Conditions: Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma Classical Hodgkin Lymphoma Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of gemcitabine, bendamustine, and nivolumab when given together and to see how well they work in treating patients with classic Hodgkin lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as gemcitabine and bendamustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving gemcitabine, bendamustine, and nivolumab may work better in treating patients with classic Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the toxicity and determine the maximum tolerated dose (MTD) of combined gemcitabine, bendamustine, and nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma.

II. To determine the efficacy of bendamustine, gemcitabine, and nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the duration of response, progression-free survival, and overall survival for patients with relapsed/refractory classical Hodgkin lymphoma who receive gemcitabine, bendamustine, and nivolumab, including those who receive nivolumab maintenance.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive gemcitabine intravenously (IV) over 30 minutes on day 1, bendamustine IV over 30 minutes on days 1 and 2, and nivolumab over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may then receive nivolumab IV over 60 minutes on day 1. Treatment with single agent nivolumab repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms:
arm 1: Patients receive gemcitabine IV over 30 minutes on day 1, bendamustine IV over 30 minutes on days 1 and 2, and nivolumab over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may then receive nivolumab IV over 60 minutes on day 1. Treatment with single agent nivolumab repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Bendamustine intervention 2: Gemcitabine intervention 3: Nivolumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol document:
Prot_SAP_001.pdf: 
1 
 
  
  
A PHASE I/II STUDY OF GEMCITABINE, BENDAMUSTINE, AND NIVOLUMAB IN PATIENTS WITH 
RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA 
 
 
Principal Investigator 
Jonathon B. Cohen, MD, MS 
Department of Hematology and Medical Oncology 
Emory University 
1365 Clifton Road, NE 
Atlanta, GA 30322 
Email: Jonathon.cohen@emory.edu 
 
 
Statistician 
 
Zhengjia “Nelson” Chen, PhD 
Department of Biostatisics and Bioinformatics  
Emory University 
Zchen38@emory.edu 
 
 
Participating Institutions 
 
 
Multi-site Coordinator 
Latrisha Moore, MPH 
Emory University – Winship Cancer Institute 
Phone: 404-778-5747 
Fax: 404-778-0417 
Email: Lmoor25@emory.edu 
 
 
 
 
Protocol Version 
1.0 
July 5,2018 
 
 


2 
 
A PHASE I/II STUDY OF GEMCITABINE, BENDAMUSTINE, AND NIVOLUMAB IN PATIENTS WITH 
RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA 
 
Patient Eligibility (See Protocol for Full Criteria) 
Initial Required Laboratory Values 
Histologically confirmed classical Hodgkin lymphoma that 
is recurrent or refractory after at least one prior therapy.  
No history of severe pneumonitis 
Measurable Disease 
Prior stem cell transplant is permitted but no active GVHD 
Non-pregnant and non-nursing 
 
ANC ≥ 1000/µL* 
Platelets ≥ 75,000/µL*  
Creatinine Clearance ≥50mL/min 
Bilirubin ≤ 2.0mg/dL  
AST/ALT ≤ 2.0 x ULN 
*Except in instance of bone marrow 
involvement 
Staging and Entry Parameters 
 
History and physical examination. 
 
CBC with differential 
 
Creatinine, bilirubin, AST, ALT, ESR 
 
PET/CT scan 
 
 
 
TREATMENT SCHEMA FOR COMBINATION CYCLES 
 
Phase I Dose Escalation Schema       Cycle Length: 21 days 
Dose level 
Gemcitabine (mg/m2) IV 
over 30 minutes day 1  
Bendamustine 
(mg/m2) 
IV  
over 30 minutes days 1 and 2 
Nivolumab (mg) on 
day 1  
-3 
800 
75 
140 
-2 
800  
90  
140  
-1 
800 
90 
240 
1 
1000 
90 
240 
2 
1000 
120 
240 
NOTE: Maintenance dosing will be nivolumab monotherapy 480mg IV day 1 of 28 day 
cycle. 


3 
 
 
 


4 
 
TABLE OF CONTENTS 
 
 
SECTION 
PAGE 
 
1.0 
INTRODUCTION ................................................................................................................... 5 
2.0 
OBJECTIVES ......................................................................................................................... 8 
3.0 
ELIGIBILITY CRITERIA ........................................................................................................... 8 
4.0 
REQUIRED DATA ................................................................................................................ 10  
5.0 
REGISTRATION PROCESS ................................................................................................... 12 
6.0 
TREATMENT PLAN ............................................................................................................. 13 
7.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ............................................... 17 
8.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION ............................................... 19 
9.0 
ANCILLARY THERAPY ......................................................................................................... 22 
10.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE ................................................. 23 
11.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ...................................................... 27 
12.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 28 
13.0 
ADVERSE EVENT REPORTING ............................................................................................ 30 
14.0 
REFERENCES ...................................................................................................................... 39 
 
 


 
5 
 
1.0 INTRODUCTION 
1.1 RELAPSED HODGKIN LYMPHOMA  
Most patients with classical Hodgkin lymphoma will be cured with combination 
chemotherapy, with long-term progression-free survival (PFS) ranging from 75% to 82% 
for patients treated with ABVD or brentuximab vedotin + AVD.1,2 However, this 
approach is not curative in all patients, and patients who relapse will require additional 
therapies.  Currently, patients with relapsed Hodgkin lymphoma who are fit receive 
intensive salvage therapies including ICE, GVD, or others followed by autologous stem 
cell transplantation (ASCT).3-5 Despite the use of high dose therapy, up to 50% of 
patients who complete stem cell transplantation will relapse and still others will either 
be poor candidates for ASCT or will not achieve adequate disease control to proceed to 
transplant.  As a result, alternative approaches are needed for the subset of patients 
who are not cured with currently available therapies. 
During the past few years, 3 agents have been approved for management of relapsed 
Hodgkin 
lymphoma: 
brentuximab 
vedotin, 
nivolumab, 
and 
pembrolizumab.  
Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate with an overall 
response rate (ORR) of 75% in patients with relapsed classical HL who had progressed 
after ASCT.6 This agent has also been evaluated as post-transplant maintenance therapy 
in patients with high risk relapsed disease undergoing ASCT (based on extranodal site of 
relapse, early relapse, or poor response to salvage therapy), and use of BV post-
transplant was associated with an improvement in PFS (median 43 months vs 24 
months) when compared to those patients who did not receive BV.  Most recently, BV 
has been evaluated in combination with AVD in the upfront setting, where there was a 
statistically improved modified PFS when compared to the standard, ABVD.2 As a result 
of these studies, BV has been integrated into the standard approach to patients with HL.  
However, BV is not effective in all patients, is not curative, and can be associated with 
significant toxicities including neuropathy, neutropenia, and others.  As a result, most 
patients who receive BV for management of relapsed disease will require additional 
therapies. 
1.2 PD1 Inhibition in Hodgkin Lymphoma  
The pathology of classical HL includes rare Reed-Sternberg cells surrounded by an 
immune infiltrate, and the role of the immune system in the development and 
progression of HL has been well-described.  The programmed death-1 (PD-1) pathway 
has been identified as a critical component of disease progression in HL, as Hodgkin RS 
cells commonly overexpress PD-1 ligand and have been shown to have amplification of 
chromosome 9p24.1, where genes encoding PD-1 and PD-1 ligand reside.7 This is felt to 
suppress the surrounding immune cells and permit the Hodgkin RS cell to continue to 
grow and proliferate, and these findings result in a rationale for targeting of the PD-1 
axis in classical HL. 


 
6 
 
Two PD-1 antibodies have been approved for use in relapsed/refractory classical 
Hodgkin Lymphoma: pembrolizumab and nivolumab.  Nivolumab was initially evaluated 
in a phase 1 study across lymphoid malignancies, where the ORR ranged from 15-40% 
based on underlying histology, which included both T-cell and B-cell NHL.8 A separate 
study in classical Hodgkin Lymphoma demonstrated an even higher ORR of 87% with a 
CR rate of 17%.9 As a result, a phase 2 study of nivolumab in classical HL was conducted 
which included patients relapsed after autologous stem cell transplantation, with 
variable prior exposure to brentuximab vedotin.10  The ORR in this study was 66%, and 
subsequent follow-up for this study has now been published and has identified durable 
remissions.  In addition, as opposed to conventional chemotherapy, patients with 
classical HL who receive nivolumab have been able to safely receive therapy beyond 
radiographic progression.11  As a result, the management of patients receiving 
checkpoint inhibitors requires careful clinical assessment in addition to radiographic 
restaging.  Despite the fact that radiographic response may not fully reflect disease 
activity in HL patients receiving checkpoint inhibitors, the majority of patients will not 
achieve a CR and nearly all will eventually have true relapse requiring additional 
therapy.  However, the use of PD1 antibodies in patients in combination with 
chemotherapy in HL has been limited, and it is possible that achievement of a CR with 
combination therapy followed by maintenance with nivolumab may significantly prolong 
remissions for patients with relapsed/refractory disease. 
1.3 Gemcitabine and Bendamustine in Relapsed/Refractory Hodgkin Lymphoma 
Despite the proliferation of novel therapies in relapsed/refractory HL, current non-
transplant therapies are not curative, and many patients require additional lines of 
treatment.  In addition, brentuximab vedotin is now being utilized more frequently in 
the front-line setting and as post-transplant consolidation for high-risk patients with 
relapsed/refractory disease and so may be less useful in the setting of a post-transplant 
relapse. 
Gemcitabine has been utilized in relapsed/refractory HL in a number of settings, both 
before and after ASCT.5,12,13  For example, in combination with vinorelbine and doxil, the 
ORR is 75% in patients with relapsed/refractory HL.  Additional chemotherapy agents 
such as bendamustine have also been evaluated in HL, both as monotherapy as in 
combination.14,15  As a single agent, the ORR is 53%, although the median duration of 
response is only 5 months.   
We have previously reported outcomes for a phase I study utilizing a combination of 
gemcitabine and bendamustine in relapsed/refractory Hodgkin lymphoma.  In our phase 
I study, there were no DLT’s identified and the maximum tolerated dose was established 
at gemcitabine 1000mg/m2 on day 1 and bendamustine 120mg/m2 on days 1 and 2 of a 
21 day cycle.  This regimen was used prior to autologous or allogeneic transplant in 
many patients, but those patients who did not proceed with transplant had a shortened 
progression-free survival.  We have now completed a phase 2 study of this combination, 
with 22/24 evaluable patients responding.  Encountered toxicities were generally 
manageable and included primarily myelosuppression as well as nausea/vomiting, and 


 
7 
 
pulmonary complications (see Table 1).  Two patients experienced severe pulmonary 
complications, including one with a biopsy-proven gemcitabine-associated pneumonitis 
who recovered fully after discontinuation of treatment and another patient who 
developed an infectious pneumonia.   In addition to the double, bendamustine and 
gemcitabine have been combined in a triplet with vinorelbine in relapsed/refractory HL 
with an ORR of 83%, and most patients moving forward with autologous stem cell 
transplantation after 4 cycles of therapy.14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 Prior Experience with Nivolumab and Chemotherapy in Solid Tumors 
 
Gemcitabine and nivolumab have been previously combined in patients with solid 
tumors.  In a phase 1 study in pancreatic cancer, gemcitabine (100mg/m2) was safely 
administered with nab-paclitaxel and nivolumab, with 3/6 patients achieving a PR and 
no DLT’s identified.  Gemcitabine, cisplatin, and nivolumab were evaluated in squamous 
cell lung cancer as well, with manageable toxicity and a 33% ORR.  Toxicities 
encountered when combined with chemotherapy have been manageable and expected.  
For example, when combined with a platinum doublet in patients with chemotherapy-
naïve non-small cell lung cancer, the most common drug-related adverse event was 
fatigue, while other toxicities including pneumonitis (7.1% of patients), anemia (5.4%), 
febrile neutropenia (3.6%), and rash (3.6%). The most common drug-related AE’s 
leading to treatment discontinuation included pneumonitis and hypersensitivity, and no 
AE-related deaths were described. 
 
In a Japanese study of nivolumab in combination with chemotherapy in patients with 
relapsed/refractory non-small lung cancer, 6 patients were treated with gemcitabine 
TABLE 1. GRADE 3/4 TOXICITIES FROM GEMCITABINE  
AND BENDAMUSTINE PHASE  1 / 2 STUDY 
GRADE 3 
GRADE 4 
LYMPHOPENIA (N=5) 
THROMBOCYTOPENIA (N=2) 
PNEUMONITIS (N=1) 
ATRIAL FIBRILLATION (N=1) 
RENAL INSUFFICIENCY (N=1) 
HYPOALBUMINEMA (N=1) 
HYPOTENSION (N=1) 
PNEUMONIA (N=1) 
RASH (N=1) 
VOMITING (N=1) 
INSOMNIA (N=1) 
HYPOKALEMIA (N=1) 
THROMBOCYTOPENIA (N=1) 
LYMPHOPENIA (N=7) 
PULMONARY TOXICITY (N=1) 


 
8 
 
and cisplatin in combination with nivolumab.  Among those 6 patients, 2 patients 
discontinued therapy due to toxicity (due to endocrine dysfunction and 
hypersensitivity).  One other patient experienced atrial fibrillation.   
 
