 18 months for all post-transplant groups without check point inhibitors is less than 50%. Each group with PFS at 18 months in 4 or more patients (57%) will be considered for eligibility in a successor phase IIB expansion trial.

Arms: arm 1: * Ipilimumab 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
* Nivolumab 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab
Intervention descriptions: intervention 1: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22 intervention 2: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26

Protocol documents:
Prot_SAP_000.pdf: 
Amendment9 
09NOV2021                                                        Page 1 of 77 
 
 
 
BLOOD AND MARROW TRANSPLANTATION PROGRAM 
HACKENSACK UNIVERSITY MEDICAL CENTER 
 
Title of Protocol 
 
Phase Ib-IIA study of combined checkpoint inhibition after autologous hematopoietic 
stem cell transplantation in patients at high risk for post-transplant recurrence 
 
(CPIT Trial 001/BMS Protocol CA209-694) 
 Amendment 9 (09 NOV 2021) 
 
 
Principal Investigators:   
Michele Donato M.D. 
 
 
 
 
Andrew L. Pecora, M.D. FACP CPE 
 
Sub-Investigators: 
Pasha Munshi, M.D.  
 
Amy Einstein, APN 
Geoffrey Gibney, M.D. 
Andre Goy M.D. 
 
 
Chaitra Ujjani, M.D. 
Robert Korngold Ph.D. 
 
Michael Atkins, M.D. 
Rena Feinman Ph.D.  
 
Noa Biran, M.D. 
 
David Vesole M.D. Ph.D. 
 
Melissa Baker, APN 
David Siegel M.D. Ph.D. 
 
Phyllis McKiernan, APN 
Tatyana Feldman M.D. 
 
Michele Boonstra, APN 
Lori Leslie M.D. 
 
 
Susan Kumka, APN  
  
 
Hyung Suh, MD                                  Sukhdeep Kaur, MD  
 
Sponsor:  
 
 
John Theurer Cancer Center at  
 
 
 
 
Hackensack University Medical Center 
 
 
 
 
 
             
             
 
 
 


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SUMMARY 
 
Phase Ib 
Primary 
Objectives 
The primary objectives of this study are: 
• 
To assess the safety of combined check point inhibition with nivolumab 
and ipilimumab after autologous hematopoietic stem cell transplantation 
in patients at high risk for post-transplant recurrence including patients 
with persistent and recurrent high risk diffuse large B cell lymphoma, high 
risk and recurrent T cell lymphoma and high risk and recurrent multiple 
myeloma. 
Primary endpoints:  
• 
Safety endpoint:  The composite endpoint consisting of the occurrence of 
at least one treatment-related limiting toxicity (after combined checkpoint 
inhibitor treatment is initiated) defined as a ≥ grade 4 non-hematologic 
toxicity as specified by the CTCAE. Exceptions listed in section 5.9 apply 
to this endpoint as well. If 3 of 7 patients in a single cohort experience a 
treatment-related limiting toxicity, that single cohort will be terminated. 
• 
Efficacy endpoint:  progression-free survival at 18 months after ASCT in 
patients at high risk for post-transplant recurrence including patients with 
persistent and recurrent high risk diffuse large B cell lymphoma, high risk 
and recurrent T cell lymphoma and high risk and recurrent multiple 
myeloma. 
 
Phase Ib 
Secondary 
Objectives 
The secondary objectives are:  
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in 
patients at high risk for post-transplant recurrence including patients with 
persistent and recurrent high risk diffuse large B cell lymphoma, high risk 
and recurrent T cell lymphoma and high risk and recurrent multiple 
myeloma. 
• 
To assess progression-free survival at 12 months after ASCT in patients 
at high risk for post-transplant recurrence including patients with 
persistent and recurrent high risk diffuse large B cell lymphoma, high risk 
and recurrent T cell lymphoma and high risk and recurrent multiple 
myeloma. 
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at 
screening (at time of informed consent), at apheresis (stem cell 
collection), and then serially the day 1 of week 1 of combined checkpoint 
inhibitors and then weeks 4, 7, 12, 18 and 26, End of Treatment, and at 
9, 12, 15, and 18 months post-transplant and at time of relapse, as it 
occurs.  
• 
Determine the toxicities resulting from administration of the treatments. 
• 
To assess tumor site immune phenotype, T cell repertoire and PD L1/2 
expression when tissue available for biopsy prior to autologous transplant 
conditioning and then at time of progression (within 18 months) after 
autologous transplant conditioning. 
 
Phase Ib 
Tertiary 
Objectives 
• 
To identify specific intestinal microbial strains associated with improved 
outcome in autologous stem cell transplantation patients treated with 
combined checkpoint inhibitors. The overall microbial composition in stool 
samples of patients will be analyzed at screening, preconditioning (to be 


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collected within 48 hours prior to transplant admission), at engraftment 
(within 72 hours of ANC > 500), and then serially, on day 1 of week 1 (to 
be collected within 48 hours prior to clinic visit) and then weeks 4, 7, 12, 
18, and 26, End of Treatment and 9, 12, 15 and 18 months post-
transplant, and at time of relapse, as it occurs. 
 
Phase IIA 
Primary 
Objective 
The primary objectives of this study are: 
• 
To assess progression-free survival at 18 months after ASCT in patients  
in cohorts that were  deemed safe in Phase Ib (no more than 3 treatment-
related toxicity) and at least 4 of 7 patients were progression free at 18 
months in the Phase Ib. 
 
Phase IIA 
Secondary 
Objectives 
 
The secondary objectives of this study are: 
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in 
patients at high risk for post-transplant recurrence including patients in 
the successor expansion cohorts following the Phase Ib trial. 
• 
To assess progression-free survival at 12 months after ASCT in patients 
at high risk for post-transplant recurrence including patients with in the 
successor expansion cohorts following the Phase Ib trial. 
• 
Determine the toxicities resulting from administration of the treatments in 
patients enrolled in the successor expansion cohorts following the Phase 
Ib trial. 
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at 
screening (at time of informed consent), at apheresis (stem cell 
collection), and then serially the day 1 of week 1 of combined checkpoint 
inhibitors and then weeks 4, 7, 12, 18 and 26, End of Treatment, and at 
9, 12, 15, and 18 months post-transplant and at time of relapse, as it 
occurs.  
 
Phase IIA 
Tertiary 
Objectives 
• 
To identify specific intestinal microbial strains associated with improved 
outcome in autologous stem cell transplantation patients treated with 
combined checkpoint inhibitors. The overall microbial composition in stool 
samples of patients will be analyzed at screening, preconditioning (to be 
collected within 48 hours prior to transplant admission), at engraftment 
(within 72 hours of ANC > 500), and then serially, on day 1 of week 1 (to 
be collected within 48 hours prior to clinic visit) and then weeks 4, 7, 12, 
18, and 26, End of Treatment and 9, 12, 15 and 18 months post-
transplant, and at time of relapse, as it occurs. 
 
Patient 
Eligibility 
 
1. 
Voluntary signed and dated IRB/IEC approved written informed 
consent form in accordance with regulatory and local guidelines.  
2. 
Be 18 years or older and 80 years or younger on the day of signing 
consent 
3. 
Have a confirmed diagnosis of:  
o (GROUP A) De novo diffuse large B cell lymphoma that fails to achieve 
a PET negative complete response to primary rituximab and 
anthracycline based multi-agent chemotherapy and at least maintains 
stable disease after salvage chemotherapy or present double/triple hit 
features defined by overexpression by standard immunohistochemistry 
of c-MYC plus BCL2 and/or BCL6 or presence of chromosomal 


Amendment9 
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translocations as detected by break-apart FISH involving IGH/MYC plus 
IGH/BCL2 and/or IGH/BCL6 and who only received standard 
chemoimmunotherapy with rituximab, cyclophosphamide, vincristine 
and prednisone (R-CHOP) for induction and present at least stable 
disease after consolidation or salvage chemotherapy. Stable disease 
(SD) for lymphoma is defined in Appendix B: Lugano Classification for 
Response Assessment of Non-Hodgkin Lymphoma. 
 
o (GROUP B) Recurrent high-risk diffuse large B cell lymphoma defined 
as relapsing within one year of completion of rituximab and anthracycline 
based multi-agent chemotherapy or a sAAIPI (second-line age-adjusted 
International Prognostic Index) intermediate or high at relapse or 
acquisition of double/triple hit features upon relapse (as defined in group 
A) and at least stable disease after salvage chemotherapy.  Patients with 
an initial diagnosis of low-grade/indolent non-Hodgkin lymphoma (i.e. 
follicular, marginal zone) who present relapse with histologic 
transformation to diffuse large B cell lymphoma (confirmed by biopsy) 
and meet the definition for high-risk as presented above, are also 
eligible. 
 
o (GROUP C) De novo high-risk T cell lymphoma with at least stable 
disease after primary therapy. High risk T cell lymphoma is defined as 
Stage III or IV disease at presentation and/or failure to achieve CR after 
frontline chemotherapy. Patients with ALK-positive ALCL will be 
excluded from the trial. Patients with ALK-negative ALCL in complete 
response will be excluded from the trial. 
 
o (GROUP D) Recurrent T cell lymphoma with at least stable disease after 
salvage therapy. Patients with ALK-positive ALCL will be excluded from 
the trial. 
 
o (GROUP E) Transplant-naïve high risk multiple myeloma with at least 
stable disease after most recent line of therapy. High risk myeloma is 
defined as those carrying 1q amplifications, 1p deletions, 13q deletions 
by conventional cytogenetics, p53 deletions, high-risk GEP 70 scores, 
t(4;14), t(14;16) and t(14;20), hypodiploidy. This cohort has been 
discontinued due to updated risks provided by the FDA. These patients 
will be followed for safety and correlative studies only. 
 
o (GROUP F) Recurrent myeloma within 3 years after a single or tandem 
autologous transplant and at least stable disease after salvage therapy. 
Stable disease for multiple myeloma is defined in Appendix C: 
International Myeloma Working Group (IMWG). This cohort has been 
discontinued due to updated risks provided by the FDA. These patients 
will be followed for safety and correlative studies only. 
 
4. 
Be deemed eligible for an autologous stem cell transplantation 
according to the  institutional guidelines of the Blood and Marrow 
Transplantation Program at John Theurer Cancer Center at 
Hackensack University Medical Center 
5. 
Have an ECOG performance status of 2 or lower   


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6. 
Women of childbearing potential (WOCBP) must use appropriate 
method(s) of contraception. WOCBP should use an adequate 
method to avoid pregnancy for 23 weeks (30 days plus the time 
required for nivolumab to undergo five half-lives) after the last dose 
of investigational drug.   
7. 
Women of childbearing potential (WOCBP) must have a negative 
serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 24 hours prior to the start of 
nivolumab. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. Female subjects 
of childbearing potential should agree to ongoing pregnancy testing, 
to be performed prior to each dosing of ipilimumab and nivolumab. 
See Note below for definition of WOCBP. 
8. 
Women must not be breastfeeding. 
9. 
Men who are sexually active with WOCBP must use any 
contraceptive method with a failure rate of less than 1% per year. 
Men receiving nivolumab, and who are sexually active with WOCBP 
will be instructed to adhere to contraception for a period of 31 weeks 
after the last dose of investigational product, even if they have had 
a vasectomy. Women who are not of childbearing potential (ie, who 
are postmenopausal or surgically sterile as well as azoospermic men 
do not require contraception). See Note below for definition of 
WOCBP. 
10. 
Females of childbearing potential must be willing to use two methods 
of birth control or be surgically sterile, or abstain from heterosexual 
activity for the course of the study through 120 days after the last 
dose of study medication. Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free 
from menses for > 2 years. See Note below for definition of WOCBP. 
11. 
Allowable transplant preparative regimens are the following: 
o For non-Hodgkin lymphoma groups (A, B,C,D) BEAM: carmustine 300 
mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -
5 to -2, melphalan 140 mg/m2 day -1 
o For Myeloma groups (E and F) Melphalan 200 mg/m2 day -1 
 
NOTE: Women of childbearing potential is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman 
over 45 in the absence of other biological or physiological causes. In 
addition, women under the age of 55 must have a documented serum follicle 
stimulating hormone (FSH) level less than 40 mIU/mL.  
 
Women of childbearing potential (WOCBP) receiving nivolumab will be 
instructed to adhere to contraception for a period of 23 weeks after the last 
dose of investigational product. Men receiving nivolumab and who are 
sexually active with WOCBP will be instructed to adhere to contraception for 
a period of 31 weeks after the last dose of investigational product. These 
durations have been calculated using the upper limit of the half-life for 
nivolumab (25 days) and are based on the protocol requirement that 


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WOCBP use contraception for 5 half-lives plus 30 days and men who are 
sexually active with WOCBP use contraception for 5 half-lives plus 90 days. 
 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject meets 
ANY of the following exclusion criteria: 
 
1. 
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to 
trial treatment. There must also be no requirement for 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug 
administration. This exception does not include carcinomatous 
meningitis, which is excluded regardless of clinical stability.   Note: 
Subjects are permitted to use topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic 
absorption). 
Physiologic 
replacement 
doses 
of 
systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone 
equivalents. A brief course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted. 
2. 
Is unable or unwilling to sign informed consent. 
3. 
Has an active, known, or suspected autoimmune disease. Subjects 
are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger 
4. 
Patients should be excluded if they have a condition requiring 
systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications 
within 14 days of study drug administration. Inhaled or topical 
steroids and adrenal replacement doses > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune 
disease. Note: Subjects are permitted to use topical, ocular, intra-
articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone 
equivalents. A brief course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted. 
5. 
As there is potential for hepatic toxicity with nivolumab or 
nivolumab/ipilimumab combinations, drugs with a predisposition to 
hepatoxicity should be used with caution in patients treated with 
nivolumab-containing regimen. 


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09NOV2021                                                        Page 7 of 77 
6. 
Has received an allogeneic stem cell transplant. 
7. 
Has a history of hypersensitivity to nivolumab, ipilimumab, or any of 
its excipients, or severe hypersensitivity reaction to any previous 
monoclonal antibody.  
8. 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 
weeks prior to Day 1 of checkpoint inhibitor treatment administration 
or who has not recovered (i.e., t administration mAb) within 4 weeks 
prior to dose of trial treatment. Rituximab within that period is 
allowed.  
9. 
Has active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. Note: Subjects are 
permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). 
Physiologic replacement doses of systemic corticosteroids are 
permitted, even if > 10 mg/day prednisone equivalents. A brief 
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. 
10. 
Has known history of, or any evidence of active, non-infectious 
pneumonitis. 
11. 
Has an active infection requiring intravenous systemic therapy. 
12. 
Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
13. 
Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. 
14. 
Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the pre-
screening or screening visit through 23 weeks for females and 31 
weeks for males after the last dose of trial treatment. 
15. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-
L2 agent, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell costimulation or immune checkpoint 
pathways. 
16. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies) or known acquired immunodeficiency syndrome 
(AIDS). 
17. 
Has positive test for Hepatitis B (e.g., HBsAg reactive) or Hepatitis 
C (e.g., HCV RNA [qualitative] is detected) indicating acute or 
chronic infection, as tested for transplant. 
18. 
Has received a live vaccine within 30 days of planned start of study 
therapy. 
NOTE: Patients who received steroids for engraftment syndrome may 
initiate treatment with ipilimumab and nivolumab once steroids have been 
tapered off and diarrhea and/or rash are grade I or better, without the need 


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for a steroid washout period. Initial dosing may be delayed up to day 28 
post-transplantation to allow for completion of steroid taper. 
 
Combined 
Check Point 
Inhibition 
Start 14 to 21 days after stem cell infusion if ANC>800 (off growth factors for at 
least 3 days) and Platelets>20,000 without transfusion 
 
Delay initiation until ANC>800 (off growth factors for at least 3 days) and 
Platelets>20,000 without transfusion up to 28 days after stem cell infusion. The 
first day of combined checkpoint inhibitor therapy will be considered 
Week 1, day 1 for the purposes of this protocol.  
 
Post ASCT therapy may be delayed up to 28 days after stem cell infusion if 
deemed appropriate by the investigator. 
Treatment 
Schema 
 
  
For all Groups A, B, C, D, E, F (7 patients per group):  
• 
Ipilimumab  1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22 
• 
Nivolumab   3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 
24, 26 
Statistical 
Consideration 
This is an open label, single-arm per cohort, phase Ib-IIA study. 
Our goal is to determine the safety and clinical effect of combined checkpoint 
inhibition administered after autologous hematopoietic stem cell transplantation 
in each of six clinical cohorts of high risk and recurrent disease. In addition to 
assessing the incidence and severity of adverse events and rates of complete 
response and progression free survival, we intend to monitor immune 
reconstitution, phenotype and TCR repertoire throughout treatment and at the 
time of disease progression. We will also analyze the gut microbiome prior to 
conditioning, throughout treatment, post-transplant and at time of relapse. We 
intend to expand cohorts that demonstrate safety and PFS >50% at 18 months 
into a phase IIA successor trial. 
Patients will accrue to study by disease groups and followed separately by 
group for incidence and severity of toxicity, ability to receive intended schedule 
of combined checkpoint inhibitors and for complete response and progression 
free survival (PFS) rates. Complete response and progression free survival 
rates will be compared to published standards for each disease group. Expected 
PFS at 18 months for all post-transplant groups without checkpoint inhibitors is 
less than 50%. Each group with PFS at 18 months in 4 or more patients (57%) 
will be considered for eligibility in a successor phase IIB expansion trial. 
 