1.5 Rationale for Current Study 
 
The use of immunotherapy in HL has resulted in significant improvements in outcome 
for patients relapsed/refractory disease, and nivolumab-containing approaches are now 
also being assessed in the frontline setting.  However, nivolumab as a single agent 
results in a complete response in the minority of cases and as a result requires 
continuous therapy.  In addition, most patients will experience radiographic progression 
within a year and many of those patients will require treatment discontinuation.  By 
inducing a deep remission with combination chemotherapy, we are hoping to 
significantly prolong remission duration and benefit of the PD-1 antibody by introducing 
maintenance therapy in the setting of remission rather than in the presence of a high 
tumor burden.  This should hopefully overcome the challenges associated with 
nivolumab monotherapy where the CR rate is modest.  In the phase 1/2 study of the 
combination of gemcitabine and bendamustine, this regimen was highly active but 
frequently required a consolidation approach to maintain remission.  However, not all 
patients are candidates for transplantation or others may have already progressed after 
transplantation.  As a result, we wish to pursue a maintenance strategy with nivolumab 
that may prolong the remission. In addition, continuation of nivolumab after completion 
of chemotherapy should allow for improved immune activity that may be compromised 
during chemotherapy but can recover afterwards and contribute to anti-tumor activity. 
 
In this study, we will be able to evaluate the benefit of such an approach which can then 
be utilized for future studies.  We will identify any safety concerns associated with 
administration of the combination followed by monotherapy maintenance.  As an 
exploratory aim, we will also be able to compare our findings to the historical response 
rates and duration of responses seen with nivolumab monotherapy and with 
gemcitabine/bendamustine cominbations in HL. 
    
2.0 OBJECTIVES  
2.1 Primary Objectives  
2.1.1 To evaluate the toxicity and determine the maximum tolerated dose (MTD) 
of combined gemcitabine, bendamustine, and nivolumab in patients with 
relapsed/refractory classical Hodgkin lymphoma. 
2.1.2 To determine the efficacy of bendamustine, gemcitabine, and nivolumab in 
patients with relapsed/refractory classical Hodgkin lymphoma.  
2.2 Secondary Objectives  


 
9 
 
2.2.1 To evaluate the duration of response, progression-free survival, and overall 
survival for patients with relapsed/refractory classical Hodgkin lymphoma 
who receive gemcitabine, bendamustine, and nivolumab, including those 
who receive nivolumab maintenance. 
3.0 
ELIGIBILITY CRITERIA 
3.1  
Histologically documented Classical Hodgkin lymphoma that is recurrent or refractory 
after standard chemotherapy. Core biopsies are acceptable if they contain adequate 
tissue for primary diagnosis and immunophenotyping. Bone marrow biopsies as the 
sole means of diagnosis are not acceptable.  At least one biopsy-proven relapse is 
required for enrollment, but patients who have multiply relapsed disease do not 
require repeat biopsy if not clinically indicated. 
3.2  
Prior Treatment: Patients must have relapsed or progressed after at least one prior 
therapy.    
3.2.1 
Patients with relapsed or refractory disease following autologous stem 
cell transplantation arepermitted. Due to the risk of treatment-refractory GVHD, 
patients who have previously completed an allogeneic transplant are excluded.. 
3.2.2 
Patients may have received gemcitabine, bendamustine, or nivolumab in 
the past but may not have discontinued therapy due to toxicity felt to be related 
to that specific drug. 
3.3  
Age > 18 years of age.  
3.4  
ECOG Performance Status 0-2. 
3.5  
Measurable disease must be present either on physical examination or imaging 
studies. Non-measurable disease alone is not acceptable. 
3.5.1 Measurable Disease 
Lesions that can be accurately measured in at least two dimensions as ≥ 1.0 x 1.0 
cm 
by 
computerized 
tomography 
(CT), 
PET/CT 
(positron 
emission 
tomography/CT), or magnetic resonance imaging (MRI).  If identified by PET/CT, 
there must be at least one lesion that demonstrates abnormal FDG avidity, 
consistent with active disease.  Ultrasound or physical examination alone may not 
be utilized to confirm measurable disease. 
3.5.2 Non-measurable Disease 
All other lesions, including small lesions (less than 1.0 x 1.0 cm) and truly non-
measurable lesions.  
Lesions that are considered non-measurable include the following: 
• Bone lesions (lesions if present should be noted) 
• Ascites 


 
10 
 
• Pleural/pericardial effusion 
• Lymphangitis cutis/pulmonis 
• Bone marrow (involvement by Hodgkin lymphoma should be noted) 
3.6 
Non-pregnant and non-nursing. Due to the teratogenic potential of these agents, 
pregnant or nursing patients may not be enrolled. Women and men of reproductive 
potential should agree to use an effective means of birth control. 
3.7  
Patients with HIV infection are eligible. Patients with HIV infection must meet the 
following: No evidence of co-infection with hepatitis B or C; CD4+ count > 400/mm; 
no evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 
copies HIV RNA/mL.  Patients with HIV must have ongoing follow-up with an 
infectious disease specialist and must have been evaluated within 90 days of cycle 1 
day 1. 
3.8  
Patients with a history of hepatitis C are eligible as long as the hepatitis C has been 
treated and cleared and they have no evidence of hepatic dysfunction related to 
hepatitis C.  Patients must have been seen by a hepatologist within 6 months of cycle 
1 day 1.   
3.9 
Patients who test positive for hepatitis B core antibody may enroll on the study as 
long as they test negative for both hepatitis B surface antigen and hepatitis B DNA, 
and if they have no evidence of hepatic dysfunction that is felt to be related to 
hepatitis B.   
3.10 Patients must have adequate pulmonary function, defined as the following: 
3.10.1 No history of drug-related, radiation-induced, or autoimmune pneumonitis 
requiring hospital admission. 
3.10.2 Baseline pulse oximetry reading of ≥92% on room air. 
3.10.3 Patients with a history of asthma or COPD must have no oxygen requirement, 
must have not had a hospital admission for COPD/asthma exacerbation within 
the past 2 years, and must not have received systemic steroids (≥10 mg 
prednisone for more than 7 days) for asthma/COPD within the past 2 years. 
3.11 Patients 
may 
not 
have 
an 
auto-immune 
disease 
requiring 
systemic 
immunosuppression, biologic therapy, and/or steroid use (≥10mg daily of prednisone 
or equivalent). Patients with hypothyroidism or type 1 diabetes mellitus that are on 
chronic hormonal therapy and which are well-controlled are eligible.  
3.12 Patients with current or prior CNS involvement with lymphoma are not eligible. 
3.13  Required Initial Laboratory Data: 
Granulocytes 
≥ 1000/µl 
Platelet count 
≥ 75,000/µl 
Creatinine Clearance 
≥50 mL/min  


 
11 
 
Bilirubin 
≤ 2.0 mg/dL 
AST/ALT 
≤ 2.0 x upper limits of normal 
 
4.0 
REQUIRED DATA  
Guidelines For Pre-Study Testing  
To be completed within 16 DAYS before cycle 1, day 1: 
- All bloodwork, history and physical exam. 
To be completed within 42 DAYS before cycle 1, day 1: 
- Scan of any type that is utilized for tumor measurement per protocol. 
 
 
Screening 
Cycle 1 
Days 1, 
8, and 15 
Day 1 of 
Cycles 2+ 
Post 
Treatment 
Follow up* 
Tests & Observations 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
Height/Weight/Body Surface Area 
X 
 
X 
 
Performance Status 
X 
X 
X 
 
Drug Toxicity Assessment 
Concomitant Medications 
Pulmonary Function Tests (w/ DLCO) 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Laboratory Studies 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
Serum Creatinine, BUN 
X 
X 
X 
X 
Serum Electrolytes (Na, K, Cl, CO2) 
X 
X 
X 
X 
Liver Function Tests  
ESR 
Serum or Urine Pregnancy Test# 
TSH 
Free T3 and Free T4 
Hepatitis B Core Antibody Total 
Hepatitis C Antibody 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
A 
X 
X 
Restaging/Disease Evaluation 
 
 
 
 
PET/CT, CT (with IV contrast), or MRI 
scan (neck, chest, abdomen, pelvis) 
B 
 
C 
X** 
Bone Marrow Aspirate and Biopsy 
D 
 
 
D 
Histologic Review 
E 
 
 
 
*  Patients who have discontinued study therapy but have not started a subsequent 
treatment should be evaluated every 3 months for 2 years from discontinuation of study 
therapy.                                                                                                                                           


 
12 
 
** Patients who discontinue study therapy but have not started a subsequent treatment 
should complete restaging every 6 months for 2 years after discontinuation of therapy. 
#  Women of childbearing potential (defined per institutional standard). 
A. 
TSH should be drawn at baseline, at the beginning of cycles C3 and C6, and at the 
beginning of cycles M3, M6, M9, M12, M15, M18, M21, and M24.  T3 and T4 is 
required at baseline for all patients but only should be checked as clinically indicated 
after the initial screening. 
B. 
PET/CT preferred at the time of study registration and at re-staging after cycles C2, 
and C6. PET/CT, CT (with IV contrast), or MRI may be utilized according to physician 
preference during maintenance cycles and follow-up. CT or MRI should include neck, 
chest, abdomen, and pelvis. 
C. 
Restaging studies should occur for patients on therapy after cycles C2 and C6 (PET/CT 
preferred after C2 and C6), and subsequently after cycles M3, M6, M9, M12, M18, 
and M26. 
D. 
Bone marrow biopsy and aspirate is only required for patients with suspected 
involvement at the discretion of the treating physician and should only be performed 
if felt to be necessary as part of the patient’s routine care.  Patients who do undergo 
bone marrow biopsy and aspirate and who are found to have involvement with 
Hodgkin lymphoma should repeat the procedure at time patient achieves a CR. 
E. 
Pathology review at the treating center is required prior to enrollment if a biopsy 
confirming relapse has not previously been evaluated at the treating center. 
 
NOTE: All study treatments may be adjusted +/- 3 days to account for circumstances including 
holidays, weather, clinic closures, or any other condition which prevents the patient from being 
treated on schedule.  However, growth factor must be administered no later than 72 hours 
after completion of day 2 bendamustine during combination cycles.  While on treatment, “day 
1” laboratory values may be obtained up to 48 hours prior to initiating therapy.  Scheduled 
scans while on treatment may be obtained +/- 7 days from day 1 of the required combination 
cycles and +/- 14 days of required maintenance cycles.  Patients who are off treatment and in 
follow-up should be evaluated +/- 30 days from the scheduled time point and required scans 
should also occur +/- 30 days from the scheduled time point. 
 
5.0 REGISTRATION PROCESS 
After each subject at participating subsites signs consent, the Central Subject Registration 
Form is to be completed and sent to Winship within 24 hours of consent. This form, along 
with the valid, signed informed consent form/ HIPAA authorization form, is to be faxed or 
emailed to Winship’s Central Subject Registrar per instructions on the form. 
The Eligibility Checklist is to be printed from OnCore and verified by 2 people, of which 
one MUST be a clinical investigator or co-investigator. The completed and signed eligibility 
checklist along with all redacted supporting source documentation must be submitted to 
the Winship Multi-site Coordinator or designee (Fax 404-778-0417) within 14 days after 


 
13 
 
pre-registration but no later than 2 business days before scheduled treatment visit.  In 
cases where it is not feasible to provide within 2 days before the first treatment visit due 
to a rapid screening, the subsites shall provide Winship with the eligibility checklist and 
source documentation as soon as possible.  This must be reviewed prior to initiating 
therapy. Eligibility will be confirmed by the site investigator or co-investigator and the 
Multi-site coordinator or designee within 1 business day of receipt of all eligibility 
documentation and confirmation will be sent to the participating site along with cohort 
assignment, if subject meets criteria. 
The clinical management system being used for this study is The Online Collaborative 
Research Environment (OnCore). OnCore will be used to record all study related 
information for all registered subjects, including their assigned patient ID and assigned 
dose cohort. All data must be entered no later than 30 days following registration and 
each visit completion. All queries are to be resolved within 4 weeks of issue. The Multi-site 
coordinator will provide OnCore training and request access to the appropriate staff at 
the participating sites. 
6.0 TREATMENT PLAN 
6.1 
Phase 1 Study  
6.1.1 Dose Escalation Schema and Treatment Plan 
Phase I Dose Escalation Schema       Cycle Length: 21 days 
Dose level 
Gemcitabine (mg/m2) 
IV over 30 minutes 
day 1  
Bendamustine (mg/m2) 
IV  over 30 minutes 
days 1 and 2 
Nivolumab (mg) on 
day 1  
-3 
800 
75 
140 
-2 
800  
90  
140  
-1 
800 
90 
240 
1 
1000 
90 
240 
2 
1000 
120 
240 
NOTE: Maintenance dosing shall be Nivolumab monotherapy 480mg IV on day 1 of a 28 
day cycle (cycles M1-M26). 
 
In the phase I trial, three patients will be enrolled at each dose level starting at dose level 1(See 
above dose escalation schema) using a standard 3+3 dose escalation phase I design.  If one 
patient experiences a dose limiting toxicity (DLT), this dose level will be expanded to 6 patients.  
The dose where 2 or more DLT’s are observed will be declared the maximum administered dose 
and will have exceeded the maximum tolerated dose (MTD).  If 2 or more DLT’s are observed at 
a given dose level, the previous dose level will be expanded to a total of 6 patients and if 1 or 


 
14 
 
fewer DLT’s is observed at this level, this will be the maximum tolerated or recommended 
phase 2 dose (RP2D).  If 2 or more DLTs are observed at dose level 1, the next cohort of 3 
patients will be accrued to dose level (-1).  If dose escalation reaches dose level 2, this dose 
level will expand to 6 patients to ensure patient safety.  If 1 or fewer patients experience DLT at 
dose level 2, this will be used as the RP2D, and the trial will proceed to phase II.  All patients 
treated within a dose level must complete one cycle of therapy prior to dose escalation to the 
next level.  Patients who do not complete prescribed treatment for the first cycle of therapy for 
reasons other than toxicity will be replaced on that dose level for the purposes of DLT 
determination but will still be followed for safety endpoints and can continue study therapy if 
they have not experienced a DLT and are felt to be suitable candidates to continue.   
 
A combination cycle will be defined as one 21-day treatment period and patients may continue 
to receive bendamustine and gemcitabine for a maximum of 6 combination cycles.  Nivolumab 
will be administered in combination with gemcitabine and bendamustine up to cycle 6, then as 
monotherapy thereafter.  Patients who experience toxicity that is felt to be related to 
gemcitabine and/or bendamustine during cycles 1-6 MAY initiate maintenance therapy early 
(i.e, before completing 6 cycles of combination treatment) if they are felt to be benefiting from 
nivolumab and have completed at least 1 full cycle of therapy without a DLT.  These patients 
must not discontinue gemcitabine or bendamustine due to a potential immunologic or any 
pulmonary toxicity.  Potential additional immunologic toxicities could include colitis, hepatitis, 
or adrenal insufficiency.  Any questions regarding a patient’s eligibility to proceed with 
monotherapy in this situation should be directed to the study chair.  Response will be assessed 
after cycles 2 and 6 during the combination phase and then as directed in Section 4.0 during the 
maintenance phase. BM biopsy will be repeated in those patients with evidence of a complete 
response and pre-treatment bone marrow involvement. 
 
The treatment schedule for maintenance dosing shall be nivolumab 480mg IV day 1 of each 28-
day cycle.  The nivolumab dose shall be 480mg during maintenance regardless of the dose 
received during combination.  If this dose/schedule is not felt to be safe by the treating 
investigator, the patient should be removed from study therapy prior to initiation of 
maintenance. 
 
This study is not designed to be utilized prior to autologous or allogeneic transplantation but in 
some instances, proceeding to an alternative therapy may be in the patient’s best interest and 
is permitted.  All patients who are not experiencing frank, clinical progression and/or 
unacceptable toxicity, should complete at least 2 cycles of combination therapy prior to 
proceeding to any subsequent therapies.  All patients who discontinue study therapy to 
proceed to transplantation or any other alternative therapies shall be considered for the 
planned safety assessments and, as able, shall be considered for response assessment.  Any 
patient who receives any alternative anti-cancer treatment outside of the study shall be 
permanently removed from the study and may not receive any subsequent combination or 
nivolumab monotherapy as part of the study. 
 
 


 
15 
 
 
 
 
 
 
6.1.2  Definition of Dose limiting toxicity during the Phase 1 Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose limiting toxicity (DLT) will be defined during cycles 1 and 2 of the phase I trial (ie, for the 
first 6 weeks of treatment). Patients with a DLT during this window will be immediately 
removed from the study. Toxicities during cycles 3-6 or that do not meet criteria for dose 
limiting toxicity will be managed according to section X. 
 
Note: All toxicities encountered during the first 2 cycles will be considered for the purposes of 
identification of a DLT.  However, toxicities that develop that are clearly and unequivocally 
unrelated to study therapy will not be considered a DLT.  This determination will be made by 
the study chair alone or in consultation with the treating physician of the patient, other co-
investigators, and other resources as indicated.  Should this occur, the reason for not 
considering a toxicity to be a DLT shall be clearly documented.   
 
6.1.3 Planned interim safety analysis during phase 1 study. 
In addition to the monitoring for DLT during cycles 1 and 2 for all patients enrolled on the 
phase 1 study, we will also plan a second safety evaluation after 6 patients have completed 
4 cycles of combination therapy (regardless of dose level).  If any of the first 6 patients 
discontinue study therapy for any reason prior to completion of cycle 4, their data will still 
be included in this safety analysis.  However, the safety analysis will not occur until 6 
patients have completed 4 cycles of therapy. 
Table 3. Definition of Dose Limiting Toxicity 
Grade 3 febrile neutropenia > 7 days 
Grade 4 infection or febrile neutropenia 
Grade ≥2 pulmonary toxicity  
Any 
grade 
≥3 
non-hematologic 
toxicity 
except 
nausea/vomiting, alopecia, or asymptomatic non-
hematologic 
laboratory 
abnormalities 
that 
are 
correctible within 72 hours. 
Grade ≥3 rash/cutaneous toxicity. 
Any dose delay of > 14 days due to therapy-related 
toxicity (including delay of initiation of cycle 3). 
Any Grade 5 toxicity 


 
16 
 
If any of the following occur prior to the completion of 4 cycles of therapy, the study will 
temporarily hold further accrual and a determination will be made by the principal 
investigator, in collaboration with the Winship Cancer Institute Data Safety Monitoring 
Committee regarding the need to adjust the treatment regimen/schedule, eligibility criteria, 
or other aspect of the study to improve safety: 
a) ≥ 20% of patients experience grade ≥ 3 pneumonitis at least possibly related to study 
therapy and not felt to be infectious 
b) ≥ 20% of patients experience grade ≥ 3 transaminase elevation (ALT or AST)  at least 
possibly related to study therapy  
c) ≥ 20% of patients experience grade ≥ 3 rash at least possibly related to study therapy 
d) ≥20% of patients experiencing grade ≥3 or unmanageable lesser-grade immune 
mediated adverse reaction. 
 
6.2 
 
Phase II Study   
The phase 2 portion of the study shall commence upon determination of the recommended 
phase 2 dose (RP2D).  For phase 2, gemcitabine, bendamustine, and nivolumab will be 
administered for up to 6 cycles at the RP2D, and nivolumab will subsequently be administered 
as a monotherapy for up to 26 additional 28-day cycles.  Gemcitabine shall be administered 
prior to bendamustine on day 1 of each cycle, and nivolumab shall be administered last on any 
days in which multiple therapies are being administered.  Patients will receive pegfilgrastim 
within 72 hours of completion of bendamustine for cycles 1-6. Pegfilgrastim will not be required 
during monotherapy/maintenance.   
 
Response will be assessed by PET/CT (preferred), CT of the chest, abdomen, and pelvis, or MRI 
after cycles 2 and 6 and again as specified in Section 4.0 above during the maintenance phase. 
Patients without evidence of disease progression may continue combination therapy for a 
maximum of 6 cycles of therapy followed by up to 26 cycles of nivolumab.  Given the evidence 
that radiographic progression does not always reflect true symptomatic progressive disease 
when PD1 antibodies are administered in Hodgkin lymphoma, patients who are receiving 
nivolumab monotherapy who experience radiographic progressive disease MAY, at the 
discretion of the treating physician, remain on single agent therapy if they are felt to be 
clinically benefitting, for up to a total of 26 maintenance cycles.  It is less clear whether a similar 
phenomenon occurs in patients receiving nivolumab in combination with chemotherapy.  As a 
result, patients who experience evidence of progression during combination therapy but who 
are having unequivocal clinical benefit may continue combination treatment in consultation 
with the study chair.   
 
This study is not designed to be utilized prior to autologous or allogeneic transplantation but in 
some instances, proceeding to an alternative therapy may be in the patient’s best interest and 
is permitted.  All patients who are not experiencing frank, clinical progression and/or 


 
17 
 
unacceptable toxicity, should complete at least 2 cycles of combination therapy prior to 
proceeding to any subsequent therapies.  All patients who discontinue study therapy to 
proceed to transplantation or any other alternative therapies shall be considered for the 
planned safety assessments and, as able, shall be considered for response assessment.  Any 
patient who receives any alternative anti-cancer treatment outside of the study shall be 
permanently removed from the study and may not receive any subsequent combination or 
nivolumab monotherapy as part of the study. 
 
 
6.3 
Study-therapy related deaths 
 
Deaths of any subjects while on active therapy or within 30 days of treatment shall be assessed 
immediately. In the event that the death is not clearly unrelated to study therapy (ie, disease 
progression), accrual shall cease until a full accounting of the event can be obtained and any 
needed amendments can be developed to address the event and prevent it from occurring in 
the future.  This may include dose reductions of any or all therapies, introduction of additional 
supportive care therapies, inclusion of more frequent laboratory or clinical assessments, or any 
other measures deemed appropriate by the study chair in consultation with co-investigators 
and other study personnel. 
 
6.4 
Criteria to temporarily hold study accrual 
 
In addition to the safety parameters identified above for DLT monitoring and the early stopping 
rules presented for the phase 1 study, we will have several additional criteria that shall be 
applied throughout the study and which will result in temporary holding of accrual.  If any of 
these criteria are met at any time (phase 1 or phase 2 portions), the study shall hold accrual 
until appropriate modifications can be made to the protocol to ensure future safety of patients.   
 
• Any study-related death at any time on treatment or within 30 days of discontinuing 
treatment 
• ≥ 5 subjects experiencing therapy-related grade ≥ 3 pneumonitis, transaminase 
elevation, or cutaneous toxicity 
• ≥5 subjects experiencing therapy-related grade ≥4 toxicity 
• ≥10 subjects who are unable to complete the 6 cycles of combination therapy (dose 
modifications are permitted; this criterion only applies to patients who must discontinue 
chemotherapy entirely) 
• The study chair may suspend accrual at any time if a significant safety concern is 
identified.  This would include unexpected toxicities associated with transplantation 
after completion of study therapy. This therapy is not specifically designed to be used 
pre-transplant but any study-related complications related to transplantation 
(autologous or allogeneic) will be captured and considered as indicated. 
 
 
 


 
18 
 
6.5 
Order of Drug Administration 
 
Gemcitabine shall be administered first on day 1, followed by bendamustine in all patients, 
at all dose levels.  Bendamustine will be administered alone on day 2.  Nivolumab shall be 
the final drug administered on all days in which multiple agents are being administered. 
 
 
6.6 
Criteria for Retreatment – Combination Phase (Cycles 1-6)  
 
On the phase I and phase II trials, patients without evidence of symptomatic disease 
progression may continue combination therapy for up to 6 cycles. To start a cycle, the 
following criteria must be met.  In addition, please note the criteria for nivolumab 
discontinuation in Section 7.3.  Any patient who requires discontinuation of nivolumab shall 
be permanently removed from study therapy: 
  
1) The absolute neutrophil count must be > 1000/µL and the platelet count must be 
>75,000/mm3  
2) Therapy-related immune-mediated toxicities and symptomatic endocrinopathies must 
be resolved to ≤ grade 1.  NOTE: Any steroids utilized to manage immune-mediated 
toxicities must be decreased to 10mg or less of prednisone (or equivalent) for at least 5 
days prior to initiating the next cycle. 
3) Asymptomatic, therapy related endocrinopathies must be ≤ grade 2. 
4) All other treatment-related non-laboratory, non-immune mediated toxicities must be 
resolved to < grade 2.   
5) Asymptomatic laboratory abnormalities (hematologic and non-hematologic) that are 
≤grade 3 and can be readily corrected do not require a dose delay.   
6) Patients with liver function test abnormalities (ALT, AST, Alkaline phosphatase) that are 
≥ Grade 3 must be delayed until recovery to Grade ≤1.    
7) Any grade 4 toxicity that is at least possibly related to study therapy requires a dose 
delay.   
 
Patients who require a treatment delay of > 21 days shall be removed from combination 
therapy but MAY continue monotherapy if felt to be clinically benefitting and the toxicity is 
felt to be most likely related to gemcitabine/bendamustine.  Patients requiring a delay of 
≤21 days but for whom continued combination therapy is felt to be unsafe may also 
continue monotherapy at the discretion of the investigator if they are felt to be clinically 
benefitting. 
 
6.7 
Criteria for Retreatment – Maintenance Phase 
 
In order for patients to initiate a maintenance cycle of single agent nivolumab, the following 
criteria must be met. In addition, please note the criteria for nivolumab discontinuation in 
Section 7.3.  Any patient who requires discontinuation of nivolumab shall be permanently 
removed from study therapy: 


 
19 
 
 
1) The absolute neutrophil count must be > 1000/µL and the platelet count must be 
>75,000/mm3  
2) Therapy-related immune-mediated toxicities and symptomatic endocrinopathies must 
be resolved to ≤ grade 1. NOTE: Any steroids utilized to manage immune-mediated 
toxicities must be decreased to 10mg or less of prednisone (or equivalent) for at least 5 
days prior to initiating the next cycle. 
3) Asymptomatic, therapy related endocrinopathies must be ≤ grade 2. 
4) All other treatment-related non-laboratory, non-immune mediated toxicities must be 
resolved to < grade 2.   
5) Asymptomatic laboratory abnormalities (hematologic and non-hematologic) that are 
≤grade 3 and can be readily corrected do not require a dose delay.   
6) Any grade 4 toxicity that is at least possibly related to study therapy requires a  dose 
delay.   
 
Patients requiring a dose delay of > 21 days due to toxicity must be removed from study 
therapy and cannot be retreated without discussion with the principal investigator.  
 