 
 


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Table of Contents 
1.0 OBJECTIVES ......................................................................................................................11 
2.0 BACKGROUND ..................................................................................................................13 
2.1 Study Rationale ...............................................................................................................13 
2.2 Rationale for Checkpoint Inhibition ..................................................................................15 
2.3 Current evidence for checkpoint inhibition after autologous hematopoietic stem cell 
transplantation ......................................................................................................................18 
3.0 BACKGROUND DRUG INFORMATION .............................................................................18 
3.1 Nivolumab .......................................................................................................................18 
3.1.1 Description ...............................................................................................................18 
3.1.2 Mechanism of action .................................................................................................18 
3.1.3 Pharmacokinetics .....................................................................................................19 
3.1.4 Non-clinical toxicology ..............................................................................................20 
3.1.5 Adverse Events ........................................................................................................20 
3.2 Ipilimumab .......................................................................................................................21 
3.2.1 Description ...............................................................................................................21 
3.2.2 Mechanism of Action  ...............................................................................................21 
3.2.3 Pharmacokinetics .....................................................................................................22 
3.2.4 Non-clinical toxicology ..............................................................................................22 
3.2.5 Adverse events .........................................................................................................22 
4.0 PATIENT ELIGIBILITY ........................................................................................................23 
4.1 Inclusion Criteria .............................................................................................................23 
4.2 Exclusion Criteria ............................................................................................................24 
5.0 TREATMENT PLAN ............................................................................................................26 
5.1 Product Information .........................................................................................................26 
5.1.1 Drug Ordering and Accountability .............................................................................26 
5.1.2 Product Description and Dosage Form .....................................................................26 
5.2 Treatment Schema ..........................................................................................................27 
    5.3 Administration .................................................................................................................28 
5.4 Dose Modifications ..........................................................................................................29 
5.5 Premedication .................................................................................................................29 
5.6 Management Algorithms for Immuno-Oncology Agents ...................................................29 
5.7 Dose Delay Criteria .........................................................................................................29 
5.8 Criteria to Resume Treatment .........................................................................................30 
5.9 Discontinuation Criteria ...................................................................................................30 
6.0 SUBJECT SCREENING EVALUATION ..............................................................................31 
6.1 Evaluation of the patient after informed consent is signed ...............................................31 
6.2 Evaluation and Response................................................................................................32 
6.2.1 For Groups A, B, C, and D: .......................................................................................32 
6.2.2 For Groups E and F: .................................................................................................33 
6.2.3 For All Groups: .........................................................................................................33 
7.0 DATA SAFETY MONITORING ............................................................................................33 
8.0 STATISTICAL CONSIDERATION .......................................................................................34 
8.1 Determination of Sample Size .........................................................................................37 
8.2 Populations for Analysis ..................................................................................................38 
8.3 Statistical Methods ..........................................................................................................38 
8.3.1 Safety Analysis .........................................................................................................38 
8.3.2 Complete Response Rate .........................................................................................38 
8.3.3 Progression Free Survival at 12, 18 months .............................................................39 
8.3.4 Longitudinal analysis of TCR repertoire and blood immune phenotype.....................39 


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8.3.5 Longitudinal analysis of the gut microbiome. ............................................................40 
8.4 Additional Endpoint Analyses ..........................................................................................41 
8.4.1 Toxicities of the treatments .......................................................................................41 
8.4.2 Evaluation of tumor site phenotype ...........................................................................41 
8.4.3 General Data Analysis ..............................................................................................41 
8.5 Withdrawal of Patients .....................................................................................................41 
8.6 Stopping Rules ................................................................................................................41 
Phase Ib Stopping Rules .......................................................................................................41 
8.7 Data Management and Analysis ......................................................................................43 
9.0 SAFETY REPORTING ........................................................................................................44 
9.1 Definitions .......................................................................................................................44 
9.1.1 Adverse Event Definition ..........................................................................................44 
9.1.2 Serious Adverse Event Definition .............................................................................44 
9.2 Pregnancy .......................................................................................................................45 
9.3 Overdose ........................................................................................................................45 
9.4 Other Safety Considerations ...........................................................................................46 
9.5 Procedures for AE and SAE Reporting ............................................................................46 
9.6 Assessment of Toxicity ....................................................................................................46 
9.7 Assessment of Causality .................................................................................................47 
9.8 Follow-up of Adverse Experiences ..................................................................................47 
10.0 ADMINISTRATIVE REQUIREMENTS ...............................................................................47 
10.1 Good Clinical Practice ...................................................................................................47 
10.2 Patient Information and Informed Consent ....................................................................47 
10.3 Protocol Registration .....................................................................................................48 
10.4 Patient Confidentiality ....................................................................................................48 
10.6 Record Retention ..........................................................................................................48 
11.0 ECOG PERFORMANCE STATUS SCALE .......................................................................48 
12.0 BODY SURFACE AREA ...................................................................................................49 
13.0 ETHICAL CONSIDERATIONS ..........................................................................................49 
13.1 Informed Consent ..........................................................................................................49 
14.0 CTCAE ..............................................................................................................................49 
15.0 REFERENCES..................................................................................................................50 
APPENDIX A: Second-Line Age Adjusted International Prognostic Index (sAAIPI) ...................52 
APPENDIX B: The Lugano Classification for Response Assessment of Non-Hodgkin Lymphoma
 .................................................................................................................................................53 
APPENDIX C: INTERNATIONAL MYELOMA WORKING GROUP ...........................................55 
APPENDIX D: STUDY FLOWCHART .......................................................................................57 
APPENDIX E: Events of Clinical Interest Reference Table .......................................................60 
APPENDIX F: ECI Management Algorithm ...............................................................................60 
APPENDIX G: Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...................69 
APPENDIX H: Sample of Drug Ordering and Pharmacy Reference Material ............................70 
APPENDIX I: Adverse Event Reporting.....................................................................................74 
APPENDIX J: Research Biospecimen Sample Collection .........................................................76 
 
 
 
 
 
 


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1.0 OBJECTIVES 
This is an open label, single-arm per cohort, phase Ib-IIA study. 
 
Our goal is to determine the safety and clinical effect of combined checkpoint inhibition 
administered after autologous hematopoietic stem cell transplantation in each of six clinical 
cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of 
adverse events and rates of complete response and progression free survival, we intend to 
monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the 
time of disease progression. We will also analyze the gut microbiome prior to conditioning, 
throughout treatment, post-transplant and at time of relapse. We intend to expand cohorts in the 
lymphoma groups that demonstrate safety and PFS >50% at 18 months into a phase IIA 
successor trial. 
 
Phase Ib 
The primary objectives of this study are: 
• 
To assess the safety of combined check point inhibition with nivolumab and 
ipilimumab after autologous hematopoietic stem cell transplantation in patients at 
high risk for post-transplant recurrence including patients with persistent and 
recurrent high risk diffuse large B cell lymphoma, high risk and recurrent T cell 
lymphoma and high risk and recurrent multiple myeloma. 
Primary endpoints:  
• 
Safety endpoint:  The composite endpoint consisting of the occurrence of at least 
one treatment-related limiting toxicity (after combined checkpoint inhibitor 
treatment is initiated) defined as a ≥ grade 4 non-hematologic toxicity as specified 
by the CTCAE. Exceptions listed in section 5.9 apply to this endpoint as well. If 3 
of 7 patients in a single cohort experience a treatment-related limiting toxicity, that 
single cohort will be terminated. 
• 
Efficacy endpoint:  progression-free survival at 18 months after ASCT in patients 
at high risk for post-transplant recurrence including patients with persistent and 
recurrent high risk diffuse large B cell lymphoma, high risk and recurrent T cell 
lymphoma and high risk and recurrent multiple myeloma. 
 
The secondary objectives are:  
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in patients 
at high risk for post-transplant recurrence including patients with persistent and 
recurrent high risk diffuse large B cell lymphoma, high risk and recurrent T cell 
lymphoma and high risk and recurrent multiple myeloma. 
• 
To assess progression-free survival at 12 months after ASCT in patients at high 
risk for post-transplant recurrence including patients with persistent and recurrent 
high risk diffuse large B cell lymphoma, high risk and recurrent T cell lymphoma 
and high risk and recurrent multiple myeloma. 
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at 
screening (at time of informed consent), at apheresis (stem cell collection), and 
then serially the day 1 of week 1 of combined checkpoint inhibitors and then weeks 
4, 7, 12, 18 and 26, End of Treatment, and at 9, 12, 15, and 18 months post-
transplant and at time of relapse, as it occurs. Immune phenotype and TCR will be 
evaluated as follows: 
 
T cell repertoire analysis 


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TCR Immunoseq for Vbeta CDR3 highest frequency specificities. 
 
Real-Time PCR analysis:  
T-bet(Th1); STAT3, RORgamma t (TH17); STAT6 (Th2); FoxP3 (Treg), granzyme 
A (GZMA) and perforin (PRF1) 
 
Flow Cytometric Phenotype Analysis for:   
 
T Cells:  
CD3; CD4; CD8; CD4+CD25+PD1+; CTLA-4 
Follicular Helper T: CD3+,CD4+,CXCR5+,PD1+ 
CD4 and CD8 T naïve (RO-; CCR7+) 
Central Memory: (TCM;RO+,CCR7+) 
Effector Memory (TEM, RO+,CCR7-)  
Terminally differentiated effector memory (TEMRA; RO-, CCR7-) 
T regulatory cells (Treg): CD4+,CD25hi, CD127low, CD39+, CD152hi, RO- (resting); 
CD4+,CD25hi, CD127low, CD39+, CD152hi, RO+ (activated) 
 
Dendritic Cells: 
Lin-, CD11c+, CD1a+, CD80 (B7-1)low, CD86 (B7-2)low, MHC Class IIlow (DC 
resting); CD11c+, CD1a+, CD123-, CD80hi, CD86hi, HLADRhi (DC1 activated); 
HLADRhi, CD11c-, CD123+, PDL-1+ (DC2) 
 
Macrophages: 
HLADR+, CD14+, CD64+, CD25+, CCR7+ (M1); HLADR+, CD14+, CD64-, 
CD206+, CD25-, CCR7-, CD209+, PDL-1+ (M2) 
 
Myeloid derived suppressor cells: 
HLADR-/low, CD11b+, CD14+,CD33+hi,CD34+, CD66b-, PDL-1+ (M-MDSC); 
HLADR-, CD11b+, CD14-,CD33+low,CD34+, CD66b+, PDL-1+ (G-MDSC) 
 
B Cells:  
CD19+, B7-1low, B7-2low, MHC Class IIlow (resting); CD19+, B7-1hi, B7-2hi, MHC 
Class IIhi (activated) 
 
NK cells: 
CD16+, CD3-, CD56+ 
 
NKT Cells: 
CD16+, CD3+, CD56+ 
 
Plasma Cytokine levels: Multiplex 25 Cytokine - Luminex 
GM-CSF, IL-1b, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, 
IL-15, IL-17, TNF alpha; MCP-1, MIP1a, MIP1b, MIG, RANTES, IFN-alpha, IFN-
gamma, IP-10, Eotaxin 
 
• 
To determine the toxicities resulting from administration of the treatments.  
• 
To assess tumor site immune phenotype, T cell repertoire and PD L1/2 expression 
when tissue available for biopsy prior to autologous transplant conditioning and 


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then at time of progression (within 18 months) after autologous transplant 
conditioning. 
 
 
The tertiary objectives are: 
• 
To identify specific intestinal microbial strains associated with improved outcome 
in autologous stem cell transplantation patients treated with combined checkpoint 
inhibitors. The overall microbial composition in stool samples of patients will be 
analyzed at screening, preconditioning (to be collected within 48 hours prior to 
transplant admission), at engraftment (within 72 hours of ANC > 500), and then 
serially, on day 1 of week 1 (to be collected within 48 hours prior to clinic visit) and 
then weeks 4, 7, 12, 18, and 26, End of Treatment and 9, 12, 15 and 18 months 
post-transplant, and at time of relapse, as it occurs. A 16S ribosomal RNA (rRNA) 
miSeq Illumina platform will be used for overall microbial composition and 
quantitative real-time PCR analysis will validate the specific microbial strains 
identified by miSeq. 
 
Phase IIA 
The primary objectives of this study are: 
 
• 
To assess progression-free survival at 18 months after ASCT in patients  in cohorts that 
were  deemed safe in Phase Ib (no more than 3 treatment-related toxicity) and at least 4 
of 7 patients progression free at 18 months in the Phase Ib. 
 
The secondary objectives of this study are: 
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in patients at high 
risk for post-transplant recurrence including patients in the successor expansion cohorts 
following the Phase Ib trial. 
• 
To assess progression-free survival at 12 months after ASCT in patients at high risk for 
post-transplant recurrence including patients with in the successor expansion cohorts 
following the Phase Ib trial. 
• 
Determine the toxicities resulting from administration of the treatments in patients enrolled 
in the successor expansion cohorts following the Phase Ib trial.  
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at screening (at 
time of informed consent), at apheresis (stem cell collection), and then serially the day 1 
of week 1 of combined checkpoint inhibitors and then weeks 4, 7, 12, 18 and 26, End of 
Treatment, and at 9, 12, 15, and 18 months post-transplant and at time of relapse, as it 
occurs.  
 
The tertiary objectives are: 
• 
To identify specific intestinal microbial strains associated with improved outcome in 
autologous stem cell transplantation patients treated with combined checkpoint inhibitors. 
The overall microbial composition in stool samples of patients will be analyzed at 
screening, preconditioning (to be collected within 48 hours prior to transplant admission), 
at engraftment (within 72 hours of ANC > 500), and then serially, on day 1 of week 1 (to 
be collected within 48 hours prior to clinic visit) and then weeks 4, 7, 12, 18, and 26, End 
of Treatment, and 9, 12, 15 and 18 months post-transplant, and at time of relapse, as it 
occurs. 
2.0 BACKGROUND 
2.1 Study Rationale 


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Autologous hematopoietic stem cell transplantation has significantly improved progression free 
survival and overall survival in patients with high risk and recurrent non-Hodgkin’s lymphoma and 
multiple myeloma. Long-term disease free survival without significant persistent or late morbidity 
can be experienced by most patients following autologous hematopoietic stem cell 
transplantation. A subset of these patients, however, continues to experience low (< 50%) 
progression free survival at 18 months following autologous hematopoietic stem cell 
transplantation and remain in need of new approaches1-3. Included are patients with: 
 
• 
De novo diffuse large B cell lymphoma that fails to achieve a PET negative complete 
response to primary rituximab and anthracycline based multi-agent chemotherapy and at 
least maintains stable disease after salvage chemotherapy or present double/triple hit 
features defined by overexpression by standard immunohistochemistry of c-MYC plus 
BCL2 and/or BCL6 or presence of chromosomal translocations as detected by break-apart 
FISH involving IGH/MYC plus IGH/BCL2 and/or IGH/BCL6 and who only received 
standard chemoimmunotherapy with rituximab, cyclophosphamide, vincristine and 
prednisone (R-CHOP) for induction and present at least stable disease after consolidation 
or salvage chemotherapy.  
 
• 
Recurrent high-risk diffuse large B cell lymphoma defined as relapsing within one year of 
completion of rituximab and anthracycline based multi-agent chemotherapy or a sAAIPI 
(second-line age-adjusted International Prognostic Index) intermediate or high at relapse 
or acquisition of double/triple hit features upon relapse (as defined in group A) and at least 
stable disease after salvage chemotherapy.  Patients with an initial diagnosis of low-
grade/indolent non-Hodgkin lymphoma (i.e. follicular, marginal zone) who present relapse 
with histologic transformation to diffuse large B cell lymphoma (confirmed by biopsy) and 
meet the definition for high-risk as presented above, are also eligible. 
 
• 
De novo high-risk T cell lymphoma with at least stable disease after primary therapy.  
 
• 
Recurrent T cell lymphoma with at least stable disease after salvage therapy. 
 
• 
Transplant-naïve high risk multiple myeloma with at least stable disease after most recent 
line of therapy. This cohort has been discontinued due to updated risks provided by the 
FDA. These patients will be followed for safety and correlative studies only. 
 
• 
Recurrent myeloma within 3 years after a single or tandem autologous transplant and at 
least stable disease after salvage therapy. This cohort has been discontinued due to 
updated risks provided by the FDA. These patients will be followed for safety and 
correlative studies only. 
 
Salvage therapy including allogeneic transplantation after progression following autologous 
hematopoietic stem cell transplantation for each of these disease settings results in limited 
(usually <25%) long term disease free survival and is often associated with significant short and 
long term morbidity among survivors4,5. Thus, it is appropriate to evaluate novel approaches to 
reduce progression after autologous hematopoietic stem cell transplantation among patients at 
an increased risk. 
 
Emerging data suggest that a new class of immune based therapy, checkpoint inhibition, is 
capable of altering the natural history of disease recurrence following autologous hematopoietic 
stem cell transplantation among these patients at high risk of recurrence6,7. Monoclonal antibodies 


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directed against check points CTLA-4 and PD-1 have, as single agents and when combined, 
demonstrated significant clinical activity in a broad array of cancer types including melanoma, 
non-small cell lung cancer, renal cell cancer, head and neck cancer, Hodgkin’s disease, non-
Hodgkin’s lymphoma and multiple myeloma6-11. In nearly all clinical settings, combined checkpoint 
inhibition with anti-CTLA-4 and anti-PD-1 has resulted in greater clinical efficacy but at the 
expense of increased incidence of immune related adverse events12.   
 
Anti-CTLA-4 therapy results in enhanced tumor specific neo-antigen presentation, clonal 
expansion and tumor infiltration of tumor specific T effector cells, down regulation of tumor specific 
T regulatory cells and enhanced NK cell function11. Anti-PD-1 therapy maintains T cell effector 
function despite the expression of its ligands, programmed cell death ligand (PD-L)-1 (B7-
H1/CD274) and PD-L2 (B7-DC/CD273) on malignant cells. When combined, the two checkpoint 
inhibitors lead to a greater number of persistent activated effectors at disease sites explaining the 
enhanced clinical efficacy8. 
 
The immediate post-autologous transplant period before recurrence provides an ideal window to 
introduce combined checkpoint inhibitors because disease burden is at a minimum and residual 
disease may be more immune responsive to checkpoint inhibition due to conditioning-induced 
apoptosis and inflammation. Moreover, anti-tumor immune reconstitution has been shown to be 
enhanced by combined checkpoint inhibition, due to the skewing of reconstituting NK cells and 
effector T cells towards an anti-tumor immune phenotype and away from tolerance13. 
 