 
 
 
6.8 Treatment Duration and Staging 
 
 
 
Re-staging should be performed after cycles 2 and 6 of combination therapy and 
subsequently subsequently after cycles M3, M6, M9, M12, M18, and M26 during 
maintenance. Patients will receive a minimum of two cycles of therapy, unless rapid disease 
progression or dose-limiting toxicity is noted. Patients without evidence of progressive 
disease may continue to receive Gemcitabine and Bendamustine for a total of 6 cycles.  
Nivolumab monotherapy can be continued for up to 26 cycles.    
 
Any patient who experiences toxicity felt to be related to study therapy that is considered 
to make further therapy unsafe shall be removed form study therapy.  Any patient with 
symptomatic progressive disease shall also be removed from therapy. 
 
**Patients who experience radiographic progression while on the combination therapy 
should be removed from treatment, but patients with radiographic progression after 
completion of the combination portion of the study MAY remain on monotherapy if they 
are felt to be clinically benefitting.  These patients should continue to have imaging 
assessments as set forth in the protocol but may complete up to the full 26 cycles of 
therapy in the absence of symptoms that are felt to be related to disease progression or 
unacceptable toxicity. 
 


 
20 
 
 
7.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
 
The following dose modifications will apply to all patients in the phase 1 trial during cycle 
1-2 who do not meet the criteria for dose limiting toxicity (see Section 6.1.2), to all patients 
receiving cycles 3+ in the phase I trial, and to all patients receiving therapy on the phase 2 
trial.  
 
Any patient who requires a dose reduction shall NOT be re-escalated at any point in the 
study. 
 
Given the demonstrated safety and efficacy of single-agent nivolumab as well as nivolumab 
administered in combination with other agents, this combination is primarily of interest 
only if we can safely combine the chemotherapy backbone with a known therapeutic dose 
of nivolumab.  As a result, we will prioritize maintaining the active dose of nivolumab, and 
there shall be NO dose reductions of nivolumab.  If a dose reduction is required, BOTH 
gemcitabine and bendamustine shall be reduced per Table 4 below.  
 
During the combination phase of the study, toxicities may be encountered that could be 
related to both gemcitabine/bendamustine and nivolumab.  These may include hepatic, 
pulmonary, hematologic, or other toxicities.   
 
While on combination therapy, any toxicity which may be immune-mediated should be 
managed per the algorithms described in the appendix, and patients meeting the criteria 
specified below in Section 7.3 shall discontinue nivolumab and study treatment.  All 
therapy shall be held until resolution of the immune-mediated toxicity. 
 Other non-hematologic toxicities that require a dose hold shall be managed as 
documented 
below 
in 
Section 
7.2 
with 
a 
dose 
modification 
of 
the 
gemcitabine/bendamustine per Table 4. In such  case, nivolumab shall also be held until 
recovery of the toxicity and all therapies shall be re-initiated at the same time. 
7.1 Hematologic Toxicity: The following dose modifications should be made for febrile 
neutropenia, nadir blood counts, and blood counts obtained within 2 days prior to each 
subsequent cycle. If more than one of these applies, use the most stringent (i.e., the 
greatest dose reduction) but only one dose reduction shall occur per cycle.   
 
Example: If a patient has a nadir platelet count of 20,000 during a cycle and an ANC of 750 
at the time of the next cycle, only one dose reduction is required at that time.  If any of 
these hematologic toxicities recur after reinitiation of therapy, a second dose reduction 
would be indicated. 
7.1.1 Febrile Neutropenia 
If febrile neutropenia (defined as temperature ≥ 38.5°C [101 F] concomitant with 
an ANC < 500/ µl) develops in a given cycle, dose reduce bendamustine and 
gemcitabine one level below the current dose according to Table 4. These dose 
reductions will be applied to the next and all subsequent cycles. 


 
21 
 
7.1.2 Nadir Blood Counts 
In patients with a platelet count < 25,000/µl or a ANC < 250/µl at any time during 
the cycle, dose reduce bendamustine and gemcitabine one dose level below the 
current dose according to Table 4. These modifications will apply to the next and 
all subsequent cycles.  
• 
Treatment should be held until the patient has an ANC ≥ 1000/µl and a 
platelet count ≥ 75,000/µl.  
• 
Treatment delays > 3 weeks will lead to study removal. 
• 
Once the ANC or platelet count has improved, therapy can be re-instituted at 
the next lowest dose level. 
• No dose modifications are required for leukopenia, lymphopenia, or anemia 
that occurs during a cycle. 
 
 
 
7.1.3  Blood Counts on Day 1 of Cycle 
In patients with a platelet count < 75,000/µl or a ANC < 1000/µl obtained on a 
planned day 1 of each cycle of therapy, dose reduce bendamustine and 
gemcitabine one dose level below the current dose according to Table 4. These 
dose reductions will apply to the next and all subsequent cycles.  
• 
Treatment should be held until the patient has an ANC ≥ 1000/µl and a 
platelet count ≥ 75,000/µl.  
• 
Treatment delays > 3 weeks will lead to study removal. 
• 
Once the ANC or platelet count has improved, therapy can be re-instituted at 
the next lowest dose level. 
Table 4. Gemcitabine and Bendamustine Dose Reductions 
Gemcitabine dosing (reduce one level 
below current dose) 
Bendamustine dosing (reduce one level below 
current dose) 
1000 mg/m2 
120 mg/m2 
800 mg/m2 
90 mg/m2 
600 mg/m2 
75 mg/m2 
Discontinue Gemcitabine 
Discontinue Bendamustine 
 


 
22 
 
7.2 Non-Hematologic Toxicity 
If a dose delay is required due to treatment-related non-hematologic toxicity, therapy should 
be held until the patient meets criteria to reinitiate therapy.  At that time, treatment should be 
reinitiated with a dose reduction per Table 4.  Nivolumab will not be dose reduced. 
There will be no required dose reductions for mid-cycle non-hematologic toxicities that have 
resolved by the completion of the cycle if a patient meets criteria to receive the next cycle of 
treatment.  However, an investigator MAY dose reduce any patient experiencing a grade 3-4 
non-hematologic toxicity during a cycle if they feel it is in the patient’s best interest.  In 
addition, a patient experiencing a mid-cycle grade 3-4 non-hematologic toxicity while on 
combination therapy MAY, at the discretion of the investigator, discontinue combination 
therapy and move to nivolumab monotherapy. 
Patients who discontinue and/or dose reduce gemcitabine and bendamustine due to toxicity, 
may NOT re-escalate these therapies. 
7.3 Immune Mediated Toxicities and Criteria for Discontinuation  of Nivolumab 
Nivolumab, like other PD1 antibodies, is associated with the development of immune mediated 
toxicities including rash, diarrhea, pneumonitis, endocrinopathy, hepatitis, and others.  
Presumed immune-mediated toxicities shall be managed per Appendix attached, and 
investigators are encouraged to consult the Nivolumab investigator brochure for further 
information. 
Any patient experiencing a nivolumab-mediated immunologic toxicity shall be managed 
according to the algorithm whenever possible, including the use of corticosteroids.   Patients 
who are felt to be unable to continue nivolumab therapy will be removed from study 
treatment. 
Nivolumab treatment should be permanently discontinued for the following: 
• Any Grade 2 drug-related uveitis, 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 AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies: 
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
− Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.  
− Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 


 
23 
 
♦ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
♦ Grade ≥ 3 drug-related AST, ALT or Total Bilirubin requires discontinuation* 
♦ Concurrent AST or ALT > 3 x ULN AND total bilirubin  >2x ULN 
NOTE: Any patient who requires discontinuation of nivolumab for the above reasons shall 
be removed from all study therapy, regardless of timing (during combination or 
monotherapy). 
 
7.4 Dose Modification for Obese Patients  
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely by 
(1) the patient’s BSA as calculated from actual weight or (2) actual weight without any 
modification. This will eliminate the risk of calculation error and the possible introduction of 
variability in dose administration.  
 
8.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
8.1 Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and 
safe disposal of chemotherapeutic agents in a self-contained, protective 
environment. 
8.2 Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for 
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial 
entry to minimize the risk of bacterial contamination. 
8.3 The total administered dose of chemotherapy may be rounded up or down within a 
range of 5% of the actual calculated dose. 
8.4 Gemcitabine  
Availability 
Gemcitabine 
 
 
Preparation 
Gemcitabine may be prepared per institutional standard 
Storage and Stability 
Gemcitabine solutions are stable for 24 hours at controlled room temperature.  
Unopened vials are stable until the expiration date indicated on the package when 
stored at controlled room temperature. 
Administration 


 
24 
 
Administer IVPB over 30 minutes 
Toxicities 
Myelosuppression, nausea, vomiting, diarrhea, stomatitis, transient elevation in 
transaminases, mild proteinuria and hematuria, fever, rash, dyspnea, edema, flu-like 
symptoms, irritation at site of injection. 
 
8.5 
Bendamustine  
 
 
 
Please refer to the FDA-approved package insert for bendamustine for product 
information and a complete list of adverse events.  
 
AVAILABILITY  
 
Bendamustine will be obtained commercially for enrolled patients.  The 
bendamustine brand (Treanda, Bendeka, or other) shall be determined per 
institutional preference/standard and is not mandated by this protocol. 
 
STORAGE &STABILITY  
Once diluted with 0.9% Sodium Chloride, the final admixture, is stable for 24 hours 
when stored refrigerated (2-8°C or 36 – 47°F) or for 3 hours when stored at room 
temperature (15 – 30°C or 59 – 86°F) and room light.  
 
PREPARATION  
 
Bendamustine will be prepared per package insert and institutional standards. 
 
ADMINISTRATION  
 
Bendamustine will be administered intravenously over 30 minutes on days 1 and 2.  
 
TOXICITY  
 
Myelosuppression: In the randomized study of bendamustine in CLL, 
myelosuppression was observed, including grade 3/4 neutropenia (24%), febrile 
neutropenia (3%), red blood cell transfusions (20%), and platelet transfusions (<1%). 
Hematologic nadirs are expected in the third week of treatment.  
 
Infection: Infections, including pneumonia and sepsis have occurred in patients 
receiving bendamustine. Cases of infection-associated hospitalization, septic shock, 
and death have been reported. Patients who develop myelosuppression are at 
higher risk of infection.  
 
Infusion Reactions and Anaphylaxis: Common infusion reactions include fever, chills, 
pruritus, and rash, but rare cases of anaphylactic and anaphylactoid reactions have 


 
25 
 
been reported. Infusion reactions seem to be more common in the second and 
subsequent cycles of therapy. Patients should be monitored for signs and symptoms 
suggestive of infusion reactions.  
 
Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine 
treatment has been reported in patients in clinical trials and in spontaneous reports. 
The onset tends to be within the first treatment cycle of bendamustine and, without 
intervention, may lead to acute renal failure and death.  
 
Dermatologic Toxicity: Skin reactions, including rash, toxic skin reactions, and 
bullous exanthema has been reported. Reports of Stevens-Johnson syndrome and 
Toxic Epidermal Necrolysis, some fatal, have been reported when bendamustine was 
administered concomitantly with allopurinol and other medications known to cause 
these syndromes. When skin reactions occur, they may be progressive and increase 
in severity with further treatment.  
 
Other Adverse Reactions: Other frequent adverse reactions include fever, nausea, 
vomiting, asthenia, fatigue, malaise, weakness, dry mouth somnolence, cough, 
constipation, headache, mucositis, and stomatitis. Worsening hypertension, 
including hypertensive crisis has been reported rarely.  
 
8.6 
Nivolumab 
 
Please refer to the FDA-approved package insert for nivolumab for product 
information and a complete list of adverse events.  
 
AVAILABILITY  
 
Nivolumab will be provided by BMS for patients enrolled on this study. 
 
STORAGE &STABILITY  
 
The product does not contain a preservative.  After preparation, nivolumab can be 
stored at room temperature for no more than 8 hours from the time of preparation 
(which includes time for administration).  Or, prepared nivolumab infusion may be 
stored under refrigeration for no more than 24 hours from the time of infusion 
preparation. 
 
PREPARATION  
 
Withdraw the required volume of nivolumab and transfer into an intravenous 
container. 
 


 
26 
 
Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose 
Injection, USP, to prepare an infusion with a final concentration ranging from 
1mg/mL to 10mg/mL.  
 
Mix diluted solution by gentle inversion.  Do not shake. 
 
Discard partially used vials or empty vials of nivolumab. 
 
 
ADMINISTRATION  
 
Nivolumab shall be administered over 60 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer).  Do not co administer other drugs through the same 
line. Flush the line at the end of infusion.   
 
Nivolumab shall be administered last on all days when it is co-administered with 
gemcitabine or bendamustine.  
 
TOXICITY  
 
See package insert and investigator brochure for details regarding toxicity. 
 
Toxicity related to nivolumab is frequently immune-mediated and includes the 
following: 
• Pneumonitis 
• Colitis 
• Hepatitis 
• Endocrinopathies (including thyroid, adrenal, and pancreatic dysfunction) 
• Nephritis/renal dysfunction 
• Cutaneous reactions 
• Encephalitis 
 
Nivolumab is also rarely associated with infusion reactions as well as increased risk 
of graft-versus-host disease and febrile syndrome when administered around the 
time of an allogeneic transplant. 
 
9.0 
Ancillary Therapy 
 
9.1 
Patients should receive full supportive care, including transfusions of blood and 
blood products, erythropoietin, antibiotics, antiemetics, etc., when appropriate. The 
reason(s) for treatment, dosage, and the dates of treatment should be recorded on 
the study case report forms. 


 
27 
 
 
9.2 
Treatment with hormones or other chemotherapeutic agents may not be 
administered except for steroids given for nausea, adrenal failure, or immune-
mediated toxicities or hormones administered for non-disease-related conditions 
(e.g., insulin for diabetes). Use of dexamethasone and other steroidal antiemetics is 
permitted. 
9.3  
Palliative radiation therapy may not be administered. Irradiate a symptomatic lesion, 
or one that may produce disability (e.g., unstable femur) prior to study initiation, 
provided other measurable disease is present. 
9.4  
Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol: 
9.4.1 Erythropoietin (EPO) 
Use of erythropoietin (EPO) is permitted at the discretion of the treating 
physician. 
9.4.2 Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1. As all patients will receive pegfilgrastim with each cycle, filgrastim (G-CSF) and 
sargramostim (GM-CSF) treatment as prophylactic treatment is prohibited unless 
a patient did not receive pegilgrastim as scheduled. 
2. The use of filgrastim or sargramostim may be indicated in patients who did not 
receive pegfilgrastim during a cycle a cycle, or who experience a clinical scenario 
with a high risk of clinical deterioration such as pneumonia, hypotension, multi-
organ dysfunction (sepsis syndrome) or fungal infection, as per the ASCO 
guidelines.  Investigators should therefore use their own discretion in using the 
CSF's in this setting.  The use of CSF (filgrastim or sargramostim) must be 
documented and reported on flow sheets.  
3. If filgrastim or sargramostim are used, they must be obtained from commercial 
sources.  
 
10.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE  
For the purposes of this study, patients will be restaged using PET/CT, CT, or MRI scan 
after cycles 2 and 6 of induction therapy, and after cycles M3, M6, M9, M12, M18, and 
M26 during the maintenance phase.  
If a patient experiences a delay in treatment, every attempt should be made to keep the 
restaging scans paired with the beginning of the cycle when it is due when possible.  For 
example, if cycle M4 is delayed two weeks, the restaging scan should also be delayed 2 
weeks.  Windows for scans are provided and should be based on the date in which the 
required cycle took place, regardless of delays.  Unavoidable and/or unexpected delays 
(such as due to laboratory toxicities on day 1 of a cycle, weather, or unrelated 


 
28 
 
emergencies preventing treatment) are expected, and if they occur and result in a scan 
being obtained outside of a defined window, this should be documented but a repeat 
scan is not required. 
10.1 Definitions of Response  
Response to therapy will be determined using the Lugano Classification (2014) for the 
purposes of determining the ORR.16  However, as an exploratory endpoint the LYRIC 
criteria, which take into account the possibility of an Indeterminant Response may be 
incorporated into the clinical decision making regarding appropriateness of 
continuing therapy for patients with radiographic PD.17 
PET/CT based response will include utilization of the 5-point Deauville score18: 
1 – No uptake above background 
2 – Uptake present but ≤ mediastinal blood pool 
3- Uptake > mediastinum by ≤ normal section of liver 
4 – Uptake moderately > liver 
5- Uptake markedly higher than liver and/or new lesions 
X – New areas of uptake unlikely to be related to lymphoma 
10.1.1 Complete Response (CR): 
If PET/CT is used (preferred): 
• Deauville Score of 1, 2, or 3 with or without a residual mass 
• No new lesions (Defined as any new FDG-avid lesion that is consistent with 
lymphoma rather than another etiology) 
o New lesions of uncertain etiology should be confirmed by either 
biopsy or subsequent scan prior to being considered progression 
• No evidence of FDG-avid disease in the bone marrow 
 
If CT alone is used: 
• 
Target nodes / nodal masses must regress to ≤1.5cm in longest diameter 
• 
No extralymphatic sites of disease 
• 
Organ enlargement regressed to normal 
• 
No non-measured lesions 
• 
No new lesions 
o New node > 1.5cm in any axis 


 
29 
 
o A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma 
o Assessable disease of any size unequivocally attributable to 
lymphoma 
o Regrowth of previously resolved lesions 
• 
Bone marrow is normal by morphology 
10.1.2 Partial Response (PR): 
If PET/CT is used (preferred): 
• Deauville score of 4 or 5 with reduced uptake compared with baseline and 
residual mass(es) of any size. 
• No new lesions (Defined as any new FDG-avid lesion that is consistent with 
lymphoma rather than another etiology) 
o New lesions of uncertain etiology should be confirmed by either 
biopsy or subsequent scan prior to being considered progression 
• Bone marrow: residual uptake higher than normal but reduced compared 
to baseline.  In the presence of a nodal response, consider a bone marrow 
biopsy and/or interval scan if there remains uptake in the bone marrow. 
 
If CT alone is used: 
• ≥ 50% decrease in the sum of the product of diameters for up to 6 target 
measurable nodes and extranodal sites 
• Lesions too small to measure on CT shall be assigned a diameter of 5mm x 
5mm 
• Lesions that are no longer visible shall be considered 0mm x 0mm 
• For nodes that are > 5mm x 5mm, use the actual measurement 
• Spleen must have regressed by > 50% in length beyond normal 
• No increase in non-measured lesions 
• No new lesions 
o New node > 1.5cm in any axis 
o A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma 
o Assessable disease of any size unequivocally attributable to 
lymphoma 
o Regrowth of previously resolved lesions 
 


 
30 
 
 
 
10.1.3 Stable Disease (SD):  
If PET/CT is used: 
• 
Deauville score of 4 or 5 with no significant change in FDG uptake from 
baseline 
• No new lesions (Defined as any new FDG-avid lesion that is consistent with 
lymphoma rather than another etiology) 
o New lesions of uncertain etiology should be confirmed by either 
biopsy or subsequent scan prior to being considered progression 
• 
Bone marrow: No change from baseline 
If CT is used: 
• 
< 50% decrease from baseline in the sum of the product of the diameters 
of up to 6 dominant, measurable nodes and extranodal sites; no criteria for 
progressive disease are met. 
• 
No increase consistent with progression in non-measured lesions and/or 
organ enlargements 
• No new lesions 
o New node > 1.5cm in any axis 
o A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma 
o Assessable disease of any size unequivocally attributable to 
lymphoma 
o Regrowth of previously resolved lesions 
 
10.1.4 Progression (PD) or Relapse: 
If PET/CT is used (preferred): 
• 
Deauville score of 4 or 5 with an increase in intensity of uptake from 
baseline in individual target nodes/nodal masses and/or new FDG-avid foci 
consistent with lymphoma. 
• 
Bone marrow: New or recurrent FDG-avid foci 
If CT is used: 


 
31 
 
• An individual node must have a Longest diameter > 1.5cm and an increase 
in 50% from the product of the proximal diameter nadir and an increase in 
the longest or shortest diameter from the nadir of 0.5cm for lesions ≤2cm 
and 1.0 cm for lesions > 2cm 
• Splenic length increased by > 50% of the extent of its prior increase 
beyond baseline.  If no prior splenomegaly, then it must increase by at 
least 2cm from baseline. 
• New or clear progression of previous non-measured lesions 
• Any new nodal lesion: 
o New node > 1.5cm in any axis 
o A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, 
its presence must be unequivocal and must be attributable to 
lymphoma 
o Assessable disease of any size unequivocally attributable to 
lymphoma 
o Regrowth of previously resolved lesions 
 


 
32 
 
10.2 Consideration of an Indeterminant Response 
For the purposes of defining the efficacy endpoint of this study, patients who experience PD 
according to the criteria above will be considered to have PD.  However, given the 
propensity for tumor flare, pseudoprogression, and other radiographic findings of 
progression that exist in patients receiving this class of therapy in the absence of clinical 
symptoms consistent with progression, patients who experience PD but who are clearly 
benefitting from treatment will be allowed to continue.   
These patients will be considered to have an Indeterminant Response, defined as having 
one of the following: 
1) Increase in overall tumor burden (as assessed by the sum of the product of the 
diameters of ≥ 50% of up to 6 measurable lesions in the first 12 weeks of therapy, 
without clinical deterioration. 
2) Appearance of new lesions or growth of one or more existing lesion(s) ≥ 50% at any time 
during treatment; occurring in the context of lack of overall progression (< 50% 
increase) of overall tumor burden, as measured by SPD of up to 6 lesions at any time 
during the treatment. 
3) Increase in FDG uptake of 1 or more lesion(s) without a concomitant increase in lesion 
size of number. 
Patients who experience radiographic PD will be assessed for the possibility of an 
indeterminant response and this will be recorded for all patients.  Note: patients do NOT 
have to achieve one of these criteria to be permitted to continue therapy in the context of 
radiographic PD as long as the patient is clearly benefitting from therapy as assessed by the 
investigator. 
11.0  REMOVAL OF PATIENTS FROM PROTOCOL THERAPY  
11.1 Duration of Treatment 
All patients not experiencing significant toxicity (including DLT) or frank, symptomatic 
disease progression shall receive at least 2 cycles of therapy.  Thereafter, selected patients 
may discontinue study therapy to proceed with off-study consolidation approaches as felt 
appropriate by their treating physician (ie, autologous transplant). 
NOTE: Patients who discontinue study therapy to proceed with alternative treatment such 
as transplantation will be permanently removed from the study treatment and may not 
receive combination therapy or nivolumab monotherapy as part of the study. 
11.1.1 CR, PR, or SD  
All patients achieving CR, PR, or SD may continue study therapy until the 
development of unacceptable toxicity, the patient or treating physician feels that 
treatment should be discontinued for any reason, or the patient has completed all 
prescribed therapy.   


 
33 
 
11.1.2 Disease Progression 
  
Any patient who experiences confirmed PD during the first 6 cycles of therapy 
shall be removed from study therapy unless they are showing unequivocal benefit 
from treatment and are not experiencing undue toxicity.  These patients may 
continue on study therapy until they have symptomatic progression of disease.  
Ideally all patients who have not experienced unacceptable toxicity will complete 
at least 2 cycles of therapy and will have their first disease assessment but 
patients with frank, clinical evidence of progressive disease may be removed from 
the study at any time. 
 
Patients experiencing PD during the monotherapy phase of the study shall be 
managed based on the scenarios below: 
 
a) Patients with radiographic evidence of progression but no clinical symptoms 
may, at the discretion of the treating investigator, continue on study therapy until 
they have completed the prescribed treatment.  These patients shall be 
considered PD for the purposes of data analysis but may continue therapy if felt 
to be benefitting. 
 
b) Patients with radiographic evidence of progression with associated symptoms 
MUST be removed from study therapy.  In addition, any patient who experiences 
PD with or without symptoms and who is felt to no longer be benefitting from 
study therapy shall be removed from study therapy. 
11.2 Extraordinary Medical Circumstances 
 
 
If, at any time the constraints of this protocol are detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, the protocol 
therapy shall be discontinued.  
 
12.0 STATISTICAL CONSIDERATIONS 
12.1 
Phase 1 Trial 
We will use the standard 3 + 3 phase I dose escalation design with 3-6 patients being 
treated at each dose level.  Dose limiting toxicity [DLT] will be defined according to Table 
2. The DLT observation period will be the first two  cycles; i.e. the first two cycles will be 
used to determine DLT and inform does escalation decision. For the purposes of DLT 
determination, the first two cycles shall end when the first chemotherapy is infused on 
cycle 3, day 1.  A patient who must delay cycle 3 for any reason will still be considered for 
DLT until they have actually initiated cycle 3 therapy. Patients who do not complete 2 
cycles of therapy for reasons other than toxicity will be replaced on that dose level for the 
purposes of dose determination but may still continue therapy and be considered for 
safety and efficacy analyses. 


 
34 
 
The maximum tolerable dose [MTD] is defined as the highest dose level where at most 
one  of 6 patients experience DLT. Three patients will be enrolled at each dose level, 
starting at dose level 1. If one patient experiences a DLT, this dose level will be expanded 
to 6 patients. The dose where 2 or more DLTs are observed will be declared the maximum 
administered dose and will have exceeded the MTD. The previous dose level will be 
expanded to a total of 6 patients and if 1 or fewer DLTs are observed at this level, this will 
be the maximum tolerated or recommended phase 2 dose (RP2D). There will be no intra-
patient dose escalation. If 2 or more DLTs are observed at dose level 1, the next cohort of 
patients will be accrued to dose level (-1).  If dose escalation reaches dose level 2, this 
dose level will expand to 6 patients to ensure patient safety. If 1 or fewer patients 
experiences DLT at dose level 2, this will be used as the recommended phase 2 dose and 
the trial will proceed to phase 2. A phase 2 study will be conducted in patients with 
relapsed or refractory Hodgkin lymphoma at the phase 1 determined MTD. Those 6 
patients at RP2D in the phase 1 study will be included in the responses evaluated as part 
of the phase 2 study of this trial.   
 