Recent experience in non-small cell lung cancer demonstrated that a dosing schedule of anti-
CTLA-4 at 1mg/kg and anti-PD1 therapy at 3mg/kg can be combined with seemingly acceptable 
toxicity and similar efficacy to higher and more frequent anti CTLA-4 dosing schedules14. 
 
Our goal is to determine the safety and clinical effect of combined checkpoint inhibition 
administered after autologous hematopoietic stem cell transplantation in each of six clinical 
cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of 
adverse events and rates of complete response and progression free survival, we intend to 
monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the 
time of disease progression. We will also analyze the gut microbiome prior to conditioning, 
throughout treatment, post-transplant and at time of relapse. The rationale for studying the gut 
microbiome is based on earlier studies demonstrating that reduced diversity of intestinal 
microbiota leads to poor outcome post-allogeneic hematopoietic stem cell15 and specific intestinal 
bacterial species have been shown to boost responses to chemotherapy16,17 and checkpoint 
inhibitors18,19 .When available, tumor site immune phenotype, TCR repertoire and PD-L1 and PD-
L2 expression prior to autologous transplant conditioning and then at time of progression (within 
18 months) after autologous transplant conditioning will be assessed. We intend to expand 
cohorts that demonstrate safety and PFS >50% at 18 months into a phase IIB successor trial. 
2.2 Rationale for Checkpoint Inhibition                                                     
Programmed Cell Death-1 (PD-1)                                                                    
 
PD-1 (CD279) is an inhibitory cell surface receptor on activated T cells that limits T cell activation 
and induces peripheral T cell tolerance. PD-1, a member of the CD28 family of T-cell costimulatory 
receptors, including CTLA-4, ICOS, and BTLA, is primarily expressed on activated T cells, B cells, 
natural killer cells and myeloid cells. The cytoplasmic tail of PD-1 contains two intracellular 
signaling motifs, a proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a distal 
immunoreceptor tyrosine-based switch motif (ITSM). Binding to PD-L1 (B7-H1/CD274) or PD-L2 


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(B7-DC/CD273) triggers the phosphorylation of ITIM and ITSM which in turn recruits the 
phosphatase SHP-2 that subsequently dephosphorylates TCR signaling, leading to the overall 
inhibition of T cell activation and effector function20,21,22. 
 
The negative regulatory role of PD-1 was demonstrated using PD-1-deficient mice. PD-1-deficient 
mice develop various autoimmune phenotypes, including dilated cardiomyopathy and a lupus-like 
syndrome with arthritis and nephritis. The emergence of these autoimmune phenotypes is 
dependent upon the genetic background of the mouse strain; many of these phenotypes emerge 
at different times and show variable penetrance. In addition to the phenotypes of null mutations, 
PD-1 inhibition by antibody-mediated blockade in several murine models has been found to play 
a role in the development of autoimmune diseases such as encephalomyelitis, graft-versus-host 
disease, and type I diabetes23. Taken together, these results suggest that PD-1 blockade has the 
potential to activate anti-self T-cell responses, but these responses are variable and dependent 
upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self-antigens. Preclinical animal models of tumors have shown that 
blockade of PD-1 by monoclonal antibodies (mAb) can enhance the anti-tumor immune response 
and result in tumor rejection. This suggests that host mechanisms limit the antitumor response24. 
 
In humans, PD-L1 is constitutively expressed on both hematopoietic cells such as macrophages 
and T cells as well as non-hematopoietic cells such as lung, vascular endothelial cells, and 
placental syncitiotrophoblasts. Aberrant expression of PD-L1 in tumor cells has been shown to 
enhance apoptosis of activated tumor-specific T cells in vitro. Additionally, the expression of PD-
L1 may protect tumor cells from T cell-induced apoptosis.  Retrospective analyses of several 
human tumor types suggest that over-expression of PD-L1 facilitates tumor evasion of immune 
surveillance24. In renal cell carcinoma, high surface expression levels of PD-L1 are correlated with 
tumor aggressiveness. Subjects with high tumor and/or lymphocyte PD-L1 levels are 4.5 times 
more likely to die from their cancer than subjects exhibiting low levels of PD-L1 expression25. In 
multivariate analysis, high expression of PD-L1 in melanoma is an independent predictor of 
vertical growth of primary melanomas and of worse outcome26. 
 
Nivolumab is a fully human, IgG4 (kappa) isotype, mAb that binds to PD-1. Blockade of the PD-1 
pathway by nivolumab resulted in a reproducible enhancement of T cell proliferation in a mixed 
lymphocyte reaction (MLR) assay. The effect of nivolumab on an antigen-specific recall response 
was investigated using a CMV-restimulation assay with human peripheral blood mononuclear 
cells (PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, versus an 
isotype-matched control antibody, augmented IFN-γ secretion from CMV-specific memory T cells 
in a dose dependent manner27. 
 
The clinical activity of nivolumab was demonstrated in a variety of tumors, including melanoma 
(MEL), renal cell cancer (RCC), non-small cell lung cancer (NSCLC), and colorectal cancer 
(CRC). Clinical activity was noted across a range of doses (1 mg/kg, 3 mg/kg, 10 mg/kg) and 
across dosing schedules. Complete response (CR) or PR has been reported at all dose levels (1, 
3, and 10 mg/kg) and in multiple tumor types (melanoma, RCC, and NSCLC). The preliminary 
objective response rates were 5/20 (25.0%), 7/17 (41.2%), and 4/19 (21.1%) for MEL subjects 
treated at 1, 3, and 10 mg/kg respectively. Response data is only available for subjects with RCC 
and NSCLC treated at the 10 mg/kg dose level. The preliminary objective response rates were 
4/19 (21.1%) for NSCLC and 6/18 (33.3%) for RCC. The preliminary median duration of response 
among MEL responders at 1, 3, and 10 mg/kg were 72.3, 40.6, and 73.0 weeks respectively. The 
median duration of response among NSCLC and RCC subjects was 29.1 and 56.3 weeks, 
respectively27-29. 
 


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Cytotoxic T lymphocyte antigen 4 (CTLA-4) 
 
Lymphocyte homeostasis is regulated by the differential effects of cytokines and an array of cell 
surface signaling molecules that affect T cell proliferation. One of the primary molecules 
responsible for T cell expansion in response to antigenic stimulation is CD28. The interaction of 
CD28 on the T cell, with CD80 (B7.1) or CD86 (B7.2) on the antigen presenting cell, stimulates T 
cell proliferation and survival. By necessity, a mechanism for elimination of antigen stimulated T 
cells is required following control of the antigenic challenge to maintain the viability of the host13. 
One important regulator of T cell contraction following antigen stimulation is cytotoxic T 
lymphocyte antigen 4 (CTLA-4)30. CTLA-4 expression on T cells is increased following antigen 
stimulation and has a significantly higher affinity for both B7 ligands than CD28. Upon control of 
an antigenic challenge, CTLA-4 preferentially interacts with the antigen presenting cell to inhibit 
continuous proliferation of T cells and helps to contract the T cell population. The fact that CTLA-
4 knockout mice have lethal systemic immune hyper-activation demonstrates the important role 
of CLTA-4 in down-regulating the amplitude of T-cell activation. 
 
Ipilimumab is a fully humanized mAb that binds to CTLA-4 and inhibits its interaction with ligands 
on antigen presenting cells11. Ipilimumab has been approved for use in over 40 countries including 
the United States in March 2011 and the European Union in July 2011. The safety profile is 
detailed below. In brief, over 12,700 subjects have received ipilimumab and the most common 
adverse events (AEs) were inflammatory in nature, consistent with ipilimumab’s mechanism of 
action, and were generally medically manageable with topical or systemic immunosuppressants. 
 
Clinical trials with ipilimumab have shown activity in a broad range of tumors, including 
hematologic malignancies. In one phase 1 trial, two of 18 patients with B cell lymphoma had a 
clinical response: one complete response at > 31 months in a patient with diffuse large B cell 
lymphoma and one partial response lasting 19 months in a patient with follicular lymphoma31. In 
another phase 1 trial, three of 27 patients with hematologic malignancies who recurred or 
progressed after allogeneic hematopoietic cell transplantation had objective responses: two 
complete responses in patients with Hodgkin lymphoma and one partial response in a patient with 
mantle cell lymphoma32. 
 
The rationale to pursue therapy with the combination of nivolumab and ipilimumab is based on 
studies using mouse models. In the MC38 colon carcinoma model, tumor-bearing mice treated 
with either anti-PD-1 or anti-CTLA-4 mAb alone had occasional complete regression of tumor. In 
contrast, most mice treated with both nivolumab and ipilimumab had complete regression of 
tumor33. 
 
A clinical trial testing the concurrent combination of nivolumab and ipilimumab resulted in even 
greater objective response rates than those seen with either agent alone in patients with 
advanced melanoma34. A total of 53 patients received concurrent therapy resulting in an objective 
response rate of 40%. Evidence of clinical activity (conventional, unconfirmed, or immune related 
response or stable disease for > 24 weeks) was observed in 65% of patients. At the maximum 
doses that were associated with an acceptable level of adverse events, 53% of patients had an 
objective response, all with tumor reduction of 80% or more. Treatment related adverse events 
were observed in 93% of subjects, with the most common events being rash (55%), pruritus 
(47%), fatigue (38%), and diarrhea (34%). Grade 3 or grade 4 treatment related events were 
noted in 53% of subjects, with the most common events being elevated levels of lipase (13%), 
aspartate aminotransferase increased (13%) and alanine aminotransferase increased (11%). Six 
of 28 subjects (21%) had grade 3 or grade 4 treatment related events that were dose-limiting. 
Eleven subjects (21%) discontinued therapy due to treatment related adverse events. The doses 


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of nivolumab at 3 mg/kg and ipilimumab at 3 mg/kg exceeded the maximum tolerated dose due 
to the occurrence of asymptomatic grade 3 or grade 4 elevated levels of lipase that persisted for 
> three weeks in three of six subjects. Doses of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg 
(n=17 subjects), in addition to nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg (n=16 subjects) 
were both tolerated. Additional clinical experience with over 900 subjects has shown that both 
combination regimens are tolerated in subjects with solid tumors10. 
2.3 Current evidence for checkpoint inhibition after autologous hematopoietic stem cell 
transplantation 
PD-1 blockade post autologous hematopoietic stem cell transplantation (ASCT) has been 
previously studied in a trial which evaluated 66 patients who had undergone ASCT for relapsed 
DLBCL (diffuse large B-cell lymphoma) and who presented with at least stable disease (SD) 
following transplantation, as compared to their pre-transplant disease status6. Patients received 
three doses of pidilizumab, a mAb targeted to PD-1, starting 1 to 3 months following 
transplantation. Primary endpoint was improvement in PFS at 16 months following the first dose 
of pidilizumab. The 16-month PFS for the whole cohort was 72% and the overall survival (OS) at 
16 months was 85%. Toxicities were mild, and the most frequent grade 3 and 4 adverse events 
(AEs) were neutropenia (19%) and thrombocytopenia (8%). Correlative studies showed that 
treatment with pidilizumab resulted in a significant increase in the absolute number of PD-L1 
bearing activated helper T cells (CD4+,CD25+,PD-L1+), apparent 24 hours after first treatment 
and sustained until at least 16 weeks as well as PD-1 ligand monocytes (CD14+, PD-L1+ and 
CD14+, PD-L2+ cells). 
 
To date, there have not been any clinical studies examining the effects of combined checkpoint 
inhibition with anti-CTLA-4 and anti-PD1 mAb in patients following autologous stem cell 
transplantation.  
3.0 BACKGROUND DRUG INFORMATION  
3.1 Nivolumab 
Full background drug information and description can be found in the Nivolumab Investigator’s 
Brochure (V14 dated 30JUN2015).  
3.1.1 Description  
Nivolumab is a fully humanized IgG4 mAb which binds to PD-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 selectively to human PD-1 and does not bind to other members of the CD28 
family. 
3.1.2 Mechanism of action 
Binding of PD-L1 and PD-L2, to the PD-1 on T cells, inhibits T-cell proliferation and cytokine 
production. Upregulation of PD-1 ligands occur in some tumors and signaling through this 
pathway contributes to tumor evasion of active T-cell immune surveillance. Nivolumab is a human 
immunoglobulin G4 (IgG4) mAb that binds to the PD-1 receptor and blocks its interaction with PD-
L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including 


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theanti-tumorimmuneresponse27.  
 
Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction 
(MLR). PD-1 blockade resulted in a reproducible enhancement of both proliferation and IFN-γ 
release in the MLR. The effect of nivolumab on antigen-specific recall response was investigated 
using a CMV-restimulation assay with human peripheral blood mononuclear cells (PBMCs), and 
was evaluated by ELISA. These data indicated that nivolumab, versus an isotype-matched control 
antibody, augmented IFN-γ secretion from CMV-specific memory T cells in a dose-dependent 
manner. 
 
In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in 
enhanced T-cell function that is greater than the effects of either antibody alone, and results in 
improved anti-tumor responses in metastatic melanoma.  
3.1.3 Pharmacokinetics 
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-
agent and in combination with ipilimumab. Nivolumab as a single agent: The PK of single-agent 
nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single 
dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric mean (% coefficient 
of variation [CV%]) clearance (CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at 
steady state (Vss) is 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) is 26.7 days 
(101%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered 
at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3-fold. The exposure 
to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered 
every 2 weeks. Nivolumab in combination with ipilimumab: The geometric mean (CV%) CL, Vss, 
and terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days 
(94.3%), respectively. When administered in combination, the CL of nivolumab was increased by 
24%, whereas there was no effect on the clearance of ipilimumab. When administered in 
combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab 
antibodies. There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab.  
 
Specific Populations: Based on a population PK analysis, the clearance of nivolumab increased 
with increasing body weight supporting a weight-based dose. The population PK analysis 
suggested that the following factors had no clinically important effect on the clearance of 
nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, tumor type, 
tumor size, renal impairment, and mild hepatic impairment.  
 
Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated 
by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2 ; n=313), 
moderate (eGFR 30 to 59 mL/min/1.73 m2 ; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; 
n=3) renal impairment. No clinically important differences in the clearance of nivolumab were 
found between patients with renal impairment and patients with normal renal function.  
 
Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was 
evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] 
less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 
to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of 
nivolumab were found between patients with mild hepatic impairment and patients with normal 
hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 


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to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and 
any AST). 
3.1.4 Non-clinical toxicology 
No studies have been performed to assess the potential of nivolumab for carcinogenicity or 
genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month 
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female 
reproductive organs; however, most animals in these studies were not sexually mature.  
 
In animal models, inhibition of PD-1 signaling increased the severity of some infections and 
enhanced inflammatory responses. Inhibition of PD-1 signaling increased the severity of some 
infections and enhanced inflammatory responses. PD-1 knockout mice have also shown 
decreased survival following infection with lymphocytic choriomeningitis virus. 
3.1.5 Adverse Events 
The overall safety experience with nivolumab, as monotherapy or in combination with other 
therapeutics, is based on experience in approximately 1,500 subjects treated to date. For 
monotherapy, the safety profile is similar across tumor types. The one exception is pulmonary 
inflammation AEs (adverse events) which may be numerically greater in subjects with non-small 
cell lung cancer because in some cases it can be difficult to distinguish between nivolumab related 
and unrelated causes of pulmonary symptoms and radiographic changes. There was no pattern 
in the incidence, severity, or causality of AEs to nivolumab dose level. 
 
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics and targeted therapies is being 
explored. Most studies are ongoing and as such, the safety profile of nivolumab combinations 
continues to evolve. The most advanced combination under development is nivolumab and 
ipilimumab in subjects with melanoma. Thus far, the combination of both agents results in a safety 
profile with similar types of AEs as either agent alone, but in some cases with greater frequency. 
 
Overall, the safety profile of nivolumab monotherapy as well as combination therapy is 
manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested, up to 10 mg/kg. There was no pattern in the incidence, severity, or 
causality of AEs to nivolumab dose level. Most AEs were low grade (grade 1 to grade 2) with 
relatively few related high grade (grade 3 to grade 4) AEs. Most high grade events were 
manageable with the use of corticosteroids or hormone replacement therapy for 
endocrinopathies.  
 
Nivolumab should not be used in subjects with active autoimmune disease given the mechanism 
of action of the antibody. 
 
The adverse events for nivolumab are mostly immune-mediated. 
 
Immune-Mediated Pneumonitis: Immune-mediated pneumonitis or interstitial lung disease, 
defined as requiring use of corticosteroids and no clear alternate etiology, including fatal cases, 
occurred with nivolumab treatment. Across clinical trial experience with solid tumors receiving 
nivolumab as a single agent, fatal immune-mediated pneumonitis occurred in 0.3% (5/1590) of 
patients. All five fatal cases occurred in a dose-finding study with nivolumab doses of 1 mg/kg 


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(two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). Across the clinical trial 
experience in 188 patients with melanoma who received nivolumab in combination with 
ipilimumab, fatal immune-mediated pneumonitis occurred in 0.5% (1/188) of patients.  
 
Immune-Mediated Colitis: Immune-mediated colitis, defined as requiring use of corticosteroids 
with no clear alternate etiology, can occur with nivolumab treatment. Across trials of nivolumab 
as single agent, the incidence of immune-mediated colitis was 25-28% in trials where nivolumab 
was used in combination with ipilimumab, the incidence of immune-mediated colitis was 33%. 
 
Immune-Mediated Hepatitis: Immune-mediated hepatitis, defined as requiring use of 
corticosteroids and no clear alternate etiology, can occur with nivolumab treatment. In trials of 
nivolumab as single agent, the incidence of auto-immune hepatitis was 0.9-1.1%.  
 
Immune-mediated endocrinopathies: Immune-mediated endocrinopathies, such as hypophysitis, 
adrenal insufficiency, hypothyroidism, hyperthyroidism and diabetes mellitus type 1 can occur 
with nivolumab treatment. In trials using nivolumab as single agent, immune-mediated 
endocrinopathies occurred in up to 8% of subjects, whereas in combination with ipilimumab it 
occurred in up to 19% of subjects. 
 