In addition to the monitoring for DLT during cycle 1-2 for all patients enrolled on the 
phase 1 study, we will also plan a second safety evaluation after 6 patients have 
completed 4 cycles of combination therapy.  If any of the first 6 patients discontinue study 
therapy for any reason prior to completion of cycle 4, their data will still be included in 
this safety analysis.  However, the safety analysis will not occur until 6 patients have 
completed 4 cycles of therapy. 
If any of the following occur prior to the completion of 4 cycles of therapy, the study will 
temporarily hold further accrual and a determination will be made by the principal 
investigator, in collaboration with the Winship Cancer Institute Data Safety Monitoring 
Committee regarding the need to adjust the treatment regimen/schedule, eligibility 
criteria, or other aspect of the study to improve safety: 
a. ≥ 20% of patients experience grade ≥ 3 pneumonitis at least possibly related to 
study therapy and not felt to be infectious 
b. ≥ 20% of patients experience grade ≥ 3 transaminase elevation (ALT or AST)  at 
least possibly related to study therapy  
c. ≥ 20% of patients experience grade ≥ 3 rash at least possibly related to study 
therapy 
d. ≥20% of patients experiencing grade ≥3 or unmanageable lesser-grade immune 
mediated adverse reaction. 
e.  
 
12.2  
Phase 2 Trial 


 
35 
 
For the phase 2 portion of the study, we will enroll patients at the MTD/RP2D as 
determined by the phase 1 study.  We will utilize a 2 stage Simon MiniMax design for 
phase 2 with CR rate as the primary endpoint.  For this study, we will use the historical CR 
rate of 25% (from the phase 1/2  study of gemcitabine/bendamustine) to evaluate the 
efficacy of this regimen and determine the interest in moving the combination forward.  
The goal CR rate for this study shall be 45%.  
 
Patients will be enrolled and evaluated for best response achieved through cycle 6.  
Patients who discontinue study therapy prior to cycle 6 but who had a response reported 
will use that response for the primary endpoint (ie, a patient achieving a CR after 2 cycles 
who discontinues therapy to move forward .  CR rate will be determined by dividing the 
number of CR’s (per Lugano criteria) by the total number of evaluable patients.  Evaluable 
patients will include patients who receive any dose of study therapy at any time.  Patients 
who discontinue study therapy due to progression as well as those who discontinue for 
other reasons prior to the first restaging assessment will be considered as non-responders 
for the purposes of the primary endpoint.   
 
In order to have 80% power to detect an improvement in CR rate from 25% to 45%, we 
will enroll a total of 36 patients to the phase 2 portion of the study.  The first stage of the 
2-stage design will include enrollment of 17 patients, and the study will continue to the 
second stage if ≥ 5 patients achieve a CR.  If 4 or fewer patients achieve a CR, the study 
will end at the conclusion of the first stage. 
 
In order to reach both planned primary endpoints (phase 1 and phase 2) we will require a 
minimum of 26 patients (9 in phase 1 and 17 in phase 2) and a maximum of 54 patients 
(18 in phase 1 and 36 in phase 2). 
 
Planned secondary analyses will include overall response rate (total number of patients 
achieving a PR or CR as best response through cycle 6 divided by total number of patients 
treated); duration of response (determined from date of best response to progression or 
death), progression free survival (determined from date of 1st dose of study drug to 
progression or death), and overall survival (determined from date of 1st dose of study drug 
to death from any cause).  We will also capture the time to next treatment as well as the 
time from progression to discontinuation of study therapy for patients who continue to 
receive therapy post progression. 
We will determine all of the above endpoints using Lugano criteria of response and to 
determine progression of disease.  However, as an exploratory endpoint, we will also 
utilize recently published Lyric guidelines for evaluation of immunotherapies. 
 
Survival endpoints will be evaluated using the Kaplan-Meier method and will presented in 
tables and graphs. 
 
We will also evaluate toxicities which will be presented in tabular form as appropriate 
based on grade and attribution.   


 
36 
 
 
As discussed above, we will also continuously monitor for immune-mediated toxicities 
throughout the study as well as any study-related deaths which shall result in a temporary 
holding of accrual while any further amendments or supportive measures are implemented. 
This is discussed in detail above. 
12.3 Statistical Analysis 
After study complete, DLTs will be listed per dose level. Because the intent is to find a 
desirable dose that meets the tolerability criteria based on DLT rate while demonstrating 
clinical activity based on response rate, descriptive statistics (n, frequency and 
percentage) will be reported. Corresponding listings of data will be generated. DLT rate by 
dose level will be calculated as proportion (Patients with DLT/Total patients) along with 
95% confidence intervals using the Clopper-Pearson method. Chi-square test or Fisher’s 
exact test will be used to compare the probability of DLT between the different dose 
levels, respectively. 
 
Other adverse events (toxicity) will be listed and summarized overall and by dose level. 
Adverse events will also be listed by severity, seriousness, and by system organ class. The 
number and percentage of subjects who experience AEs will be presented in tabular 
and/or graphical format and summarized descriptively, where appropriate. No formal 
statistical comparison between the dose levels will be performed. AEs will be presented 
with and without regard to causality based on the investigator’s judgment. The frequency 
of overall toxicity, categorized by toxicity grades 1 through 5, will be described. Additional 
summaries will be provided for AEs that are observed with higher frequency. 
 
Planned secondary analyses will include overall response rate (total number of patients 
achieving a PR or CR as best response through cycle 6 divided by total number of patients 
treated); duration of response (determined from date of best response to progression or 
death), progression free survival (determined from date of 1st dose of study drug to 
progression or death), and overall survival (determined from date of 1st dose of study drug 
to death from any cause).  We will also capture the time to next treatment as well as the 
time from progression to discontinuation of study therapy for patients who continue to 
receive therapy post progression. We will determine all of the above endpoints using 
Lugano criteria of response and to determine progression of disease.  However, as an 
exploratory endpoint, we will also utilize recently published Lyric guidelines for evaluation 
of immunotherapies. 
 
Response rate (ORR or CBR) will be calculated as proportion (Responders/Total patients) 
along with 95% confidence intervals using the Clopper-Pearson method. Chi-square test 
or Fisher’s exact test will be used to compare the efficacy in term of response rate 
between the different groups stratified by dose level or other factors, respectively. 
Logistics regression model will be further employed to test the adjusted effect of dosage 
on the response rate after adjusting for other clinical factors and demographic factors.  
 


 
37 
 
Overall survival (OS) and progression free survival (PFS) rates of two patient groups 
stratified by dose levels or other factors will be estimated with the Kaplan-Meier method 
and compared between different groups using the log-rank test, respectively. The PFS and 
OS of each patient group at specific time points, such as 6 moths, 1 year, 3 year, and 5 
year, etc. will be also estimated alone with 95% CI. Cox proportional hazards models will 
be further used in the multivariable analyses to assess adjusted effect of dose levels on 
the patients’ OS and PFS after adjusting for other factors. Interaction terms between 
these factors will also be tested for statistical significance. The proportional hazards 
assumption will be evaluated graphically and analytically with regression diagnostics. 
Violations of the proportional hazards assumptions will be addressed by use of time-
dependent covariates or extended Cox regression models.  
 


 
38 
 
13.0 Adverse Event Identification and Reporting 
• All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of discontinuation of dosing must be recorded 
and reported to BMS Worldwide Safety, whether related or not related to study drug. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy). 
• Following the subject’s written consent to participate in the study, all AEs, 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 AE 
occurring after these aforementioned time periods, which is believed to be related to 
study drug or protocol-specified procedure. 
• An SAE report should be completed for any event where doubt exists regarding its 
seriousness;  
• 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 the BMS safety address is not included in the protocol document (eg, 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. 
• An appropriate SAE form (e.g.  ex-US = CIOMS form or USA = Medwatch form) should be 
used to report SAEs to BMS . The BMS protocol ID number must be included on whatever 
form is submitted by the Sponsor/Investigator.  
o The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
o The MedWatch form is available at: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM
048334.pdf 
•  
• Worldwide.Safety@bmsaepbusinessprocess@bms.com 
• In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). 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 a SUSAR Report.  
o Other important findings which may be reported by BMS as an Expedited Safety 
Report (ESR) include: increased frequency of a clinically significant expected SAE, an 
SAE considered associated with study procedures that could modify the conduct of 


 
39 
 
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 to the Sponsor Investigator’s responsibility to report events to the FDA 
and their local IRB, 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). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on either CIOMS or MedWatch form & pregnancies 
must be reported on a Pregnancy Surveillance Form or can be submitted on the 
aforementioned SAE form to BMS. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
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 (or designee) 
using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence.  
If the event is fatal or is deemed to be life threatening, the report will be made within 7 
calendar days.  The IND sponsor will also make an assessment of whether the event constitutes 
an unanticipated problem posing risks to subjects or others (UP). This assessment will be 
provided to Emory University IRB, which in turn will make a final determination. If the Emory 
IRB determines an event is a UP it will notify the appropriate regulatory agencies and 
institutional officials. 


 
40 
 
DEFINITIONS 
SERIOUS ADVERSE EVENTS 
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 participant 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 (see 
NOTE below) 
• 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 [eg, 
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.)  
• Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis 
must be reported). 
The following hospitalizations are not considered SAEs:  
− 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) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 


 
41 
 
− Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
− Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
− Admission for administration of anticancer therapy in the absence of any other SAEs  
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
• Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [eg, IND 
US trial] as part of an annual reporting requirement.  
• Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the 
subjects.  
A non-serious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting 


 
42 
 
The collection of non-serious AE information should begin at initiation of study drug. All 
non-serious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following 
the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the participant to have study drug discontinued 
or interrupted 
• any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
Potential Drug Induced Liver Injury (DILI)  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 


 
43 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form.  A BMS Pregnancy Surveillance Form 
may be provided upon request. 
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. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this 
information.  
Overdose 
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. 
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 non-serious or serious 
AE, as appropriate, and reported accordingly.  
Adverse Events at Subsites: 
For participating subsites, adverse events collected at weekly treatment visits is to be entered 
into OnCore no later than 14 calendar days after data collection.  
 


 
44 
 
Site investigators must also report all SAEs and unanticipated problems to the sponsor-
investigator within 24 hours of the participating site becoming aware of the event. The 
participating site will submit the MedWatch Form 3500A to the Winship regulatory staff and 
will also enter the data into OnCore within the specified timelines above. The Emory sponsor 
must review and sign off on the event and return to the Winship regulatory staff.  Regulatory 
will review the assessment to determine IRB and/or FDA reporting requirements. 
 
The Winship Cancer Institute Data Safety Monitoring Committee 
 
The study will also be followed by the Winship Cancer Institute Data Safety Monitoring 
Committee to allow for local review and confirmation of proper study execution and safety 
measures.   
 
Patient safety, study efficacy and compliance will be reviewed at the Winship Cancer Institute 
Lymphoma Working Group meeting. The Data and Safety Monitoring Committee (DSMC) of the 
Winship Cancer Institute will also oversee the conduct of this study (every 6 months or annually 
– depending on the risk level of the protocol). This committee will review pertinent aspects of 
study conduct including patient safety, compliance with protocol, data collection and efficacy. 
For studies deemed High Risk, initial study monitoring will occur within 6 months from the date 
of the first subject accrued, with 2 of the first 5 subjects being reviewed.  For studies deemed 
Moderate Risk, initial study monitoring will occur within 1 year from the date of the first subject 
accrued, with 2 of the first 5 subjects being reviewed.  Subsequent monitoring will occur in 
routine intervals per the Winship Data and Safety Monitoring Plan (DSMP). The Committee 
reserves the right to conduct additional audits if necessary. The Principal Investigator (PI) or 
designee is responsible for notifying the DSMC about the accrual of patients when the first 5 
have been entered to the study. The PI or designee will also notify the DSMC of study status 
within 2 months before the next scheduled review is due. 
 
Procedures to assure data integrity and protocol adherence 
 
Imaging and clinical data will be analyzed in a quarterly meeting of investigators, clinical 
research coordinators and regulatory personnel. 
 
Adverse event reporting will utilize NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 and is detailed in section 13 above. 
 
Study Team Oversight:  The study progress in terms of enrollment, activity of current patients 
under active treatment, observed toxicities will be reviewed in the weekly Emory Lymphoma 
Working Group.  Here there will be random and selected case report form and chart review.  
Special and problematic items requiring additional attention will be addressed in separate 
sessions of the Lymphoma Working Group occurring up to weekly including selected study 
investigators, clinical research coordinators and regulatory personnel.   
 


 
45 
 
Training of investigators, clinical research coordinators and regulatory personnel at all sites will 
be performed by one of the site investigators utilizing the written protocol and a summary of 
pertinent treatment activities.  Completion of the training of investigators, clinical research 
coordinators and regulatory personnel will be documented on a study training log.  
 
On-site Audits 
Regulatory authorities, the IRB and BMS may request access to all source documents, data 
capture records, and other study documentation for on-site audit or inspection.  Direct access 
to these documents must be guaranteed by the investigator, who must provide support given 
reasonable notice at all times for these activities. 
Monitoring plan of Subsite(s): 
 
At the time of study initiation at a non-Emory site, the Emory Sponsor, Winship regulatory 
specialist, and Winship research coordinators will perform a site initiation teleconference. 
During this teleconference, the Emory team will review the study, enrollment, reporting, and 
regulatory compliance. The participating site will have internal monitoring meetings. These 
meetings which will include the participating site investigator, the clinical research coordinator 
and the regulatory affairs coordinator, will meet at least on a monthly basis to review and 
discuss study data to ensure subject safety. The research coordinators will maintain  a spread 
sheet which will be de-identified and will summarize all the patient data for subjects actively 
being treated on the trial as well as a roadmap detailing pending tests/treatments for each 
individual subject. The spread sheet will be shared with the Emory PI via e-mail monthly. 
Teleconferences will be conducted at least once monthly between the PI at Emory and the 
research team at the participating site(s). The purpose of the meetings is to discuss the 
enrollment, regulatory updates, monitor toxicities, and evaluate the progress of the trial. The 
minutes from the teleconference will be maintained in the regulatory binder for the study. In 
addition electronic copies will be sent via email to the principal investigators at each site. 
Scheduled teleconferences may stop after all patients have completed assigned protocol 
therapy and the PI at Emory will communicate with participating sites via monthly email as 
needed. Chart reviews will be performed on selected cases by the participating site staff to 
confirm that the data collection is accurate. 
Winship’s Multi- Site Coordinator will perform an on-site or remote monitoring visit within the 
first three months of enrollment of the first subject. Quarterly monitoring visits will occur 
(annually once onsite and three times remotely) until subject follow-up is terminated.. Monthly 
reviews of data in OnCore will be conducted to ensure compliance or identify discrepancies.   
 
 
 


 
46 
 
16.0  References 
 
 
1. 
Gordon LI, Hong F, Fisher RI, et al: Randomized phase III trial of ABVD versus 
Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin 
lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group 
(E2496). J Clin Oncol 31:684-91, 2013 
 
2. 
Connors JM, Jurczak W, Straus DJ, et al: Brentuximab Vedotin with 
Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med 378:331-344, 2018 
 
3. 
Schmitz N, Pfistner B, Sextro M, et al: Aggressive conventional chemotherapy 
compared with high-dose chemotherapy with autologous haemopoietic stem-cell 
transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 
359:2065-71, 2002 
 
4. 
Moskowitz CH, Bertino JR, Glassman JR, et al: Ifosfamide, carboplatin, and 
etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization 
regimen for transplant-eligible patients with non-Hodgkin's lymphoma. J Clin Oncol 17:3776-
85, 1999 
 
5. 
Bartlett NL, Niedzwiecki D, Johnson JL, et al: Gemcitabine, vinorelbine, and 
pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: 
CALGB 59804. Ann Oncol 18:1071-9, 2007 
 
6. 
Younes A, Gopal AK, Smith SE, et al: Results of a pivotal phase II study of 
brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 
30:2183-9, 2012 
 
7. 
Green MR, Monti S, Rodig SJ, et al: Integrative analysis reveals selective 9p24.1 
amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular 
sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 
116:3268-77, 2010 
 
8. 
Lesokhin AM, Ansell SM, Armand P, et al: Nivolumab in Patients With Relapsed 
or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 
34:2698-704, 2016 
 
9. 
Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in 
relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372:311-9, 2015 
 
10. 
Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin's 
lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: 
a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-94, 2016 
 
11. 
Cohen JB, Engert A, Ansell SM, et al: Nivolumab Treatment Beyond 
Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical 
Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study. Blood 130:650-650, 2017 
 
12. 
Moccia AA, Hitz F, Hoskins P, et al: Gemcitabine, dexamethasone, and cisplatin 
(GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-
cell lymphoma and Hodgkin lymphoma. Leuk Lymphoma 58:324-332, 2017 
 
13. 
Suyani E, Sucak GT, Aki SZ, et al: Gemcitabine and vinorelbine combination is 
effective in both as a salvage and mobilization regimen in relapsed or refractory Hodgkin 
lymphoma prior to ASCT. Ann Hematol 90:685-91, 2011 
 
14. 
Santoro A, Mazza R, Pulsoni A, et al: Bendamustine in Combination With 
Gemcitabine and Vinorelbine Is an Effective Regimen As Induction Chemotherapy Before 
Autologous Stem-Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: Final 
Results of a Multicenter Phase II Study. J Clin Oncol 34:3293-9, 2016 
 
15. 
Moskowitz AJ, Hamlin PA, Jr., Perales MA, et al: Phase II study of bendamustine 
in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 31:456-60, 2013 
 
16. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. J Clin Oncol 32:3059-68, 2014 
 
17. 
Cheson BD, Ansell S, Schwartz L, et al: Refinement of the Lugano Classification 
lymphoma response criteria in the era of immunomodulatory therapy. Blood 128:2489-2496, 
2016 


 
47 
 
 
18. 
Meignan M, Gallamini A, Haioun C, et al: Report on the Second International 
Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8-9 
April 2010. Leukemia & Lymphoma 51:2171-2180, 2010 
 
 
 


 
48 
 
APPENDIX: Suggested algorithms for common immunologic toxicities related to nivolumab.   
 
NOTE – the algorithms below do not take the place of clinical judgment and are meant as 
suggested approaches. 
 
PULMONARY: 
 
Grade 1:  
• 
May continue nivolumab treatment 
• 
Monitor every 2-3 days with clinical exam 
• 
Re-image (Chest X-Ray or CT Chest as indicated) at least every 3 weeks if not resolved 
• 
If worsens, treat as if grade 2 
 
Grade 2:  
• 
Withhold nivolumab treatment  
• 
Initiate 1-2mg/kg/day prednisone (or equivalent) followed by 1 month steroid taper 
• 
Workup: Consider pulmonary and/or infectious disease consultation, bronchoscopy w/ 
biopsy, and repeat imaging every 1-3 days as indicated. 
• 
Steroids should be tapered prior to consideration of restarting nivolumab. Patients 
should only be rechallenged with nivolumab in consultation with the study chair. 
 
Grade 3-4:  
• 
Permanently discontinue nivolumab and remove from study therapy 
• 
Initiate prednisone 1-2mg/kg/day (or equivalent) and taper steroids over 6 weeks. 
• 
Consider inpatient hospitalization, pulmonary/infectious disease consultation, and 
bronchoscopy w/ biopsy. 
• 
Consider non-corticosteroid immunosuppression if symptoms worsen after 2 days. 
 
 
GASTROINTESTINAL 
 
Grade 1: 
• 
Continue nivolumab treatment 
• 
Administer symptomatic treatment as indicated 
• 
Monitor closely for worsening symptoms and counsel the patient to contact the clinical 
team immediately with worsening symptoms. 
• 
If worsens, treat as if grade 2 
 
Grade 2: 
• 
Withhold nivolumab 
• 
Treat with symptomatic measures 
• 
If grade 2 colitis for > 5 days, initiate 0.5-1mg/kg/day of prednisone (or equivalent) and 
taper steroids over 1 month.  May increase to 1-2mg/kg/day if no improvement. 
• 
May resume treatment if improved to grade ≤ 1 if steroids have been tapered. 
 
Grade 3: 
• 
Withhold nivolumab 
• 
Treat with 1-2mg/kg/day of prednisone (or equivalent) with a taper for at least 1 month 
• 
Consider colonoscopy 
• 
Steroids must be tapered and symptoms improved to grade ≤ 1to resume treatment. 
• 
If symptoms persist > 3-5 days or recur, consider addition of a non-corticosteroid 
immunosuppressive agent. 
 


 
49 
 
Grade 4: 
• 
Permanently discontinue nivolumab and remove patient from study therapy 
• 
Treat with 1-2mg/kg/day of prednisone (or equivalent) with a taper for at least 1 month 
• 
Consider colonoscopy 
• 
If symptoms persist > 3-5 days or recur, consider addition of a non-corticosteroid 
immunosuppressive agent. 
 
HEPATIC (Note discontinuation rules for hepatic toxicity documented in Section 7.3) 
 
Grade 1: 
• 
Continue nivolumab 
• 
Monitor LFT’s throughout treatment 
• 
If symptoms worsen, treat as grade 2 
 
Grade 2: 
• 
Withhold nivolumab 
• 
Increase frequency of monitoring to every 3 days 
• 
Consider 0.5-1mg/kg/day prednisone or equivalent with taper over at least 1 month 
• 
Toxicity must be returned to grade ≤ 1 after a steroid taper before restarting nivolumab 
 
Grade 3-4: 
• 
Permanently discontinue nivolumab and remove from study therapy 
• 
Monitor every 1-2 days 
• 
Consult hepatology 
• 
Initiate 1-2mg/kg/day prednisone (or equivalent) followed by taper of at least one 
month 
• 
Consider non-steroid immunosuppression if no improvement in 3-5 days 
 
 
CUTANEOUS 
 
Grade 1-2: 
• 
Continue treatment 
• 
Administer symptomatic treatments (ie, topical steroids) 
• 
Consider skin biopsy and/or drug discontinuation if symptoms persist for > 1-2 weeks 
 
Grade 3: 
• 
Withhold nivolumab 
• 
Consider dermatology consultation and skin biopsy 
• 
Start 1-2mg/kg/day of prednisone or equivalent with at least a 1 month taper 
• 
May consider resuming nivolumab if improved to grade ≤ 1 after steroid taper 
 
Grade 4 (or confirmed SJS or TEN): 
• 
Permanently discontinue nivolumab and remove from study therapy 
• 
Consider dermatology consultation and skin biopsy 
• 
Start 1-2mg/kg/day of prednisone or equivalent with at least a 1 month taper 
 