Immune-Mediated Nephritis: Immune-mediated nephritis, defined as renal dysfunction occurred 
in up to 19% of subjects. In trials where nivolumab was used as single agent, the incidence of 
immune-mediated nephritis was as high as 0.7%. When used in combination with ipilimumab, the 
incidence was up to 2.1%. 
 
Immune-Mediated Rash: In clinical trials using nivolumab as single agent, immune-mediated rash 
was seen in up to 28% of patients. In trials using nivolumab in combination with ipilimumab, the 
incidence was up to 37%. 
 
Immune-mediated encephalitis: Across clinical studies of 8490 patients receiving nivolumab as a 
single agent or in combination with ipilimumab, less than 1.0% of patients were identified as 
having encephalitis. 
 
Other immune-mediated adverse reactions: The following clinically significant, immune-mediated 
adverse reactions occurred in less than 1.0% of patients receiving nivolumab as a single agent 
or in combination with ipilimumab: uveitis, pancreatitis, facial and abducens nerve paresis, 
demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barre syndrome, 
hypopituitarism, and systemic inflammatory response syndrome. 
3.2 Ipilimumab  
Full background drug information and description please reference Ipilimumab Investigator’s 
Brochure (V18 dated 10MAR2015). 
3.2.1 Description 
Ipilimumab is a recombinant, human mAb that binds to the cytotoxic T-lymphocyte-associated 
antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular 
weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.  
3.2.2 Mechanism of action 


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CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a mAb that binds to CTLA-4 and 
blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been 
shown to augment T-cell activation and proliferation, including the activation and proliferation of 
tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell 
function, which may contribute to a general increase in T cell responsiveness, including the anti-
tumor immune response9. 
3.2.3 Pharmacokinetics 
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or 
metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. 
The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following administration of 
ipilimumab every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state 
concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady state was 
19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent 
coefficient of variation) based on population PK analysis for the terminal half-life (t1/2) was 15.4 
days (34%) and for clearance (CL) was 16.8 mL/h (38%). 
 
The effects of various covariates on the PK of ipilimumab were assessed in population PK 
analyses. The CL 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 CL 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.  
3.2.4 Non-clinical toxicology 
The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies, and 
the genotoxic potential of ipilimumab has not been evaluated. Fertility studies have not been 
performed with ipilimumab. 
3.2.5 Adverse events 
More than 12,700 subjects with several cancer types have received ipilimumab in completed and 
ongoing studies, as well as a compassionate use program. The focus of the clinical program is in 
melanoma, prostate cancer, and lung cancer, with advanced melanoma being the most 
comprehensively studied indication. Ipilimumab is being investigated both as monotherapy and in 
combination with other modalities such as chemotherapy, radiation therapy, and other 
immunotherapies. Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer.  
 
The unique immune based mechanism of action is also reflected in the safety profile. The most 
common treatment related adverse events (AEs) are inflammatory in nature, consistent with the 
mechanism of action of ipilimumab, and generally medically manageable with topical or systemic 
immunosuppressants. Such immunological safety events are described as immune-related AEs 
(irAEs). The irAEs are described as AEs of unknown etiology that were consistent with an immune 
phenomenon, and were considered causally related to drug exposure by investigators. The irAEs 
primarily involve the gastrointestinal tract and the skin. Immune-related AEs in the liver were also 
observed, particularly in subjects receiving 10 mg/kg. Endocrinopathy and neuropathy were 
important irAEs observed less frequently. 


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4.0 PATIENT ELIGIBILITY  
4.1 Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must meet the following inclusion 
criteria: 
 
1. Voluntary signed and dated IRB/IEC approved written informed consent form in 
accordance with regulatory and local guidelines.  
2. Be 18 years or older and 80 years or younger on the day of signing consent 
3. Have a confirmed diagnosis of:  
 
o (GROUP A) De novo diffuse large B cell lymphoma that fails to achieve a PET 
negative complete response to primary rituximab and anthracycline based multi-
agent chemotherapy and at least maintains stable disease after salvage 
chemotherapy or present double/triple hit features defined by overexpression by 
standard immunohistochemistry of c-MYC plus BCL2 and/or BCL6 or presence of 
chromosomal translocations as detected by break-apart FISH involving IGH/MYC 
plus 
IGH/BCL2 
and/or 
IGH/BCL6 
and 
who 
only 
received 
standard 
chemoimmunotherapy with rituximab, cyclophosphamide, vincristine and 
prednisone (R-CHOP) for induction and present at least stable disease after 
consolidation or salvage chemotherapy. Stable disease (SD) for lymphoma is 
defined in Appendix B: Lugano Classification for Response Assessment of Non-
Hodgkin Lymphoma. 
 
o (GROUP B) Recurrent high-risk diffuse large B cell lymphoma defined as relapsing 
within one year of completion of rituximab and anthracycline based multi-agent 
chemotherapy or a sAAIPI (second-line age-adjusted International Prognostic 
Index) intermediate or high at relapse or acquisition of double/triple hit features 
upon relapse (as defined in group A) and at least stable disease after salvage 
chemotherapy.  Patients with an initial diagnosis of low-grade/indolent non-
Hodgkin lymphoma (i.e. follicular, marginal zone) who present relapse with 
histologic transformation to diffuse large B cell lymphoma (confirmed by biopsy) 
and meet the definition for high-risk as presented above, are also eligible. 
 
o (GROUP C) De novo high-risk T cell lymphoma with at least stable disease after 
primary therapy. High risk T cell lymphoma is defined as Stage III or IV disease at 
presentation and/or failure to achieve CR after frontline chemotherapy. Patients 
with ALK-positive ALCL will be excluded from the trial. Patients with ALK-negative 
ALCL in complete response will be excluded from the trial. 
 
o (GROUP D) Recurrent T cell lymphoma with at least stable disease after salvage 
therapy. Patients with ALK-positive ALCL will be excluded from the trial. 
 
4. Be deemed eligible for an autologous stem cell transplantation according to the  
institutional guidelines of the Blood and Marrow Transplantation Program at John Theurer 
Cancer Center at Hackensack University Medical Center 
5. Have an ECOG performance status of 2 or lower  
6. Women of childbearing potential (WOCBP) must use appropriate method(s) of 
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks 


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(30 days plus the time required for nivolumab to undergo five half-lives) after the last dose 
of investigational drug.   
7. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of nivolumab. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. Female subjects of childbearing 
potential should agree to ongoing pregnancy testing, to be performed prior to each dosing 
of ipilimumab and nivolumab. See Note below for definition of WOCBP. 
8. Women must not be breastfeeding. 
9. Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Men receiving nivolumab, and who are sexually active 
with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after 
the last dose of investigational product, even if they have had a vasectomy. Women who 
are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well 
as azoospermic men do not require contraception). See Note below for definition of 
WOCBP. 
10. Females of childbearing potential must be willing to use two methods of birth control or be 
surgically sterile, or abstain from heterosexual activity for the course of the study through 
120 days after the last dose of study medication. Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free from menses for > 2 
years. See Note below for definition of WOCBP. 
11. Allowable transplant preparative regimens are the following: 
o For non-Hodgkin lymphoma groups (A, B,C,D) BEAM: carmustine 300 mg/m2 day 
-6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 
mg/m2 day -1 
o For Myeloma groups (E and F) Melphalan 200 mg/m2 day -1 
 
NOTE: Women of childbearing potential is defined as any female who has experienced menarche 
and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who 
is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman 
over 45 in the absence of other biological or physiological causes. In addition, women under the 
age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 
mIU/mL.  
 
Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to 
contraception for a period of 23 weeks after the last dose of investigational product. Men receiving 
nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception 
for a period of 31 weeks after the last dose of investigational product. These durations have been 
calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the 
protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who 
are sexually active with WOCBP use contraception for 5 half-lives plus 90 days. 
4.2 Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject meets ANY of the 
following exclusion criteria: 
 
1. 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to baseline), 


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have no evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to trial treatment. There must also be no requirement for 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone 
equivalents) for at least 2 weeks prior to study drug administration. This exception does 
not include carcinomatous meningitis, which is excluded regardless of clinical stability.   
Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement 
doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone 
equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
2. 
Is unable or unwilling to sign informed consent. 
3. 
Has an active, known, or suspected autoimmune disease. Subjects are permitted to enroll 
if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring systemic treatment, 
or conditions not expected to recur in the absence of an external trigger 
4. 
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled or topical steroids and 
adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. Note: Subjects are permitted to use topical, 
ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic 
absorption). Physiologic replacement doses of systemic corticosteroids are permitted, 
even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
5. 
As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab 
combinations, drugs with a predisposition to hepatoxicity should be used with caution in 
patients treated with nivolumab-containing regimen. 
6. 
Has received an allogeneic stem cell transplant. 
7. 
Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients, or 
severe hypersensitivity reaction to any previous monoclonal antibody.  
8. 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 of 
checkpoint inhibitor treatment administration or who has not recovered (i.e., t 
administration mAb) within 4 weeks prior to t dose of trial treatment. Rituximab within that 
period is allowed.  
9. 
Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, 
and inhalational corticosteroids (with minimal systemic absorption). Physiologic 
replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day 
prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye 
allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted. 
10. 
Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. 
Has an active infection requiring intravenous systemic therapy. 
12. 
Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 


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duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
13. 
Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
14. 
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 23 
weeks for females and 31 weeks for males after the last dose of trial treatment. 
15. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or 
immune checkpoint pathways. 
16. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or 
known acquired immunodeficiency syndrome (AIDS). 
17. 
Has positive test for Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected) indicating acute or chronic infection, as tested for transplant. 
18. 
Has received a live vaccine within 30 days of planned start of study therapy. 
 
NOTE: Patients who received steroids for engraftment syndrome may initiate treatment with 
ipilimumab and nivolumab once steroids have been tapered off and diarrhea and/or rash are 
grade I or better, without the need for a steroid washout period. Initial dosing may be delayed up 
to day 28 post-transplantation to allow for completion of steroid taper. 
 
5.0 TREATMENT PLAN 
5.1 Product Information  
5.1.1 Drug Ordering and Accountability 
Bristol-Meyers Squibb is supplying study drug. Please see Appendix H for information on 
provisions for ordering study drug from BMS. It is possible that sites may have more than one 
clinical study on the same drug ongoing at the same time. It is imperative that only drug product 
designated for this protocol be used for this study. The investigator is responsible for ensuring 
that the investigational product is stored under the appropriate environmental conditions 
(temperature, light, and humidity). If concerns regarding the quality or appearance of the 
investigational product arise, do not dispense the investigational product, and contact BMS 
immediately.  
 
It is the investigator’s responsibility to ensure that arrangements have been made for drug 
destruction, including the disposal, and that procedure for proper disposal have been established 
according to applicable regulations, guidelines, and institutional procedures. 
5.1.2 Product Description and Dosage Form 
Please provide information on the product as shown in the sample table below: 
Product 
Description & 
Dosage Form 
Potency  
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging (Qty)/ 
Label Type 
Appearance 
Storage 
Conditions 
(per label)  
Nivolumab 
BMS-936558-
01 Solution for 
Injectiona 
100 
mg 
(10 
mg/mL) 
10 mL vial 
5 or 10 vials per 
carton/ Open-label 
Clear 
to 
opalescent 
colorless 
to 
pale 
yellow 
2 
to 
8oC. 
Protect 
from 
light 
and 
freezing 


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liquid. 
May 
contain 
particles 
Ipilimumab 
Solution 
for 
Injection 
200 mg (5 
mg/mL) 
40 mL vial 
4 
vials 
per 
carton/Open-label 
Clear, 
colorless 
to 
pale 
yellow 
liquid. 
May 
contain 
particles 
2 
to 
8°C. 
Protect 
from 
light 
and 
freezing. 
aNivolumab may be  labeled as BMS-936558-01 or Nivolumab Solution for Injection 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab and ipilimumab include laboratory coats and 
gloves. For additional details on prepared drug storage and use time of nivolumab or ipilimumab 
under room temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) and 
Ipilimuab Investigator Brochure section for “Recommended Storage and Use Conditions.” 
5.2 Treatment Schema  
• 
Patients must sign informed consent and be registered.   
• 
Informed consent should be signed within 60 days prior to beginning of ASCT conditioning. 
Subject recruitment and informed consent will take place in the BMT Service at 
HackensackUMC and in the BMT service at Georgetown University. Patients who already 
had stem cell mobilization and collection will also be allowed to sign informed consent and 
be enrolled in the trial.  
• 
The first administration of study therapy will be administered in the BMT Service.  
• 
14 to 21 days after stem cell infusion, if ANC>800 (off growth factors for at least 3 days) 
and Platelets>20,000 without transfusion, ipilimumab and nivolumab should be started. 
• 
Delay initiation of post ASCT therapy until ANC>800 (off growth factors for at least 3 days) 
and Platelets>20,000 without transfusion up to 28 days after stem cell infusion. 
• 
Post ASCT therapy may be delayed up to 28 days after stem cell infusion if deemed 
appropriate by the investigator. 
• 
The first day of ipilimumab/nivolumab infusion will be considered Day 1 of Week 1. Prior 
to patient’s drug administration on Day 1 of Week 1, all patients must be re-assessed to 
confirm eligibility.  
• 
Laboratory assessments must be evaluated within 72 hours prior to re-dosing 
• 
All visits will be given a +/- 2-day window.  
• 
At screening visit and each subsequent visit, the patient should be given a stool collection 
kit. 
 
Group A 
De novo diffuse large B cell lymphoma that fails to achieve a PET negative 
complete response to primary rituximab and anthracycline based multi-
agent chemotherapy and at least maintains stable disease after salvage 
chemotherapy 
or 
present 
double/triple 
hit 
features 
defined 
by 
overexpression by standard immunohistochemistry of c-MYC plus BCL2 
and/or BCL6 or presence of chromosomal translocations as detected by 
break-apart FISH involving IGH/MYC plus IGH/BCL2 and/or IGH/BCL6 and 
who only received standard chemoimmunotherapy with rituximab, 
cyclophosphamide, vincristine and prednisone (R-CHOP) for induction and 
present at least stable disease after consolidation or salvage 
chemotherapy. 


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Group B 
Recurrent high-risk diffuse large B cell lymphoma defined as relapsing 
within one year of completion of rituximab and anthracycline based multi-
agent chemotherapy or a sAAIPI (second-line age-adjusted International 
Prognostic Index) intermediate or high at relapse or acquisition of 
double/triple hit features upon relapse (as defined in group A) and at least 
stable disease after salvage chemotherapy.  Patients with an initial 
diagnosis of low-grade/indolent non-Hodgkin lymphoma (i.e. follicular, 
marginal zone) who present relapse with histologic transformation to diffuse 
large B cell lymphoma (confirmed by biopsy) and meet the definition for 
high-risk as presented above, are also eligible. 
Group C 
De novo high-risk T cell lymphoma with at least stable disease after primary 
therapy. Patients with ALK-positive ALCL will be excluded from the trial. 
Patients with ALK-negative ALCL in complete response will be excluded 
from the trial. 
Group D 
Recurrent T cell lymphoma with at least stable disease after salvage 
therapy. Patients with ALK-positive ALCL will be excluded from the trial.  
5.3 Administration  
Nivolumab 3 mg/kg for 12 doses, on day 1 of weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26 
Ipilimumab 1 mg/kg for 6 doses, on day 1 of weeks 1, 4, 7, 10, 16, 22 
 
 
Nivolumab is to be administered as a 60-minute IV infusion, using a volumetric pump with a 
0.2/1.2 micron pore size, low-protein binding polyethersulfone membrane in-line filter at the 
protocol-specified dose. The drug can be diluted with 0.9% normal saline for delivery but the total 
drug concentration of the solution cannot be below 1 mg/mL. It is not to be administered as an IV 
push or bolus injection. At the end of the infusion, flush the line with a sufficient quantity of normal 
saline.  
 
Ipilimumab is to be administered as a 90-minute IV infusion, using a volumetric pump with a 
0.2/1.2 micron low-protein binding in-line filter. Ipilimumab is given undiluted or further diluted in 
0.9% NaCl Injection, USP or 5% Dextrose Injection, USP in concentrations between 1 mg/mL and 
4 mg/mL.  
 
The dosing calculations should be based on the actual screening body weight. If the subject’s 
weight on the day of dosing differs by > 10% from the weight used to calculate the dose, the dose 
must be recalculated. All doses should be rounded up or to the nearest milligram per institutional 
standard. There will be no dose modifications allowed.  
 
When infusions of ipilimumab and nivolumab are given on the same day, the preferred treatment 
is to give nivolumab followed by ipilimumab. Separate infusion bags and filters must be used for 
each infusion. 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 approximately 30 minutes after completion of the nivolumab infusion. 
 
Patients may be dosed 2 days prior or up to 2 days after the scheduled date, if necessary. The 
original scheduled date should be adhered to throughout the protocol.  
 
Toxicity management for the combined agents follows the same template guidelines and 
algorithms for single agent nivolumab. 


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5.4 Dose Modifications  
There will be no dose modifications permitted for study drug, with the exception of changes due 
to fluctuation in weight. Dose reductions or dose escalations are not permitted. 
5.5 Premedication  
Only needs to be given for transfusion reactions (See Appendix G for Transfusion Reactions) 
5.6 Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab and ipilimumab are 
considered immuno-oncology agents in this protocol. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of adverse 
events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological.  
 
Early recognition and intervention are recommended according to the management algorithms; 
and in addition include ophthalmologic evaluations for any visual symptoms in order to evaluate 
for nivolumab or ipilimumab related uveitis. 
 
The recommendations are to follow the algorithms in the nivolumab investigator brochure for 
immune related events; while the ipilimumab investigator brochure contains similar algorithms, 
the algorithms in the nivolumab brochure have been aligned to accommodate combinations as 
well as nivolumab monotherapy. Therefore, the algorithms recommended for utilization are in 
Appendix G for reference. 
 
For subjects expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following recommendations  
• 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections. 
• 
Early consultation with an infectious disease specialist should be considered. Depending 
on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 
• 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis. 
 
Additional details on the safety of nivolumab and ipilimumab, including results from clinical 
studies, are available in the IB. 
5.7 Dose Delay Criteria 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab, ipilimumab or both). All study drugs must be delayed until 
treatment can resume. In the case that a treatment cannot be administered at a scheduled visit 
(with +/-2 day window), proceed to the next scheduled dose.   
 
Nivolumab and ipilimumab administration should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 


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o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
• 
Any Grade 3 skin, drug-related adverse event 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin: 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is 
recommended to consult with the principle investigator for Grade 3 amylase or 
lipase abnormalities. 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥  2 toxicity 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥  3 toxicity 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the investigator, warrants delaying the dose of study medication. 
5.8 Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue  
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity  
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 5.9) should have treatment permanently discontinued 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the next scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed until dosing resumes.  
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation Section 5.9. 
 
Peripheral blood and stool sample collection will continue to take place for subjects discontinued 
from the study up to 18 months post ASCT and/or relapse, if it occurs.  
5.9 Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment  


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09NOV2021                                                        Page 31 of 77 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion 
reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or non-hematological laboratory abnormality, 
except for the following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate 
management within 72 hours of their onset 
• 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab or ipilimumab dosing 
• 
Any patient that meets disease-specific criteria for relapse or progressive disease should 
be discontinued from study therapy.  
 
Peripheral blood and stool sample collection will continue to take place for subjects discontinued 
from the study up to 18 months post ASCT and/or at relapse, if it occurs.  
6.0 SUBJECT SCREENING EVALUATION  
6.1 Evaluation of the patient after informed consent is signed. Any of the evaluations listed below 
will be accepted if performed prior to signing consent if done within the described timeframe, 
without need for repeating procedures.  
• 
History and physical examination within 30 days prior to start of ASCT conditioning regimen. 


Amendment9 
09NOV2021                                                        Page 32 of 77 
• 
CBC, differential, haptoglobin, LFTs, total CK, complete metabolic panel within 30 days prior 
to start of ASCT conditioning regimen. 
• 
Evaluation for CMV, HIV, HTLV, and hepatitis B & C within 30 days prior to start of ASCT 
conditioning regimen. 
• 
Baseline electrocardiogram (EKG) and MUGA scan or echocardiogram with measurement of 
LVEF within 90 days prior to start of ASCT conditioning regimen. 
• 
Chest radiography within 90 days prior to start of ASCT conditioning regimen. 
• 
Pulmonary function test (PFT) within 90 days prior to start of ASCT conditioning regimen. 
• 
Cut-off values for the above-mentioned studies will be consistent with institutional standard 
operating procedures (SOPs) for eligibility screening prior to ASCT. 
• 
For groups A,B,C,D: PET-CT scan and CT scan with intravenous/oral contrast of neck, chest, 
abdomen and pelvis within 30 days prior to initiation of ASCT conditioning 
• 
For groups E and F: Within 30 days prior to initiation of ASCT conditioning: Serum protein 
electrophoresis with immunofixation, quantitative serum IgG, IgM, IgA (IgE in cases where 
this is the involved immunoglobulin), serum free light chains, 24-hour urine for protein 
electrophoresis with immunofixation and protein quantification.  
• 
For groups E and F: Within 30 days prior to initiation of ASCT conditioning: Skeletal Survey. 
• 
For all groups, within 30 days prior to ASCT conditioning (at the time of informed consent): 
Peripheral blood collection for blood immune phenotype and metabolomics analysis. 
• 
For all groups post consent, prior to ASCT conditioning: Stool samples will be collected for 
baseline gut microbiome analysis. 
• 
For all groups: Acquisition of tumor tissue biopsy (either new or archival tissue, if available) or 
bone marrow biopsy (if known involvement) for evaluation of PD1/PDL1 expression and 
baseline tumor immune profile. Tumor Biopsies and/or Bone Marrow Biopsies for Lymphoma 
subjects (Groups A through D) and Bone Marrow Biopsies for Multiple Myeloma subjects 
(Groups E & F) will be collected at screening, end of treatment, complete response, and at 
relapse, if clinically indicated. For Bone Marrow Biopsies, the research sample will be 
collected (aspirate, send the first pull, yellow top tube) to Dr. Korngold’s lab. Additional 
samples for all disease groups will be sent to pathology for immunostaining of fixed tissue for 
PDL1 expression on tumor cells and for the in situ presence of CD4 and CD8 T cells with PD1 
expression. If viable biopsy material is unavailable for research purposes, Dr. Korngold’s lab 
will access fixed archival tumor materials for preparing tumor lysates and possibly for 
retrieving T cell DNA for repertoire analysis. Samples for Georgetown University subjects are 
to be shipped via Fed Ex on the day of collection – tubes banded in sealed plastic bag and 
wrapped in bubble wrap at room temperature to Dr. Korngold’s lab. 
6.2 Evaluation and Response  
6.2.1 For Groups A, B, C, and D: 
• 
PET-CT scan and/or CT scan with intravenous/oral contrast of neck, chest, abdomen and 
pelvis will be performed for response evaluation 90-100 days post ASCT, 180-200days 
post ASCT, 360-380 days post ASCT and 540-560 days post ASCT.  Response criteria 
will follow the Lugano Classification (see Appendix B). Both PET/CT and CT scan should 
be done within 30 days prior to initiation of ASCT conditioning for baseline response 
evaluation purposes. Either PET/CT or CT scan are acceptable for response evaluation 
after ASCT, and should be compared to the pre-ASCT baseline scan. 
• 
Physical exam, laboratory work-up and correlative studies will be performed as delineated 
in the Clinical Trial Flowchart (Appendix D) 


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09NOV2021                                                        Page 33 of 77 
6.2.2 For Groups E and F:  
• 
Serum protein electrophoresis with immunofixation, quantitative serum IgG, IgM, IgA (IgE 
or IgD in cases where this is the involved immunoglobulin), serum free light chains, 24-
hour urine for protein electrophoresis with immunofixation and protein quantification will 
be collected for response evaluation 30-40 days post ASCT, 60-70 days post ASCT, 90-
100 days post ASCT, 180-200 days post ASCT, 270-290 days post ASCT, 360-380 days 
post ASCT, 450-470 days post ASCT and 540-560 days post ASCT. Response criteria 
will follow the International Myeloma Working Group (IMWG) Uniform Response Criteria 
for Multiple Myeloma (see Appendix C). For patients who achieve CR by IMWG Criteria, 
a bone marrow biopsy will be required for confirmation and tumor immunophenotype 
analysis 
• 
Physical exam, laboratory work-up, and correlative studies will be performed as delineated 
in the Clinical Trial Flowchart (Appendix D) 
6.2.3 For All Groups:  
• 
If a patient signs consent but does not receive treatment, the patient will not be evaluable 
and no further safety information will be collected. The slot will be released and may be 
re-assigned to another patient.  
• 
If there is progressive disease or relapse documented by any of the criteria, a confirmatory 
lymph node and/or bone marrow biopsy will be performed for confirmation of disease 
relapse and tumor immunophenotype studies.  
7.0 DATA SAFETY MONITORING 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this multi-site trial.  As this study is an investigator initiated Phase Ib/IIa study 
utilizing a non-FDA approved drug for this indication which the FDA has deemed IND-exempt, it 
is considered a high-risk study, which requires real-time monitoring, by the PI and study team and 
reviewed every 4 months by the LCCC Data and Safety Monitoring Committee (DSMC). 
 
The Principal Investigator and the Co-Investigators will review the data including safety monitoring 
at their weekly institution based disease group meetings and on monthly disease group 
teleconferences.   
 
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the 
IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 4 months from the time the first patient is enrolled on the study. 
Results of the DSMC meetings will be forwarded to the IRB with recommendations regarding 
need for study closure.  
 
DSMC recommendations should be based not only on results for the trial being monitored as well 
as on data available to the DSMC from other studies.  It is the responsibility of the PI to ensure 
that the DSMC is kept apprised of non-confidential results from related studies that become 
available.  It is the responsibility of the DSMC to determine the extent to which this information is 
relevant to its decisions related to the specific trial being monitored. 


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09NOV2021                                                        Page 34 of 77 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does not 
concur with the DSMC recommendations, then the LCCC Associate Director of Clinical Research 
must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, and the LCCC 
AD for Clinical Research will be responsible for reaching a mutually acceptable decision about 
the study and providing details of that decision to the IRB.  Confidentiality must be preserved 
during these discussions.  However, in some cases, relevant data may be shared with other 
selected trial investigators and staff to seek advice to assist in reaching a mutually acceptable 
decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the trial 
be closed for any reason, the recommendation will be reviewed by the Associate Director for 
Clinical Research at G-LCCC.  Authority to close a trial for safety reasons lies with the IRB, with 
the above described input from DSMC and the AD for Clinical Research.   
8.0 STATISTICAL CONSIDERATION  
This is an open label, single-arm per cohort, phase Ib-IIA study. 
 
Our goal is to determine the safety and clinical effect of combined checkpoint inhibition 
administered after autologous hematopoietic stem cell transplantation in each of six clinical 
cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of 
adverse events and rates of complete response and progression free survival, we intend to 
monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the 
time of disease progression. We will also analyze the gut microbiome prior to conditioning, 
throughout treatment, post-transplant and at time of relapse. We intend to expand cohorts that 
demonstrate safety and PFS >50% at 18 months into a phase IIA successor trial. 
This is an open label, single-arm per cohort, phase Ib-IIA study. 
 
Phase Ib 
The primary objectives of this study are: 
• 
To assess the safety of combined check point inhibition with nivolumab and ipilimumab 
after autologous hematopoietic stem cell transplantation in patients at high risk for post-
transplant recurrence including patients with persistent and recurrent high risk diffuse 
large B cell lymphoma, high risk and recurrent T cell lymphoma and high risk and recurrent 
multiple myeloma. 
Primary endpoints:  
• 
Safety endpoint:  The composite endpoint consisting of the occurrence of at least one 
treatment-related limiting toxicity (after combined checkpoint inhibitor treatment is 
initiated) defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE. 
Exceptions listed in section 5.9 apply to this endpoint as well. If 3 of 7 patients in a single 
cohort experience a treatment-related limiting toxicity, that single cohort will be terminated. 
• 
Efficacy endpoint:  progression-free survival at 18 months after ASCT in patients at high 
risk for post-transplant recurrence including patients with persistent and recurrent high risk 
diffuse large B cell lymphoma, high risk and recurrent T cell lymphoma and high risk and 
recurrent multiple myeloma. 
 


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The secondary objectives are:  
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in patients at high 
risk for post-transplant recurrence including patients with persistent and recurrent high risk 
diffuse large B cell lymphoma, high risk and recurrent T cell lymphoma and high risk and 
recurrent multiple myeloma. 
• 
To assess progression-free survival at 12 months after ASCT in patients at high risk for 
post-transplant recurrence including patients with persistent and recurrent high risk diffuse 
large B cell lymphoma, high risk and recurrent T cell lymphoma and high risk and recurrent 
multiple myeloma. 
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at screening (at 
time of informed consent), at apheresis (stem cell collection), and then serially the day 1 
of week 1 of combined checkpoint inhibitors and then weeks 4, 7, 12, 18 and 26, and at 
9, 12, 15, and 18 months post-transplant and at time of relapse, as it occurs. Immune 
phenotype and TCR will be evaluated as follows: 
T cell repertoire analysis 
TCR Immunoseq for Vbeta CDR3 highest frequency specificities. 
 
Real-Time PCR analysis:  
T-bet(Th1); STAT3, RORgamma t (TH17); STAT6 (Th2); FoxP3 (Treg), granzyme 
A (GZMA) and perforin (PRF1) 
 
Flow Cytometric Phenotype Analysis for:   
 
T Cells:  
CD3; CD4; CD8; CD4+CD25+PD1+; CTLA-4 
Follicular Helper T: CD3+,CD4+,CXCR5+,PD1+ 
CD4 and CD8 T naïve (RO-; CCR7+) 
Central Memory: (TCM;RO+,CCR7+) 
Effector Memory (TEM, RO+,CCR7-)  
Terminally differentiated effector memory (TEMRA; RO-, CCR7-) 
T regulatory cells (Treg): CD4+,CD25hi, CD127low, CD39+, CD152hi, RO- 
(resting); CD4+,CD25hi, CD127low, CD39+, CD152hi, RO+ (activated) 
 
Dendritic Cells: 
Lin-, CD11c+, CD1a+, CD80 (B7-1)low, CD86 (B7-2)low, MHC Class IIlow (DC 
resting); CD11c+, CD1a+, CD123-, CD80hi, CD86hi, HLADRhi (DC1 activated); 
HLADRhi, CD11c-, CD123+, PDL-1+ (DC2) 
 
Macrophages: 
HLADR+, CD14+, CD64+, CD25+, CCR7+ (M1); HLADR+, CD14+, CD64-, 
CD206+, CD25-, CCR7-, CD209+, PDL-1+ (M2) 
 
Myeloid derived suppressor cells: 
HLADR-/low, CD11b+, CD14+,CD33+hi,CD34+, CD66b-, PDL-1+ (M-MDSC); 
HLADR-, CD11b+, CD14-,CD33+low,CD34+, CD66b+, PDL-1+ (G-MDSC) 
 
B Cells:  
CD19+, B7-1low, B7-2low, MHC Class IIlow (resting); CD19+, B7-1hi, B7-2hi, 
MHC Class IIhi (activated) 
 


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NK cells: 
CD16+, CD3-, CD56+ 
 
NKT Cells: 
CD16+, CD3+, CD56+ 
 
Plasma Cytokine levels: Multiplex 25 Cytokine - Luminex 
GM-CSF, IL-1b, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, 
IL-15, IL-17, TNF alpha; MCP-1, MIP1a, MIP1b, MIG, RANTES, IFN-alpha, IFN-
gamma, IP-10, Eotaxin 
• 
To determine the toxicities resulting from administration of the treatments. 
• 
To assess tumor site immune phenotype, T cell repertoire and PD L1/2 expression when 
tissue available for biopsy prior to autologous transplant conditioning and then at time of 
progression (within 18 months) after autologous transplant conditioning. 
 
 
The tertiary objectives are: 
• 
To identify specific intestinal microbial strains associated with improved outcome in 
autologous stem cell transplantation patients treated with combined checkpoint inhibitors. 
The overall microbial composition in stool samples of patients will be analyzed at 
screening, preconditioning (to be collected within 48 hours prior to transplant admission), 
at engraftment (within 72 hours of ANC > 500), and then serially, on day 1 of week 1 (to 
be collected within 48 hours prior to clinic visit) and then weeks 4, 7, 12, 18, and 26, End 
of Treatment, and 9, 12, 15 and 18 months post-transplant, and at time of relapse, as it 
occurs. A 16S ribosomal RNA (rRNA) miSeq Illumina platform will be used for overall 
microbial composition and quantitative real-time PCR analysis will validate the specific 
microbial strains identified by miSeq. 
 
Phase IIA 
Primary Objective 
 
• 
To assess progression-free survival at 18 months after ASCT in patients  in cohorts that 
were  deemed safe in Phase Ib (no more than 3 treatment-related toxicity) and at least 4 
of 7 patients progression free at 18 months in the Phase Ib. 
 
Secondary Objectives 
• 
To assess complete response rate at 3, 6 and 12 months after ASCT in patients at high 
risk for post-transplant recurrence including patients in the successor expansion cohorts 
following the Phase Ib trial. 
• 
To assess progression-free survival at 12 months after ASCT in patients at high risk for 
post-transplant recurrence including patients with in the successor expansion cohorts 
following the Phase Ib trial. 
• 
Determine the toxicities resulting from administration of the treatments in patients enrolled 
in the successor expansion cohorts following the Phase Ib trial.  
• 
To assess blood immune reconstitution, phenotype and TCR repertoire at screening (at 
time of informed consent), at apheresis (stem cell collection), and then serially the day 1 
of week 1 of combined checkpoint inhibitors and then weeks 4, 7, 12, 18 and 26, and at 
9, 12, 15, and 18 months post-transplant and at time of relapse, as it occurs.  
 
Tertiary Objectives 
• 
To identify specific intestinal microbial strains associated with improved outcome in 
autologous stem cell transplantation patients treated with combined checkpoint inhibitors. 


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The overall microbial composition in stool samples of patients will be analyzed at 
screening, preconditioning (to be collected within 48 hours prior to transplant admission), 
at engraftment (within 72 hours of ANC > 500), and then serially, on day 1 of week 1 (to 
be collected within 48 hours prior to clinic visit) and then weeks 4, 7, 12, 18, and 26, End 
of Treatment, and 9, 12, 15 and 18 months post-transplant, and at time of relapse, as it 
occurs. 
8.1 Determination of Sample Size 
• 
The Phase Ib  feasibility trial will require 42 patients divided in 6 cohorts, with 7 patients 
each.Enrolled patients will have hematologic malignancies with a high risk for post-
autologous stem cell transplant recurrence including patients with persistent and recurrent 
high risk diffuse large B cell lymphoma, high risk and recurrent T cell lymphoma and high 
risk and recurrent multiple myeloma. 
• 
The Phase IIA will require up to 148 patients, assuming all cohorts followed in Phase Ib 
meet the criteria for expansion.  
 
Accrual goal is 7 patients per cohort. Accrual period goal is 36 months. Patients will accrue to 
study by disease groups (cohorts) and followed separately by group for incidence and severity of 
toxicity, ability to receive intended schedule of combined checkpoint inhibitors and for complete 
response and progression free survival (PFS) rates. Complete response and progression free 
survival rates will be compared to published standards for each disease group. Expected PFS at 
18 months (PFS18) for all post-transplant groups without checkpoint inhibitors is 40-50%1-3. 
Groups A, B, C, and D with PFS at 18 months in 4 or more patients (57%) will be considered for 
eligibility in a successor phase IIa expansion trial. The primary efficacy endpoint of the phase Ib 
portionis to achieve PFS of 18 months in ≥4 patients per cohort (≥57%).  
 