ICF_000.pdf: 
Informed Consent Form 
WINSHIP4388-18: A Phase I/II Study of Gemcitabine, Bendamustine, and 
Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma 
NCT Number: NCT03739619 
Document IRB Approval Date: 09/01/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD       
    Page 1 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom.
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used.
What Should I Do Next?
1. Read this form, or have it read to you.
2. Make sure the study doctor or study staff explains the study to you.
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)
4. If there will be medical treatment, know which parts are research and which are
standard care.
5. Take time to consider this, and talk about it with your family and friends.
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 2 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
Emory University and Saint Joseph’s Hospital
Consent to be a Research Subject / HIPAA Authorization 
Title: Winship 4388-18: A Phase I/II Study of Gemcitabine, Bendamustine, and Nivolumab in Patients with Relapsed or 
Refractory Classical Hodgkin Lymphoma
Principal Investigator: Jonathon B. Cohen, MD MS
Investigator-Sponsor: Jonathon B. Cohen, MD MS
Study-Supporter: Bristol Myers Squibb, Inc. (BMS)
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything you need to think 
about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to take part, you 
can change your mind later on and withdraw from the research study. The decision to join or not join the research 
study will not cause you to lose any medical benefits.  If you decide not to take part in this study, your doctor will 
continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would like to 
participate. You may wish to discuss your decision with family or friends. Do not sign this consent form unless you have 
had a chance to ask questions and get answers that make sense to you.  By signing this form you will not give up any 
legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site 
will not include information that can identify you. At most the Web site will include a summary of the results. You can 
search this Web site at any time.
What is the purpose of this study?
The purpose of this study is to learn about the safety of the combination of gemcitabine, bendamustine, and nivolumab 
in patients with Hodgkin lymphoma that has returned after at least one treatment.  We are also interested in learning 
about the effectiveness of this treatment.
What will I be asked to do?
If you participate in this study, you will complete a series of tests to determine if you are eligible to receive the study 
treatment. This will include a test of your lung function, blood oxygen levels and other blood tests.  We will also 
complete a PET/CT or other scan through radiology to determine whether your lymphoma is active.  Your physician 
and/or team will provide you with the results of these tests and will tell you whether you are able to receive treatment 
on the trial.
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 3 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
If you are eligible to participate, you will receive three drugs administered every 3 weeks for a total of 6 cycles.  On the 
first day of each cycle, you will receive gemcitabine, bendamustine, and nivolumab.  On day 2 of each cycle, you will 
receive only bendamustuine.  You will receive an injection on days 3 or 4 after each cycle, called pegfilgrastim (neulasta), 
which will help your white blood cell count (your immune system) recover between treatments.  You may choose to 
receive neulasta through an automated device placed on your arm after completing treatment.  This can be decided on 
the day of each treatment.  This treatment will repeat for up to 6 times.
After completing 6 cycles, or if your treatment team feels you are no longer able to take all three drugs, you will move to 
the maintenance phase where you will receive one infusion of nivolumab every 4 weeks for up to 2 years.  You will not 
receive any additional chemotherapy during this time.
You will also have scans performed by your physician from time to time to see how the treatment is working.  You will 
also have clinic visits throughout the study to ensure that you are tolerating the treatment.  These will include lab 
evaluations, physical examinations, and questions about how you are feeling.  If you are not feeling well or having other 
side effects related to the treatment, your study team may decide to lower your dose, delay your dose, or stop one or 
more drugs.  
NOTE: There is no placebo or randomization in this study.  All enrolled patients will receive all three drugs.
We plan to enroll up to 54 patients on this trial, 30 patients from Emory.  
How will my medicine be provided? 
The medicine that you will take will be dispensed by the pharmacy and delivered to the principal investigator or study 
team member.  The principal investigator or health care providers on his/her research team will provide the medicine to 
you.  If you have questions about the medicine, you should ask the principal investigator or study nurse.  You may also 
call the pharmacy if you have questions about the medicine. The number for the pharmacy is included on your medicine 
package.
If you participate in this study, nivolumab will be provided to you at no charge.  The costs of gemcitabine and 
bendamustine will be your responsibility and these charges will be billed to your insurance company.
Who owns my study information?
If you join this study, you will be donating your study information.  You will not receive any compensation if your 
information are used to make a new product. If you withdraw from the study, data that were already collected may be 
still be used for this study. You may withdraw from the study at any time for any reason.  However, if you choose to stop 
study therapy in the middle of a cycle, your doctor may ask you to return to clinic for a few weeks to make sure you have 
recovered from any side effects from the treatment. In this case, this follow-up would not be part of the study.  
What are the possible risks and discomforts?
There may be side effects from the study drugs or procedures that are not known at this time.  All three drugs utilized in 
this study are approved by the US Food and Drug Administration.
The most common risks and discomforts expected in this study are:
Nivolumab (Opdivo):
Fatigue (15%)
Diarrhea (9%)
Itching (8%)
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 4 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
Nausea (8%)
Rash (6%)
Fever (3%)
Lung injury/ difficulty breathing (2-3%)
Decreased appetite (6%)
Vomiting (3%)
Constipation (2%)
Headache (2%)
Muscle or joint aches (2-4%)
Colitis (1%)
Liver enzyme elevation (2-3%)
Increase amylase or lipase (pancreas enzyme; 1-2%)
Kidney toxicity (1%)
Other rare toxicities including endocrine (hormone) disorders and changes in electrolytes such as sodium and potassium.
Gemcitabine:
Anemia (low blood count; 68%)
Low neutrophil count (63%)
Low platelet count (24%)
Abnormal liver enzymes (67-68%)
Kidney toxicity (up to 45%)
Nausea/vomiting (69%)
Fever (41%)
Rash (30%)
Shortness of breath (23%)
Diarrhea (19%)
Bleeding (17%)
Infection (16%)
Hair loss (15%)
Mouth sores (11%)
Fatigue/tiredness (11%)
Numbness/tingling (10%)
Bendamustine:
Common blood related toxicities occurring > 15% of the time including low lymphocyte count, low red blood cells 
(anemia), low white blood cells, low platelet count, and low neutrophil count.
Common non-blood related toxicities occurring > 15% of the time include nausea, fatigue, vomiting, diarrhea, fever, 
constipation, poor appetite, cough, headache, decreased weight, shortness of breath, rash, and mouth soreness.
If you are a woman: to protect against possible side effects of the study drug, women who are pregnant or nursing a 
child may not take part in this study. If you become pregnant, there may be risks to you, the embryo, or fetus. These 
risks are not yet known. If you are a woman of childbearing ability, you must use an adequate birth control method or 
abstinence for the duration of the stud.  If you think that you have gotten pregnant during the study, you must tell the 
study doctor immediately.  Pregnant women will be taken out of the study.
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 5 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
If you are a man: the effect of the study drug on sperm is not known.  To protect against possible side effects, if you are 
a man you should not get a sexual partner pregnant while taking the study drug and for two months after the last dose.  
You and the study doctor should agree on an adequate method of birth control to use throughout the study.
If you will be taking the study drug home, keep it out of the reach of children or anyone else who may not be able to 
read or understand the label.  Do not let anyone else take the study drug besides you.
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  You may be 
asked to sign a new consent form that includes the new information if you decide to stay in the study.
Radiation Safety Risks
You will be exposed to radiation from nuclear medicine and CT scans. These procedures are necessary for your medical 
care and will occur even if you do not participate in this study. The radiation dose estimate that you will receive is equal 
to or less than the radiation exposure allowed to be received by a radiation worker for 4 years.  The principal risk 
associated with a radiation dose is the possibility of developing a radiation-induced cancer later in life.  Although the risk 
from radiation is cumulative it is not expected to adversely affect your condition or treatment.  The Emory University 
Radiation Safety Committee has reviewed and approved the use of radiation in this research study. 
Contrast Agents
Your PET-CT, CT or MRI procedure may require the use of a contrast agent, which is a substance that helps the 
radiologist interpret the images. The contrast agent will be injected by either a hand-held needle or a machine that does 
the injection. Most contrast agents stay in your body for only a few minutes, but some of them can remain for a few 
hours or days without any harm to you or anyone near you. Contrast agents are generally quite safe, but any injection 
involves some risks. The injection could harm a nerve, artery or vein, or cause infection. The contrast agent could affect 
kidney function or cause an allergic reaction, though these outcomes are rare. The contrast agent could also leak from 
your veins a little, causing swelling and discomfort, which is typically treated with ice packs.
PET-CT
For your PET-CT scan, a small amount of radioactive material will be injected by either a hand-held needle or a machine. 
Such injections are generally quite safe, but any injection involves some risks. The injection could harm a nerve, artery or 
vein, or cause infection. The radioactive material could also leak from your veins a little, causing swelling and discomfort. 
After injection and a waiting period for the drug to circulate within your body, you will be asked to lie very still for 
several minutes while the scan takes place.
Will I benefit directly from the study? 
This study is not designed to benefit you directly, but it is being offered to you due to the fact that we think these drugs 
will be safe and effective for patients like you.  Your lymphoma may improve while you are in this study but it may not, 
and it may even get worse.  This study is designed to learn more about relapsed/refractory Hodgkin lymphoma and the 
safety of this combination of treatment. The study results may be used to help others in the future.
Will I be compensated for my time and effort?
You will not be offered compensation for being in this study.  
What are my other options?
If you decide not to enter this study, there is care available to you outside of this research study.  This would include 
common chemotherapy regimens or possible nivolumab by itself among others.  The study doctor will discuss these with 
you.  You do not have to be in this study to be treated for Hodgkin lymphoma.
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 6 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
Taking part in this study, however, may make you unable to participate in some other research studies, if they exclude 
people who have taken certain treatments.  You should discuss this with the researchers if you have concerns. You may 
wish to research other study options at websites like clinicaltrials.gov and ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and other 
identifying information will not appear when we present or publish the study results.
Study records can be opened by court order.  They also may be provided in response to a subpoena or a request for the 
production of documents. 
Storing and Sharing your Information
De-identified data from this study, may be shared with the research community at large to advance science and health. 
Data from this study may be placed into public databases where, in addition to having no direct identifiers, researchers 
will need to sign data use agreements before accessing the data. We will remove or code any personal information that 
could identify you before your information is shared. This will ensure that, by current scientific standards and known 
methods, it is extremely unlikely that anyone would be able to identify you from the information we share. Despite 
these measures, we cannot guarantee anonymity of your personal data.
Medical Record
If you have been an Emory Healthcare and Saint Joseph’s Hospital patient before, then you already have an Emory 
Healthcare and Saint Joseph’s Hospital medical record.  If you have never been an Emory Healthcare and Saint Joseph’s 
Hospital patient, you do not have one.   An Emory Healthcare and Saint Joseph’s Hospital medical record will be made 
for you if an Emory and Saint Joseph’s Hospital provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare and Saint Joseph’s 
Hospital medical record you have now or any time during the study.  
Emory Healthcare and Saint Joseph’s Hospital may create study information about you that can help with your care.  For 
example, the results of study tests or procedures.  These study results will be put in your Emory Healthcare and Saint 
Joseph’s Hospital medical record. Anyone who has access to your medical records will be able to have access to all the 
study information placed there.  The confidentiality of the study information in your medical record will be protected by 
laws like the HIPAA privacy rule.  State and federal laws may not protect the research information from disclosure. 
Tests and procedures done at non-Emory and Saint Joseph’s Hospital places may not become part of your Emory and 
Saint Joseph’s Hospital medical record. Also, if you decide to be in this study, it is up to you to let your other health 
providers know. 
In Case of Injury
If you believe you have become ill or injured from this research, you should contact Dr. Jonathon Cohen at telephone 
number 
. You should also let any health care provider who treats you know that you are in a research 
study. 
If you get ill or injured from being in the study, Emory and Saint Joseph’s Hospital will help you get medical treatment.  
Neither Emory, Saint Joseph’s nor the study supporter will pay for your medical treatment.  Your insurer will be billed for 
your treatment costs.  If you do not have insurance, or if your insurance does not pay, then you will have to pay these 
costs.   
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 7 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
Emory, Saint Joseph’s and the study supporter have not, however, set aside any money to pay you if you are injured as a 
result of being in this study or to pay for this medical treatment. For Emory and Saint Joseph’s, the only exception is if it 
is proven that your injury or illness is directly caused by the negligence of an Emory or Saint Joseph’s employee. 
“Negligence” is the failure to follow a standard duty of care. You do not give up any legal rights you may have by being in 
this study, including any right to bring a claim for negligence. 
Costs
The study supporter will pay for certain items and services that you may receive if you take part in this study.  
You will have to pay for the items or services for which the study supporter does not pay. The sponsor will not pay for 
your regular medical care. If you have insurance, Emory will submit claims to your insurance for items and services that 
the sponsor does not cover.  Emory and Saint Joseph’s Hospital will send in only those claims for items and services that 
it reasonably believes your insurance will pay and that the sponsor has not paid. 
The actual amount that you have to pay depends on whether or not you have health insurance and whether or not that 
insurance will pay for any research study costs. Generally, insurance companies will not pay for items and services that 
are required just for a research study. Some insurance companies will not pay for regular medical treatment or 
treatment for complications if you are in a study.  How much you will have to pay for any co-payments, deductibles or 
co-insurance depends on your plan.  Emory and Saint Joseph’s Hospital and the sponsor will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask them what 
they will pay for and what they will not pay for.  You can also ask the study team for help in figuring out what you will 
have to pay. 
If you do not have insurance, Emory and Saint Joseph’s Hospital will review your case as part of its program for low-
income patient care.  The standard policies of that program will apply.  The program will figure out if you have to pay 
any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study treatment.  If you 
leave the study before the final planned study visit, the researchers may ask you to have some of the final steps done.  
The researchers also have the right to stop your participation in this study without your consent for any reason, especially if 
they believe it is in your best interest or if you were to object to any future changes that may be made in the study plan.
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that identifies you, your 
“protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, including the 
Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy 
Rules.”  Here we let you know how we will use and disclose your PHI for the study.
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 8 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017

Medical information about you including your medical history and present/past medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share your 
PHI to provide you with study related treatment and for payment for such treatment.  We will also use and 
share your PHI to conduct normal business operations.  We may share your PHI with other people and places 
that help us conduct or carry out the study, such as laboratories, data management centers, data monitors, 
contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
we may use your PHI to determine your health, vital status or contact information. 
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests or orders that 
require us to disclose your PHI. These include subpoenas or court orders.  
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this document. You do not 
have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this form, then you may 
not participate in the research study or receive research-related treatment.  You may still receive non-research 
related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research study:

The Principal Investigator and the research staff will use and disclose your PHI to conduct the study and 
give you study related treatment.

Emory and Saint Joseph’s Hospital may use and disclose your PHI to get payment for study related 
treatment and to run normal business operations. 

The Principal Investigator and research staff will share your PHI with other people and groups to help 
conduct the study or to provide oversight for the study.

Dr. Cohen is the Sponsor of the study.  The Sponsor may use and disclose your PHI to make sure the 
research is done correctly and to collect and analyze the results of the research.  The Sponsor may 
disclose your PHI to other people and groups like study monitors to help conduct the study or to provide 
oversight for the study.  

The following people and groups will use your PHI to make sure the research is done correctly and 
safely:
o
Emory and Saint Joseph’s Hospital offices that are part of the Human Research Participant 
Protection Program and those that are involved in study administration and billing.  These 
include the Emory IRB, the Emory Research and Healthcare Compliance Offices, and the Emory 
Office for Clinical Research. 
o
Government agencies that regulate the research including:  Office for Human Research 
Protections; Food and Drug Administration.
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 9 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017

Sometimes a Principal Investigator or other researcher moves to a different institution. If this happens, 
your PHI may be shared with that new institution and their oversight offices. PHI will be shared securely 
and under a legal agreement to ensure it continues to be used under the terms of this consent and 
HIPAA authorization.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If you want 
to do this, you must contact the study team at: 1365 Clifton Road, NE, Atlanta, GA 30322
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the information you 
already gave them so they can follow the law, protect your safety, or make sure that the study was done properly and 
the data is correct.  If you revoke your authorization you will not be able to stay in the study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, health care 
payers, and health care clearinghouses.  If we disclose your information to people who are not covered by the Privacy 
Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  People who do not have to 
follow the Privacy rules can use or disclose your information with others without your permission if they are allowed to 
do so by the laws that cover them.  
To maintain the integrity of this research study, you generally will not have access to your PHI related to this research 
until the study is complete.  When the study ends, and at your request, you generally will have access to your PHI that 
we maintain in a designated record set.  A designated record set is data that includes medical information or billing 
records that your health care providers use to make decisions about you. If it is necessary for your health care, your 
health information will be provided to your doctor. 
We may remove identifying information from your PHI.  Once we do this, the remaining information will not be subject 
to the Privacy Rules.  Information without identifiers may be used or disclosed with other people or organizations for 
purposes besides this study.  
IRB00104033
IRB Approved
9/1/2021


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
PI: Jonathon Cohen, MD                                         Page 10 of 10 
Version Date: 05/14/2019
Protocol #: Winship 4388-18
 IRB Form 12152017
Contact Information
Contact Dr. Jonathon Cohen at 
:

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

if you have questions, concerns or complaints about the research
Contact the Emory Institutional Review Board at 
:

if you have questions about your rights as a research participant.

if you have questions, concerns or complaints about the research.

You may also let the IRB know about your experience as a research participant through our Research Participant 
Survey at http://www.surveymonkey.com/s/6ZDMW75.
Consent and Authorization
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in this research study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the signed form to keep.
Name of Subject 
 am / pm
Signature of Subject (18 or older and able to consent)
Date
Time (please circle)
 am / pm
Signature of Legally Authorized Representative with authority for
Date
Time (please circle)
research decisions
Authority of Legally Authorized Representative or Relationship to Subject
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
 am / pm
Signature of Person Conducting Informed Consent Discussion
Date
Time (please circle)
IRB00104033
IRB Approved
9/1/2021