Phase Ib 
The initial part of the trial titled is designed as a feasibility Phase Ib study. This will determine 
which of 6 cohorts of patients would be studied in an expansion Phase IIa trial. In this pilot 
feasibility study, designed to assess the safety of the combined checkpoint inhibitor, sample size 
was not performed to estimate power, as it was designed to obtain initial estimates of toxicity to 
inform the successor trial Phase IIA. Therefore, this pilot feasibility study is not powered to detect 
significant differences in PFS. We have preemptively established a cut-off of ≥57% PFS at 18 
months as the minimum benefit needed to proceed to Phase IIa for each individual cohort, if a 
maximum of 3 patients in each cohort experience severe adverse events which would lead to trial 
discontinuation (for that particular cohort). Historical data for such patient populations predicts 
PFS 40-50% at 18 months. 
 
Phase IIa 
For the expansion cohort, the efficacy endpoint is PFS at 18 months. Then, to determine the 
sample size for testing if PFS at 18 months is at least 57%, we need to define a clinically 
uninteresting rate of surviving progression against which the 57% will be compared. Exploring 
PFS18 ranging from 40%, to 45%, we obtained the following sample size for detecting the check 
point inhibition effect with 80% power, using significance level of 0.05 and 0.10 for a one-sided 
test. For this Phase II study, we can use alpha=0.10. 
 
Historical 
PFS18 months 
Required sample 
Size 
Approximate upper Critical Cut-off 
 
Alpha=0.05 
Alpha=0.10 
Alpha=0.05 
Alpha=0.10 
0.40 
49 
37 
0.53 
0.52 


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09NOV2021                                                        Page 38 of 77 
0.41 
55 
42 
0.53 
0.52 
0.42 
63 
48 
0.54 
0.52 
0.43 
73 
55 
0.54 
0.52 
0.44 
85 
64 
0.54 
0.53 
0.45 
100 
75 
0.54 
0.53 
 
 
Samples sizes were calculated using one arm survival module in Stats tools from Cancer 
Research and Biostatistics (CRAB) (https://stattools.crab.org/), assuming 36 months accrual and 
18 month of follow-up for progression event. 
 
When utilizing a PFS18 of 40% as the uninteresting rate in the check point inhibitor naïve 
population, then according to the calculations in the table provided, each expansion cohort would 
require a sample size of 37 to examine if PFS18 ≥ 57%. Approximately, if PFS18 is at least 52% 
then study will have demonstrated the early efficacy that was being sought.  
 
Num of cohorts 
Total required sample Size 
 
Alpha=0.05 
Alpha=0.10 
1 
49 
37 
2 
98 
74 
3 
147 
111 
4 
196 
148 
 
Thus, if all the cohorts had met the criteria for expansion after Phase I, the total study will be 148 
(37x4); if only 3 groups met the criteria, study size will be 111; if only 2 groups met the criteria, 
study size will be 74; and if only 1 group met the criteria, study size will be 37. 
8.2 Populations for Analysis 
• 
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses. 
Descriptive tables that summarize the number and percentage of subjects that experience 
adverse events as categorized in the NCI CTCAE Version 4.03 will be generated by 
cohort/group. 
• 
The intent-to-treat (ITT) population will be employed for response and PFS analyses. 
Descriptive tables that summarize the number and percentage of subjects with responses and 
PFS will be generated by cohort/group. 
8.3 Statistical Methods 
8.3.1 Safety Analysis 
The safety of combined checkpoint inhibition with nivolumab and ipilimumab, after autologous 
hematopoietic stem cell transplantation in patients at high risk for post-transplant recurrence, will 
be evaluated for composite endpoint (at least one treatment-related toxicity and all adverse events 
observed in each cohort and presented as counts (percentages) and corresponding exact 
binomial 95% confidence intervals for proportion. Adverse events will include Immune-mediated 
colitis, hepatitis, endocrinopathies, nephritis, rash, encephalitis and immune-related AEs (irAEs).  
8.3.2 Complete Response Rate 


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09NOV2021                                                        Page 39 of 77 
Complete response rate will be evaluated at 3, 6 and 12 months after ASCT in each of the 6 
cohorts. The estimates of the CR will be presented as count (proportion) and corresponding exact 
binomial 95% confidence intervals for proportion at each time point. 
8.3.3 Progression Free Survival at 12, 18 months 
Progression-free survival (PFS) is defined as time interval from date of transplantation to 
pathologic disease progression or death from any cause. PFS of patients at high risk for post-
autologous stem cell transplant recurrence in each cohort will be estimated using Kaplan-Meier 
method and probabilities will be calculated for months 12 months and 18 months, along with 95%.  
In Phase II, if PFS18 is at least 52% then study will have demonstrated the early efficacy that was 
sought in that particular cohort, i.e. PFS18 ≥ 57%. 
8.3.4 Longitudinal analysis of TCR repertoire and blood immune phenotype  
Longitudinal analysis of TCR repertoire analysis results reported as diversity scores will be 
conducted on samples as determined by DNA sequencing and analyzed by ImmunoSeq software 
(Adaptive Biotechnologies). TCR repertoire diversity scores in evaluable patient samples will be 
over time using mixed model repeated measures (MMRM) by utilizing PROC MIXED SAS 9.4.  In 
this models, the status of infection as a time-dependent will be included to examine the effect of 
both time and infection on cell cytokine levels. 
 
Longitudinal analysis will be performed on blood samples collected at 14 time points: 
1) Screening Visit (at time of informed consent)  
2) Apheresis Sample (except for group F, due to stem cell collection 
having occurred previously). For those patients who sign informed 
consent after apheresis has already occurred, the Apheresis Sample 
will be performed on the previously collected, frozen product. 
3) Day 1 of Week 1 of combined checkpoint therapy,  
4) Day 1 of Week 4 of combined checkpoint therapy,  
5) Day 1 of Week 7 of combined checkpoint therapy,  
6) Day 1 of Week 12 of combined checkpoint therapy,  
7) Day 1 of Week 18 of combined checkpoint therapy, and  
8) Day 1 of Week 26 of combined checkpoint therapy.   
9) End of Treatment Visit 
10) Post-transplant,  9 months,  
11) Post-transplant,  12 months,  
12) Post-transplant, 15 months,  
13) Post-transplant, 18 months and / or  
14) Relapse, as it occurs. 
Cell counts in all subsets will be analyzed as repeated measurements obtained at the 14 
timepoints to examine the changes over time or less when time of relapse as the last timepoint.  
This longitudinal analysis will be performed by fitting an overall model across subsets of cells and 
a separate longitudinal analysis within each subpopulation. 
1.  Overall model  
Using all subsets,  T cells, (T cells (CD4 versus CD8, Tregs, memory (central versus effector 
versus terminally differentiated effector memory), dendritic cells,  macrophages, myeloid 
suppression cells, B cells, NK cells, NKT cells, analysis of cell counts will be performed to 
examine changes in counts over time (14 time points) and difference in counts between levels 


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09NOV2021                                                        Page 40 of 77 
of their state, naïve versus activated, as appropriate. The covariates in this model will be 
timepoints (14 timepoints listed above) and  subset of cell population. 
2. Within each subset, the following separate longitudinal analysis of cell counts over time will 
conducted: 
i. 
Count of dendritic cells as a function of time (14 timepoints) and status (DC1 versus 
DC2), 
ii. 
Count of DC2 as a function of time (14 timepoints) and PDL-1+/- status, 
iii. 
Count of macrophages as a function of time (14 timepoints)  and status (M1 versus  
M2) 
iv. 
Count of M2 cell as a function of time (14 timepoints)  and PDL-1+/- status, 
v. 
Count of CD4 T cells as a function of time (14 timepoints) and follicular helper function 
status, 
vi. 
Count of T cells as a function of time (14 timepoints) and activated status (activated 
versus naïve), 
vii. 
Count of activated T cells as a function of time (14 timepoints) and PD1+/- status,  
viii. 
Count of Tregs as a function of time (14 timepoints) and activated status (activated 
versus resting), 
ix. 
Count of memory T cells as a function of time (over 14 timepoints) and type of memory 
cells (effector versus central memory versus terminally differentiated effector memory, 
x. 
Count of B cells as a function of time (14 timepoints) and activated status (activated 
versus resting), 
xi. 
Count of myeloid suppressor cells as a function of time (14 timepoints) and PDL-1+/-  
status, 
 
For these count variables, Poisson Regression Analysis based on generalized estimating 
equations (GEE) method will be performed by utilizing the procedure PROC GENMOD SAS 9.4 
with Poisson distribution, log link function and independent covariance structure.  
 
Continuous variables such as cytokine levels ( GM-CSF, IL-1b, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-
6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, TNF alpha; MCP-1, MIP1a, MIP1b, MIG, RANTES, 
IFN-alpha, IFN-gamma, IP-10, Eotaxin) will be examined over time (14 timepoints) using mixed 
model repeated measures (MMRM) by utilizing PROC MIXED SAS 9.4.  In both of the models to 
be fit to these immune markers, the status of infection as a time-dependent covariate will be 
included to examine the effect of both time and infection on cell cytokine levels.  
8.3.5 Longitudinal analysis of the gut microbiome.  
The time points of stool sample collection are:  
1) Screening Visit (up to 7 days post consent). If patient signs consent within 7 days of 
transplant admission, stool sample collection will start from item “2” (Preconditioning)   
2) Preconditioning (to be collected within 48 hours prior to transplant admission)    
3) Engraftment, (within 72 hours of ANC > 500)  
4) Day 1 of Week 1 of combined checkpoint therapy,  
5) Day 1 of Week 4 of combined checkpoint therapy,  
6) Day 1 of Week 7 of combined checkpoint therapy,  
7) Day 1 of Week 12 of combined checkpoint therapy,  
8) Day 1 of Week 18 of combined checkpoint therapy, and  
9) Day 1 of Week 26 of combined checkpoint therapy. 
10) End of Treatment Visit   
11) Post-transplant, 9 months,  
12) Post-transplant, 12 months,  


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09NOV2021                                                        Page 41 of 77 
13) Post-transplant, 15 months,  
14) Post-transplant, 18 months and / or 
15) Relapse, as it occurs.  
 
Counts of specific intestinal microbial strains will be examined overtime (15 time points) using 
Poisson regression analysis utilizing PROC GENMOD as described in analysis of blood immune 
markers.  In each of the models for each microbial strain, status of infection as a time-dependent 
covariate will be included as microbial along timepoint variable. 
The overall microbial composition will be determined by 16S rRNA miSeq Illumina platform and 
analyzed by Second Genome Solutions proprietary 16S bioinformatic data analysis software 
package. 
8.4 Additional Endpoint Analyses 
8.4.1 Toxicities of the treatments 
The toxicity of combined checkpoint inhibition with nivolumab and ipilimumab after autologous 
hematopoietic stem cell transplantation in patients at high risk for post-transplant recurrence will 
be evaluated for all adverse events with grade 3 or grade 4 observed in each cohort and presented 
as counts (proportion) and corresponding exact binomial 95% confidence intervals for proportion. 
8.4.2 Evaluation of tumor site phenotype 
Absolute number of PD-L1/L2-bearing activated helper T cell subpopulations from biopsy at tumor 
site will be examined for two time points prior to conditioning and time of progression (within 18 
months post-transplant) using Poisson regression analysis with GEE described in analysis of 
blood phenotype above. 
8.4.3 General Data Analysis   
The summary of the demographic characteristics will be presented. Continuous variables will be 
summarized using mean (SD) or median (interquartile range) depending on whether or not the 
data follow the normal distribution. Categorical variables will be summarized by frequency 
(percentage). All adverse events will be presented as listings. All analysis will be performed using 
SAS version 9.4 (SAS Institute Inc. Cary, NC, USA). 
8.5 Withdrawal of Patients  
Patients may withdraw from the study treatment and assessments at any time.  Specific reasons 
for withdrawal include: 
A. Voluntary withdrawal of consent by the patient or guardian 
B. Safety reasons requiring discontinuation as determined by the physician(s) caring for the 
patient 
C. Non-compliance to protocol 
D. Loss to follow-up 
E. Completion of all study procedures and follow-up 
8.6 Stopping Rules 
Phase Ib Stopping Rules 


Amendment9 
09NOV2021                                                        Page 42 of 77 
If 3 of 7 patients in a single cohort experience a treatment-related limiting toxicity (after combined 
checkpoint inhibitor treatment is initiated) defined as a > grade 4 non-hematologic toxicity as 
specified by the Common Terminology Criteria for Adverse Events v4.03 (CTCAE), that single 
cohort will be terminated. Exceptions listed in section 5.9 apply to this endpoint as well. 
(http://ctep.cancer.gov/reporting/ctc.html)  
 
Phase IIA Stopping Rules 
Toxicity monitoring rule for each cohort of 37 patients treated with ipilimumab/nivolumab in Phase 
IIA was derived using toxicity based on repeated significance testing method obtained from R-
Package “Clinfun” in R version 3.4.3, the R Foundation for Statistical Computing, Vienna, Austria. 
Based on toxicity rate observed in Phase 1b, we considered toxicity rate of 0.25 to be the 
acceptable rate and occurrence rate of 0.30 to the unacceptable rate of toxicity. Thus, using 
CLINFUN function ’toxbdry’ with arguments pLo=0.25, pHi=0.30, sequence of looks 2:37, 
significance level (probability of declaring treatment as unacceptable when toxicity rate is 
0.30=0.10, 90% power of declaring Ipinivo treatment with toxicity 0.30 as unacceptable, boundary 
shape parameter delta=0.15 and taking the alternative priority error threshold, the monitoring rule 
given in Table 7 was obtained.  
 
Table-A Stopping Boundaries for combined checkpoint inhibition with nivolumab and ipilimumab 
after  autologous hematopoietic stem cell transplantation 
 
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of Toxicities is 
at least 
 
1 
 
2 
1 
2 
5 
2 
3 
9  
3 
4 
13 
4 
5 
17 
5 
6 
21 
6 
7 
25 
7 
8 
29 
8 
9 
33 
9 
10 
37 
10 
 
In each expansion cohort of size 37 the trial will be terminated based on the above table-A using 
the rules: 
Out of the first 2 patients, stop if 1 or more report toxicities. Out of the first 5 patients, stop if 2 or 
more report toxicities. Out of the first 5 patients, stop if 2 or more report toxicities. Out of the first 
9 patients, stop if 3 or more report toxicities. Out of the first 13 patients, stop if 4 or more report 
toxicities. Out of the first 17 patients, stop if 5 or more report toxicities. Out of the first 21 patients, 
stop if 6 or more report toxicities. Out of the first 25 patients, stop if 7 or more report toxicities. Out 
of the first 29 patients, stop if 8 or more report toxicities. Out of the first 33 patients, stop if 9 or 
more report toxicities. Out of the first 37 patients, stop if 10 or more report toxicities.  
 
Table-B Operating Characteristics of Toxicity Monitoring for Pa=0.25 vs Pu=0.30 (n=37) 
 
 
Toxicity 
rate  
number 
 
 
 
Toxicity 
Rate 
 
Prob. of 
crossing 
low 
boundary 
 
Prob. of 
stopping 
low 
boundary 
Expected 
sample 
size for 
low 
boundary 
 
Prob. of 
crossing 
high 
boundary 
 
Prob. of 
stopping 
high 
boundary 
Expected 
sample 
size for 
high 
boundary 


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09NOV2021                                                        Page 43 of 77 
1 
0.25 
0.781 
0.776 
13.3 
0.772 
0.766 
13.9 
2 
0.26 
0.810 
0.805 
12.5 
0.802 
0.796 
13.0 
3 
0.27 
0.837 
0.831 
11.7 
0.830 
0.824 
12.2 
4 
0.28 
0.861 
0.856 
10.9 
0.855 
0.849 
11.4 
5 
0.29 
0.883 
0.877 
10.2 
0.877 
0.872 
10.6 
6 
0.30 
0.902 
0.897 
9.5 
0.897 
0.892 
9.9 
Pa, toxicity rate that is acceptable; Pu, toxicity rate that is unacceptable; Prob, probability 
 
From the operating characteristics in Table B, it observed that the stopping guideline will have 
90% power (prob. crossing high boundary=0.897) to terminate the trial in any cohort of size 37 
when the true toxicity rate is 0.30, and expected sample size for early termination at this rate will 
be 10 patients(expected sample size for high boundary=9.9).  
The definition of unacceptable toxicity will be as follows: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment  
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion 
reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or non-hematological laboratory abnormality, 
except for the following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate 
management within 72 hours of their onset 
• 
Any Grade 5 drug-related death 
8.7 Data Management and Analysis 
Case report forms will be created for management of data collected during this study, and will be 
available in electronic format. A database in Access will be created based on the case report 
forms. All study data will be imported into SAS and data management will be utilized to flag, and 
generate queries on out of range data issues until they are resolved. All analysis will be performed 
using SAS software version 9.4 (SAS Institute Inc. Cary, NC).    


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09NOV2021                                                        Page 44 of 77 
9.0 SAFETY REPORTING 
9.1 Definitions 
9.1.1 Adverse Event Definition 
An adverse event (AE) is any new untoward medical occurrence or worsening of a preexisting 
medical condition in a patient administered a pharmaceutical product, which does not necessarily 
have a causal relationship with the treatment. An adverse event can be any unfavorable and 
unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the drug, whether or not it is considered to be drug related.  This 
includes any newly occurring event or previous condition that has increased in severity or 
frequency since the administration of drug. The following information should be considered when 
determining whether or not to record a test result, medical condition, or other incident when 
collecting and reporting Adverse Events: 
• 
From the time of informed consent through the day prior to Day 1 Week 1 of combined 
checkpoint therapy, only study protocol-related AEs should be recorded. A protocol-
related AE is defined as an untoward medical occurrence as a result of a protocol 
mandated procedure that is not standard of care.  
• 
All medical conditions present or ongoing pre-dose on Day 1 Week 1 of combined 
checkpoint therapy should be recorded.  
• 
All AEs or complications associated with any procedures (study related or not) should be 
recorded from Day 1 Week 1 of combined checkpoint therapy through the end of the 
safety-reporting period of 100 days after the last dose of study therapy or until the start of 
a subsequent systemic anti-cancer therapy, if earlier. 
• 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety-reporting period should be recorded.  
• 
Generally, abnormal laboratory values should not be recorded as an AE unless it is 
associated with clinical signs or symptoms requires an intervention, or results in a serious 
adverse event, or results in study termination, or interruption/discontinuation of study 
treatment. When recording an AE resulting from a laboratory abnormality, the resulting 
medical condition rather than the abnormality itself should be recorded.  
9.1.2 Serious Adverse Event Definition  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization. The 
following hospitalizations are not considered SAEs:  
o a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-threatening 
event) 


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09NOV2021                                                        Page 45 of 77 
o elective surgery, planned prior to signing consent 
o admissions as per protocol for a planned medical/surgical procedure 
o routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 
o Medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
o Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect  
• 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.)  
• 
Potential drug induced liver injury (DILI) is also considered an important medical event.  
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
9.2 Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety).  
The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
9.3 Overdose 


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09NOV2021                                                        Page 46 of 77 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
9.4 Other Safety Considerations  
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
X rays, and any other potential safety assessments, whether or not these procedures are required 
by the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and 
reported accordingly. 
9.5 Procedures for AE and SAE Reporting 
All Adverse Events and Serious Adverse Events (SAEs) that occur following the subject’s first 
dose of therapy on Day 1 of Week 1 of combined checkpoint therapy in the study through 100 
days of discontinuation of dosing or until the start of a subsequent systemic anti-cancer therapy, 
if earlier, must be reported to BMS Worldwide Safety, and according to local regulations. All 
serious adverse events (SAE) regardless of causality must be reported to the PI, (within 24 hours) 
and the research coordinator for notification of Hackensack University Medical Center’s IRB. 
 
The local IRB must be informed of any serious, unexpected, or alarming adverse events that 
occur during the approval period involving a subject within seven days of occurrence, or sooner 
if local guidelines apply. Any deaths of subjects require immediate (within 24 hours) reporting.  
 
Sponsor generated reports of adverse events occurring at other investigative sites within fourteen 
days of receipt if the event is definitely related or possibly related to the research protocol as 
deemed by the sponsor lead investigator, and/or the DSMB.   
 
Intensity for each adverse event, including any lab abnormality, will be determined by using the 
NCI CTCAE, version 4.03, as a guideline, wherever possible.  The criteria are available online at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  
 9.6 Assessment of Toxicity 
Common Terminology Criteria for Adverse Events (CTCAE) will be used for the assessment and 
grading 
of 
all 
toxicities 
experienced 
by 
patients 
enrolled 
into 
this 
study 
(http://ctep.cancer.gov/forms/CTCAE_Index.pdf) 
 
If the nature of the adverse experience is listed in the CTCAE, the maximum grade will be 
reported.      
 
If the adverse experience is not listed in the NCI CTCAE Common Terminology Criteria Adverse 
Events, report the toxicity grade using the following criteria:  
• 
Grade 1 = Mild: an adverse experience which is easily tolerated by the patient, causing 
minimal discomfort and not interfering with everyday activities. 
• 
Grade 2 = Moderate: an adverse experience which is sufficiently discomforting to interfere 
with normal everyday activities. 
• 
Grade 3 = Severe: an adverse experience which is incapacitating and prevents normal 
everyday activities. 


Amendment9 
09NOV2021                                                        Page 47 of 77 
• 
Grade 4 = Life Threatening: an adverse experience which places the patient at immediate 
risk of death. 
• 
Grade 5 = Death 
9.7 Assessment of Causality 
The local Investigator will explain each adverse experience and assess its relationship, if any, to 
study drug treatment. Causality will be determined by the local Investigator using the following 
categories: Not Related, Unlikely, Suspected (Reasonable Possibility), Probable. 
• 
Not related: The adverse experience is definitely not related to the test drug. 
• 
Unlikely:  There are other, more likely causes and the drug is not suspected as a cause. 
• 
Suspected (reasonable possibility): A direct cause and effect relationship between the 
drug and the adverse experience has not been demonstrated but there is a reasonable 
possibility that the experience was caused by the drug. 
• 
Probable: There probably is a direct cause and effect relationship between the adverse 
experience and the study drug. 
The degree of certainty with which an adverse experience is attributed to drug treatment (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will 
be determined by how well the experience can be understood in terms of one or more of the 
following: 
Known pharmacology of the drug.  Reaction of similar nature being previously observed 
with this drug or class of drug.  The experience having often been reported in literature for 
similar drugs as drug related e.g. skin rashes, blood dyscrasia.  The experience being 
related by time to drug ingestion terminating with drug withdrawal (dechallenge) or 
reproduced on rechallenge.   
9.8 Follow-up of Adverse Experiences 
Patients with adverse experiences or serious adverse events will be actively followed until the 
event has subsided (disappeared) or until the condition has stabilized. 
10.0 ADMINISTRATIVE REQUIREMENTS 
10.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator clinical documents will be maintained to demonstrate the validity of the 
study and the integrity of the data collected.  Master files should be established at the beginning 
of the study, maintained for the duration of the study and retained according to the appropriate 
regulations.   
10.2 Patient Information and Informed Consent  
After the study has been fully explained, written informed consent will be obtained from   either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply with 
ICH-GCP and all applicable regulatory requirement(s). 


Amendment9 
09NOV2021                                                        Page 48 of 77 
 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  All potential risks associated with 
the use of Nivolumab and ipilimumab will will be discussed as objectively as possible.  The patient 
has the right to review and correct the results of the pre-transplant evaluation. 
10.3 Protocol Registration 
All patients will be assigned a unique patient number (UPN) in accordance with HUMC Standard 
Practice. 
10.4 Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The investigator will grant monitor(s) and auditor(s) or its designees and regulatory authority(ies) 
access to the patient accountability records, study reports and communications.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
10.6 Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). The licensed medical records department, affiliated with the institution where the 
patient receives medical care, maintains all original inpatient and outpatient chart documents. 
11.0 ECOG PERFORMANCE STATUS SCALE  
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 


Amendment9 
09NOV2021                                                        Page 49 of 77 
12.0 BODY SURFACE AREA  
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
 
or 
BSA = 
 
13.0 ETHICAL CONSIDERATIONS  
This study is to be conducted according to US and international standards of Good Clinical 
Practice (GCP), FDA Title 21 part 312 and International Conference on Harmonization guidelines, 
applicable government regulations and Institutional research policies and procedures. This study 
is to be performed by personnel who are qualified by education, training, and experience to 
perform their respective tasks and that the study will not use the services of study personnel for 
whom sanctions have been invoked or where there has been scientific misconduct or fraud.  
 
This protocol, informed consent form, and any accompanying materials provided to the subject, 
will be submitted to a properly constituted independent Ethics Committee (EC) or Institutional 
Review Board (IRB), in agreement with local legal regulations, for formal approval of the study 
conduct. The decision of the EC/IRB concerning the conduct of the study will be made in writing 
to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study. Any modifications made to the protocol after receipt of the EC/IRB 
approval must be submitted by the investigator to the committee as an amendment, in accordance 
with local procedures and regulatory requirements. This study is to be conducted according to the 
IRB/EC approved protocol.  
13.1 Informed Consent  
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The information includes, but is not limited to: the purpose, potential risks and benefits, 
alternatives to participation, confidentiality statement, and other critical issues regarding the 
clinical study in which they volunteer to participate. This consent form will be submitted with the 
protocol for review and approval by the EC/IRB for the study. The formal consent of a subject, 
using the EC/IRB-approved consent form, must be obtained before that subject undergoes any 
study procedure. The consent form must be signed and dated by the subject or legally acceptable 
representative, and the investigator designated research professional obtaining the consent. 
14.0 CTCAE 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE4.032010-06-
14QuickReference8.5x11.pdf  
3131
)
(
)
(
lbs
Wt
inches
Ht
×
3600
)
(
)
(
kg
Wt
cm
Ht
×


Amendment9 
09NOV2021                                                        Page 50 of 77 
15.0 REFERENCES  
1. 
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with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. The 
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2. 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
relapsed large B-cell lymphoma in the rituximab era. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2010;28(27):4184-4190. 
3. 
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma 
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4. 
Rezvani AR, Kanate AS, Efron B, et al. Allogeneic hematopoietic cell transplantation after failed 
autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning. Bone 
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5. 
Donato ML, Siegel DS, Vesole DH, et al. The graft-versus-myeloma effect: chronic graft-versus-
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6. 
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Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory 
Hodgkin's lymphoma. The New England journal of medicine. 2015;372(4):311-319. 
8. 
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
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9. 
O'Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel 
strategy for the treatment of melanoma and other malignancies. Cancer. 2007;110(12):2614-2627. 
10. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. The New England journal of medicine. 2015;373(1):23-34. 
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Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class 
of immunomodulatory antibodies for cancer treatment. Journal of clinical oncology : official 
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12. 
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. The New England journal of medicine. 2015;372(21):2006-2017. 
13. 
Sledzinska A, Menger L, Bergerhoff K, Peggs KS, Quezada SA. Negative immune checkpoints on 
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Antonia SJ, Bendell JC, Taylor MH. Phase I/II study of nivolumab with or without ipilimumab for 
treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Annual Meeting. 2015. 
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Taur Y, Jenq RR, Ubeda C, van den Brink M, Pamer EG. Role of intestinal microbiota in 
transplantation outcomes. Best Pract Res Clin Haematol. 2015;28(2-3):155-161. 
16. 
Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by 
modulating the tumor microenvironment. Science. 2013;342(6161):967-970. 
17. 
Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune 
effects of cyclophosphamide. Science. 2013;342(6161):971-976. 
18. 
Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on 
the gut microbiota. Science. 2015;350(6264):1079-1084. 
19. 
Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity 
and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-1089. 


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20. 
Xia Y, Medeiros LJ, Young KH. Immune checkpoint blockade: Releasing the brake towards 
hematological malignancies. Blood Rev. 2015. 
21. 
Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X. New immunotherapies targeting 
the PD-1 pathway. Trends Pharmacol Sci. 2015;36(9):587-595. 
22. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annual review of immunology. 2008;26:677-704. 
23. 
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune 
diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. 
Immunity. 1999;11(2):141-151. 
24. 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells 
in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proceedings of the National Academy of Sciences of the United States of America. 
2002;99(19):12293-12297. 
25. 
Xu F, Xu L, Wang Q, An G, Feng G, Liu F. Clinicopathological and prognostic value of 
programmed death ligand-1 (PD-L1) in renal cell carcinoma: a meta-analysis. Int J Clin Exp Med. 
2015;8(9):14595-14603. 
26. 
Massi D, Brusa D, Merelli B, et al. The status of PD-L1 and tumor-infiltrating immune cells predict 
resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. 
Ann Oncol. 2015;26(9):1980-1987. 
27. 
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 
(MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2010;28(19):3167-3175. 
28. 
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous 
Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015;373(17):1627-1639. 
29. 
Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP. Long-term survival 
of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-
PD-1, BMS-936558, ONO-4538) in a phase I trial. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2014;32(Supplement):9002. 
30. 
McKinstry KK, Strutt TM, Swain SL. Regulation of CD4+ T-cell contraction during pathogen 
challenge. Immunol Rev. 2010;236:110-124. 
31. 
Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 
monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. 
Clinical cancer research : an official journal of the American Association for Cancer Research. 
2009;15(20):6446-6453. 
32. 
Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of 
malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581-1588. 
33. 
Yu P, Steel JC, Zhang M, Morris JC, Waldmann TA. Simultaneous blockade of multiple immune 
system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine 
metastatic colon carcinoma model. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2010;16(24):6019-6028. 
34. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. 
The New England journal of medicine. 2013;369(2):122-133. 
35. 
Williams, C. D., et al. (2001). "High-dose therapy and autologous stem-cell support for 
chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study 
from the European Bone Marrow Transplant Registry." J Clin Oncol 19(3): 727-735. 
36. 
Andreadis, C., et al. (2005). "Long-term event-free survivors after high-dose therapy and 
autologous stem-cell transplantation for low-grade follicular lymphoma." Bone Marrow Transplant 
36(11): 955-961. 
 
 


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APPENDIX A: Second-Line Age Adjusted International Prognostic Index (sAAIPI)  
 
Factors: 
 
- 
Stage III or IV 
- 
LDH> Upper limit of normality 
- 
ECOG Performance Status ≥ 2 
 
 
Low-risk: 0 factors 
Low-Intermediate: 1 factor 
High-intermediate: 2 factors 
High: 3 factors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: The Lugano Classification for Response Assessment of Non-
Hodgkin Lymphoma  
 
 
 
 
 
 
 
 
 


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As published by Cheson et al, JCO August 11, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: INTERNATIONAL MYELOMA WORKING GROUP  
International Myeloma Working Group uniform response criteria for multiple myeloma 
 
Durie et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 
20:1467-1473. 
Criteria for multiple myeloma disease assessment: 
 
 


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APPENDIX D: STUDY FLOWCHART  
 
Screening 
Phase 
Treatment 
cycles 
Safety 
Visits 
End of 
treatment 
Post treatment 
 
Screening 
(Visit 1) 
Day 1 (+/- 2 
days) of weeks 
1, 4, 7, 10, 12, 
14, 16, 18, 20, 
22, 24, 26 
Week 1 is 
defined as 
initiation of 
checkpoint 
inhibitors, not 
weeks post 
ASCT. 
Day 1 (+/- 2 
days) of 
weeks 2, 3, 5, 
6, 8, and 9 
Week 1 is 
defined as 
initiation of 
checkpoint 
inhibitors, 
not weeks 
post ASCT. 
For study 
completion or 
discontinuation 
of therapy 
 (discon) 
(To be completed 
within 2 weeks of 
last dose) 
(+/- 14 days) 
Safety visit 
30 days 
post End of 
Treatment 
Visit  
(+/- 14 
days) 
Follow up 
visits every 
12 weeks 
post End of 
Treatment 
Visit (+/- 14 
days) 
Survival 
visits 
every 12 
weeks 
post End 
of 
Treatment 
(+/- 14 
days) 
 
Administrative Procedures 
Informed Consent 
Xa 
 
 
 
 
 
 
Informed Consent for 
Future 
Biomedical 
Research - Optional 
Xn 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Demographics/Medical 
History 
Xa 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
X 
X 
X 
Xg 
 
Trial 
Treatment 
Administration 
(See 
Section 5.0) 
 
X 
 
 
 
 
 
Post-study 
disease 
status 
 
 
 
X 
X 
X 
 
Survival Status  
 
 
 
 
 
 
Xh 
 
Clinical Procedures/Assessments 
Review Adverse Events  
X 
X 
X 
X 
X 
Xg 
 
Physical Examination  
X d 
X 
X 
X 
X 
X 
 
Vital Signs and Weight  
X d 
X 
X 
X 
X 
X 
 
12-Lead 
Electrocardiogram 
Xb 
 
 
 
 
 
 
MUGA or ECHO with 
LVEF  
Xb 
 
 
 
 
 
 
Imaging Assessment e 
Xb, e 
 
 
 
 
 
 
Pulmonary 
Function 
Test 
Xb 
 
 
 
 
 
 
ECOG PS 
X d 
X 
 
X 
X 
X 
 
 
Laboratory Assessments 
CMV, 
HIV, 
HTLV, 
Hepatitis B, Hepatitis C 
evaluations 
X d 
 
 
 
 
 
 
Pregnancy Test c 
X d 
X 
 
X 
X 
 
 
CBC with differential 
Xd 
X 
X 
X 
X 
X 
 


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Complete 
Metabolic 
Panel (Na, K, BUN, 
Creatinine, Cl, CO2, 
Anion Gap, Ca, P, Mg, 
Uric Acid, Alk Phos, 
AST, 
ALT, 
bilirubin, 
albumin, LDH, Glucose, 
GGTP). 
Xd 
X 
X 
X 
X 
X 
 
Total CK 
X d 
X 
 
 
X 
 
 
LFTs (PT/INR, aPTT, 
albumin, total bilirubin) 
Xd 
 
 
 
 
 
 
Baseline 
disease 
assessments 
X d,  f 
 
 
 
 
 
 
Urinalysis  
X d 
On weeks 
1,7,14,22 and 
26 only 
 
X 
 
 
 
Haptoglobin 
X d 
On weeks 1, 7, 
12, 16, 20, and 
24 only 
 
 
X 
 
 
TSH, T3 and free T4; 
lipase and amylase, 
cortisol 
X d 
On weeks 
1,7,14,22 and 
26 only 
 
X 
 
 
 
Bone Marrow Biopsy / 
Tumor Biopsy 
Xk 
  
 
 
Xk 
 
 
 
Peripheral 
blood 
collection for blood 
immune 
phenotype 
and 
metabolomics 
analysis  
XL 
X 
On weeks 1, 4, 
7, 12, 18 and 26 
only 
 
 
 
 
Post 
transplant 
months 9, 
12,15 and 
18 and at 
time of 
relapse 
 
Stool 
sample 
for 
microbiome analysis 
Xm 
X 
On weeks 1,4, 
7, 12, 18 and 26 
only 
 
 
 
Post 
transplant 
months 9, 
12,15 and 
18 and at 
time of 
relapse 
 
 
Response Assessment 
For groups A,B,C,D 
 
PET-CT scan and/or CT scan with intravenous/oral contrast of neck, chest, abdomen, 
and pelvis will be performed for response evaluation 90-100 days post ASCT, 180-200 
days post ASCT, 360-380 days post ASCT and 540-560 days post ASCT. Response 
criteria will follow the Lugano Classification (see Appendix B).  
For groups E and F 
 
Serum protein electrophoresis with immunofixation, quantitative serum IgG, IgM, IgA 
(IgE or IgD  in cases where this is the involved immunoglobulin), serum free light 
chains, 24-hour urine for protein electrophoresis with immunofixation and protein 
quantification will be collected for response evaluation 30-40 days post ASCT, 60-70 
days post ASCT, 90-100 days post ASCT, 180-200 days post ASCT, 270-290 days post 
ASCT, 360-380 days post ASCT, 450-470 days post ASCT and 540-560 days post ASCT. 


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Response criteria will follow the International Myeloma Working Group (IMWG) 
Uniform Response Criteria for Multiple Myeloma (see Appendix C).  
 
a To be completed within 60 days prior to start of ASCT conditioning regimen  
b To be completed within 90 days prior to start of ASCT conditioning regimen  
c Pregnancy test can be urine or serum Beta-HCG (for women of child-bearing potential)  
d To be completed within 30 days prior to start of ASCT conditioning regimen  
e Chest radiography to be completed within 90 days prior to start of ASCT conditioning regimen.      
f  For groups A, B, C, D: PET-CT scan and/or CT scan with intravenous/oral contrast of neck, chest,  
  abdomen, and pelvis within 30 days prior to initiation of ASCT conditioning must be completed  
For groups E&F: Skeletal Survey must be completed within 30 days prior to initiation of ASCT conditioning. Serum 
protein electrophoresis with immunofixation, quantitative serum IgG, IgM, IgA (IgE or IgD  in cases where this is the 
involved immunoglobulin), serum free light chains, 24-hour urine for protein electrophoresis with immunofixation 
and protein quantification will be collected for response evaluation. 
g Subjects will be followed through 100 days of discontinuation of dosing or until the start of a subsequent systemic 
anti-cancer therapy, if earlier, for Adverse Events and Concomitant Medications 
h Survival Status may be conducted by telephone  
k Tumor Biopsies and/or Bone Marrow Biopsies for Lymphoma subjects (Groups A through D) and Bone Marrow 
Biopsies for Multiple Myeloma subjects (Groups E & F) will be collected at screening, end of treatment, complete 
response, and at relapse, if clinically indicated . Tumor Biopsies and/or Bone Marrow Biopsies will be performed to 
confirm complete response at the discretion of the investigator. For Bone Marrow Biopsies, the research sample will 
be collected (aspirate, send the first pull, yellow top tube) to Dr. Korngold’s lab. Additional samples for all disease 
groups will be sent to pathology for immunostaining of fixed tissue for PDL1 expression on tumor cells and for the 
in situ presence of CD4 and CD8 T cells with PD1 expression. If viable biopsy material is unavailable for research 
purposes, Dr. Korngold’s lab will access fixed archival tumor materials for preparing tumor lysates and possibly for 
retrieving T cell DNA for repertoire analysis. Samples for Georgetown University subjects are to be shipped via Fed 
Ex on the day of collection – tubes banded in sealed plastic bag and wrapped in bubble wrap at room temperature 
to Dr. Korngold’s lab. 
L Two time points are to be collected for peripheral blood samples prior to combined checkpoint therapy initiation: 
1. During the screening visit; and 2. An apheresis sample from the Apheresis product (1x yellow top tube – ½ full 
(4mL)). For patients in groups A-E who already had Apheresis product collected, the apheresis sample may be 
performed on the frozen product. For group F ONLY, apheresis sample will not be collected. 
m Three time points are to be collected for stool samples prior to combined checkpoint therapy initiation: 1. 
Screening Visit (up to 7 days post consent); 2. Preconditioning (to be collected within 48 hours prior to transplant 
admission); and 3. At engraftment (within 72 hours of ANC > 500). For patients who sign consent within 7 days of 
transplant admission, the Screening Visit sample will not be collected, and collection will start with the 
Preconditioning sample.  
n An optional informed consent for the Hackensack University Medical Center sampling protocol, TMBK 06.05.039, 
will be presented at time of screening if the subject is not currently participating.  
 
 


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APPENDIX E: Events of Clinical Interest Reference Table 
 
 
 
 
 
 


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APPENDIX F: ECI Management Algorithm   
 
 
 
Where I-O therapy is referred, it means Ipilimumab and Nivolumab combination therapy. 
 
In general terms, each immune-related adverse event (irAE) should be managed as follows: 
 
• 
Grade I: Continue treatment as scheduled, manage with symptomatic treatment 
• 
Grade II: Withhold therapy with I-O until improvement to grade I or better. If patient misses 
a dose of treatment drug due to an irAE, the following dose will be given as per the original 
schedule, and there will not be “catch-up” doses (i.e. treatment with I-O should not exceed 
original 26 weeks from initiation) 
• 
If there has been no improvement within 7 days, then steroid therapy should be initiated. 
Dosage should be 1-2mg/kg/day of methylprednisolone IV (or equivalent) divided in 2 daily 
doses. The initial dosage should be continued until irAE have improved to Grade I or 
better. At that time, steroid should be tapered over the course of 2 weeks to the equivalent 
of 20 mg/day of methylprednisolone. If there has been no exacerbation of irAE with steroid 
taper, once the steroid dosage is 20 mg/day, as above, I-O can be resumed. Steroids 
should continue to be tapered off completely over a course of 2 additional weeks.  
• 
Grades III-IV: Interrupt therapy and start steroids as per protocol above (Grade II). I-O 
should be resumed as described above. 
 
If irAE persists after 3-5 days of high-dose steroids, or if it recurs after initial improvement, 
consideration should be given to infliximab 5 mg/kg or mycophenolate mofetil 500-750mg three 
times a day. 
 
If there is recurrence of Grade III or IV irAE, subject should be removed from study.  
 
Please follow algorithms below for specific irAE management.  
 
 
 
 
 
 
 


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APPENDIX G: Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
Since Nivolumab and ipilimumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.   
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE (version 4.03)) guidelines.  
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
• 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premeditations are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nivolumab or ipilimumab administrations. 
 
• 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours).  
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor subject until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate. Monitor subject closely. If 
symptoms recur then no further nivolumab or ipilimumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject 
until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premeditations are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab or ipilimumab administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
• 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for other 
clinical sequelae [e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; 
pressor or ventilator support indicated).  


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Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of 
normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be 
monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab 
or ipilimumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms. In the case of late-occurring hypersensitivity 
symptoms (eg, appearance of a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (e.g., oral antihistamine, or 
corticosteroids). 
 
 
 
 
 
 


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APPENDIX H: Sample of Drug Ordering and Pharmacy Reference Material  
Initial Orders  
• 
Following submission and approval of the required regulatory documents, a supply of 
nivolumab and ipilimumab may be ordered from by completing a Drug Request Form 
provided by BMS for this specific trial.  
• 
The initial order should be limited to the amount needed for two doses. Allow 5 business 
days for shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug products will be shipped by courier in a 
temperature-controlled container. It is possible that sites may have more than one 
nivolumab clinical study ongoing at the same time. It is imperative that only drug product 
designated for this protocol number be used for this study. 
• 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents,  
In-line filters and infusion tubing 
Re-Supply 
• 
Drug re-supply request form should be submitted electronically at  least 7 business days 
before the expected delivery date.  Deliveries will be made Tuesday through Friday. 
• 
When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
Drug Excursions 
• 
Drug  excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 
 
Please refer to the most recent version of the nivolumab and ipilimumab Investigator Brochure for 
additional information to be included as per institutional or regulatory standards. 
 
Nivolumab (BMS-936558) Pharmacy Reference Material 
As this is provided for guidance only, please see investigator brochure for additional information 
regarding preparation and administration.  
 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials are 
provided in a carton. 
 
Storage Conditions & Handling: 
• 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
• 
If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.    
• 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic 
technique.  
• 
Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. For further information, please either discuss with 
your BMS CSR&O protocol manager or refer to your site IP Destruction policies and procedures  
 


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Use Time/Stability: Please refer to the appropriate section of the current Investigator 
Brochure/Addendum. Due to parameters surrounding the use time of nivolumab and ipilimumab, 
the time of preparation should be noted in the Pharmacy Source documents [accountability logs] 
or in study files as required for investigator sponsored research [FDA and GCP] 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be 
completed within 24 hours of preparation. If not used immediately, the infusion solution may be 
stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and 
used within 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature 
(20°-25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature 
and room light conditions for undiluted and diluted solutions of BMS-936558-01 injection in the IV 
bag includes the product administration period. 
 
Preparation and Administration: 
1. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution 
may have a pale-yellow color), or if there is foreign particulate matter other than a few 
translucent-to-white, amorphous particles.Note: Mix by gently inverting several times.  Do 
not shake. 
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV. bag.  If multiple vials are needed for a subject, it is important to use a 
separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. Do not 
enter into each vial more than once.  Do not administer study drug as an IV push or bolus 
injection 
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection  solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
4. Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] 
5. Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
6. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
7. At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents. 
 
Ipilimumab Pharmacy Reference Material 
Ipilimumab vials (40 mL) are shipped in quantities of four..  
Ipilimumab (BMS-734016) Injection (5 mg/ml) must be stored refrigerated (2-8°C, 36-46°F) with 
protection from light and from freezing. Ipilimumab may be stored in IV infusion bags (PVC, non-
PVC/non-DEHP) or glass infusion containers for up to 24 hours at room temperature (20-25°C, 
68-77°F) or refrigerated (2-8°C, 36-46°F). This would include any time in transit and the total time 
for infusion. Drug must be completely delivered within 24 hours of preparation. 
 
Storage Conditions & Handling: 
Ipilimumab injection may be stored undiluted, 200 mg/vial (5 mg/mL), or following dilution to 
concentrations between 1 mg/mL and 4 mg/mL in 0.9% Sodium Chloride Injection (USP), or 5% 
Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 hours in the 
refrigerator (2°C to 8°C) or at room temperature/room light. For longer storage, ipilimumab should 
be kept refrigerated (2°C to 8°C) with protection from light. 
Ipilimumab injection must not be frozen. 


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Partially used vials or empty vials of Ipilimumab Injection should be discarded at the site according 
to appropriate drug disposal procedures.  
 
Preparation and Administration 
As this is provided for guidance only, please see investigator brochure for additional information 
regarding preparation and administration. 
1. As ipilimumab is stored long term at refrigerated temperatures (2-8ºC) and protected from 
light, allow the appropriate number of vials of ipilimumab to stand at room temperature for 
approximately five minutes. 
2. Ensure that the ipilimumab solution is clear colorless, essentially free from particulate 
matter on visual inspection. If multiple vials are needed for a subject, it is important to use 
a separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall, etc. 
3. Aseptically transfer the required volume of ipilimumab solution into a syringe. [Note: A 
sufficient excess of ipilimumab is incorporated into each vial to account for withdrawal 
losses].  
4. Do not draw into each vial more than once. Discard partially used vials or empty vials. 
5. Ipilimumab solution should be added to an appropriate size infusion container to 
accommodate the calculated final volume. 
Total dose should be calculated using the most recent subject weight; if weight on dosing 
day differs by 10% from prior weight used to calculate dosing, the dose should be 
recalculated and study drug adjusted accordingly. 
Mix by GENTLY inverting several times. DO NOT shake. 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP. 
6. Visually inspect the final solution. If the initial diluted solution or final solution for infusion 
is not clear or contents appear to contain precipitate, the solution should be discarded. 
7. Immediately after the infusion is complete, flush with an adequate amount of 0.9% Sodium 
Chloride injection (USP) or 5% Dextrose injection (USP)  to completely flush the residual 
fluid (dead space) in your administration set (approximately 30-50mL); this will ensure that 
all active drug is delivered to the study participant 
8. Safely discard any unused portion of the infusion solution. Do not store for reuse. 
 
Ipilimumab should be administered under the supervision of a physician experienced in the use 
of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only 
 
It is possible that sites may have more than one ipilimumab clinical study ongoing at the same 
time. It is imperative that only product designated for this protocol be used for this study. 
 
 
 


Amendment9 
09NOV2021                                                        Page 74 of 77 
APPENDIX I: Adverse Event Reporting  
• 
All Adverse Events and Serious Adverse Events (SAEs) that occur following the subject’s 
first dose of therapy on Day 1 of Week 1 of combined checkpoint therapy in the study 
through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, 
and according to local regulations.  
• 
If the BMS safety address is not included in the protocol document (e.g. multicenter studies 
where events are reported centrally), the procedure for safety reporting must be 
reviewed/approved by the BMS Protocol Manager.  Procedures for such reporting must 
be reviewed and approved by BMS prior to study activation. 
• 
The BMS SAE form should be used to report SAEs.  If the BMS form cannot be used, 
another acceptable form (i.e CIOMS or Medwatch) must be reviewed and approved by 
BMS.  The BMS protocol ID number must be included on whatever form is submitted by 
the Sponsor/Investigator. 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring after 
these time periods that is believed to be related to study drug or protocol-specified 
procedure.  
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). In the European Union (EU), an event meeting these criteria is termed 
a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of 
these events will be in the form of an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack 
of efficacy that poses significant hazard to study subjects, clinically significant 
safety finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision to 
end or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. 
The investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
o In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health authorities 
in all concerned countries according to local regulations (either as expedited and/or 
in aggregate reports). 
 
Serious Adverse Event Collection and Reporting 
Following the subject’s first dose of therapy on Day 1 of Week 1 of combined checkpoint therapy  
to participate in the study, all SAEs, whether related or not related to study drug, must be 
collected, including those thought to be associated with protocol-specified procedures. All SAEs 
must be collected that occur within 100 days of discontinuation of dosing. 
 
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy).  The 


Amendment9 
09NOV2021                                                        Page 75 of 77 
investigator should report any SAE that occurs after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a 
Pregnancy Surveillance Form. 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.Safety@bms.com 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
 
All SAEs should be followed to resolution or stabilization. If the investigator believes that an SAE 
is not related to study drug, but is potentially related to the conditions of the study (such as 
withdrawal of previous therapy or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution 
or stabilization.  All SAEs should be followed to resolution or stabilization. 
 
The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS 
and any applicable health authority during the conduct of the study. This reconciliation will occur 
at least quarterly and be initiated by the sponsor/investigator. Sponsor/investigator will request a 
reconciliation report from: aepbusinessprocess@bms.com. During reconciliation, any events 
found to not be reported previously to BMS must be sent to Worldwide.Safety@BMS.com. 
 
 
 
 


Amendment9 
09NOV2021                                                        Page 76 of 77 
APPENDIX J: Research Biospecimen Sample Collection 
CPIT Trial 001 
Date of Transplant: 
Patient ID 
Disease: 
Code for Correlative Studies 
CPIT 001-(PtID) (Timepoint) (Date) 
Peripheral Blood Samples 
(8x Yellow top tubes (BD Vacutainer ACD Solution A Blood 
Collection tubes – 8.5ml) – 68 ml 
*to be collected prior drug administration* 
Timepoint ID 
Screening Visit  
S 
Apheresis product 
(1x Yellow top tube – 1/2 full – 4mL) 
Aph 
Day 1 (+/-2 days), Week 1* 
1 
Day 1 (+/-2 days), Week 4* 
4 
Day 1 (+/-2 days), Week 7* 
7 
Day 1 (+/-2 days), Week 12* 
12 
Day 1 (+/-2 days), Week 18* 
18 
Day 1 (+/-2 days), Week 26* 
26 
End of Treatment Visit 
ET 
Post BMT, 9 mo 
9M 
Post BMT, 12 mo 
12M 
Post BMT, 15 mo 
15M 
Post BMT, 18 mo 
18M 
Relapse 
R 
All Peripheral blood samples are to be kept at room temperature – no immediate processing needed.  
 
Samples for HackensackUMC subjects are to be delivered via courier to lab in Room 352, Jurist 
Research Building ASAP. If sample is collected in the late afternoon, please store at room 
temperature on a shaker (slow speed) until delivered to Dr. Korngold’s Laboratory the next day. 
 
Samples for Georgetown University subjects are to be shipped via Fed Ex on the day of collection. 
The tubes are to be banded in sealed plastic bag and wrapped in bubble wrap. If sample is collected in 
the late afternoon, please store at room temperature on a shaker (slow speed) until next shipment day. 
 
Please  ship  to:  
Robert Korngold, PhD 
Hackensack University Medical Center 
Jurist Research Building  
40 Prospect Ave 
Room 352 
Hackensack, NJ  07601 
A subset of the Peripheral blood samples delivered to Dr. Korngold’s Laboratory will be shipped to 
Georgetown Lombardi Comprehensive Cancer Center for Metabolomics Analysis.  


Amendment9 
09NOV2021                                                        Page 77 of 77 
 
 
Note: For those patients who sign informed consent after apheresis has already occurred, the 
Apheresis Blood Sample will be performed on the previously collected, frozen product. 
 
Note: If patient signs consent within 7 days of transplant admission, stool sample collection will 
start from item “2” (Preconditioning).   
Stool Samples 
To be collected up to 48 hours prior to clinic visit and           
* prior to drug administration 
Timepoint ID 
Screening Visit  
S 
Preconditioning 
(to 
be 
collected 
within 48 
hours 
prior to 
transplant admission) 
P 
Engraftment (within 72 hours of ANC ≥ 500) 
E 
Day 1, Week 1* 
1 
Day 1, Week 4* 
4 
Day 1, Week 7* 
7 
Day 1, Week 12* 
12 
Day 1, Week 18* 
18 
Day 1, Week 26* 
26 
End of Treatment Visit 
ET 
Post BMT, 9 mo 
9M 
Post BMT, 12 mo 
12M 
Post BMT, 15 mo 
15M 
Post BMT, 18 mo 
18M 
Relapse 
R 
All stool samples at HackensackUMC are to be kept at -80oC – no immediate processing needed. 
 
Samples for HackensackUMC Subjects are to be delivered via courier to lab in an insulated 
container or pouch with an ice pack or ice to Room 352, Jurist Research Building ASAP.  
 
Samples for Georgetown University subjects are to be shipped via Fed Ex on the day of collection– 
The tubes are to be placed in sealed plastic bag and shipped on dry ice. If sample is collected in the late 
afternoon, please store immediately at -20oC and ship on dry ice the following day.  
 
Please  ship  to:  
  
Robert Korngold, PhD 
Hackensack University Medical Center 
Jurist Research Building  
40 Prospect Ave 
Room 352 
Hackensack, NJ  07601