Clinical trial NCT03586999
Conditions: Peripheral T Cell Lymphoma
Keywords: Nivolumab First Line Treatment EPOCH Standard of Care
Sponsor: University of Colorado, Denver
Start date: 2018-11-07; Completion date: 2022-09-20
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This regimen aims to become the first line treatment for peripheral T cell lymphoma, using nivolumab with the standard of care chemotherapy.

Detailed description:
Patients in this study will receive nivolumab in combination with the standard of care dose-adjusted EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) for six 21 day cycles. Patients will then have an autologous stem cell transplant or continue to receive maintenance therapy with nivolumab.

Arms: arm 1: Patients will all receive nivolumab in combination with standard dose adjusted EPOCH for a planned 6 cycles, unless treatment is stopped early for disease progression or toxicity. Patients that have already received up to 1 cycle of standard of care chemotherapy will receive 5 cycles of experimental nivolumab + DA-EPOCH (dose adjusted, continuous infusion etoposide, prednisone, vincristine, doxorubicin, and bolus dosing of cyclophosphamide) for a total of 6 cycles of chemotherapy.
Interventions: intervention 1: Nivolumab intervention 2: Etoposide intervention 3: Prednisolone intervention 4: Oncovin intervention 5: Cyclophosphamide intervention 6: Hydroxydaunorubicin
Intervention descriptions: intervention 1: Nivolumab injection is to be administered as an IV infusion. intervention 2: Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications. intervention 3: Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications. intervention 4: Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications. intervention 5: Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications. intervention 6: Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
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Nivolumab with standard of care chemotherapy for the 
first line treatment of peripheral T cell lymphoma 
 
Protocol Number:  
 
COMIRB Number: 
CA209-8J6 
 
18-0708 
Principal Investigator:  
 
Bradley Haverkos, MD 
IND/IDE:  
139751 
Coordinating Center and Lead 
Principal Investigator:  
University of Colorado, Bradley Haverkos 
Funded by:  
Bristol-Myers Squibb 
Version Date:   
Version 7.0, Dated October 8, 2020 
 


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STATEMENT OF COMPLIANCE 
 
This is an investigator-initiated study. The principal investigator (PI), Bradley Haverkos, MD, is 
conducting the study and acting as the sponsor. As the sponsor-investigator, both the legal/ethical 
obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United States 
(US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
 
The PI will assure that no changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB). All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments.  
 
 
 
Sponsor-Lead Principal Investigator:   
Bradley Haverkos, MD 
 
 
  
 
 
 
 
 
 
                         
 
 
Print/Type Name  
 
 
Signed:   
 
 
 
 
 
 
 
 
 
Date:    
 
  
 
 
 
Site Principal Investigator:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                        Print/Type Name  
 
 
Signed:  
 
 
 
 
 
 
 
Date:    
 
 


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LIST OF ABBREVIATIONS 
 
ACRONYM DESCRIPTION 
AITL 
angioimmunoblastic T cell lymphoma 
BEAM 
BCNU, etoposide, cytarabine, melphalan 
BMS 
Bristol-Meyers Squibb 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CHOEP 
CHOP with etoposide 
CNSL 
central nervous system lymphoma 
CTL 
cytotoxic T lymphocytes 
CTX 
cyclophosphamide 
DA-EPOCH 
dose adjusted, continuous infusion etoposide, prednisone, vincristine, 
doxorubicin, and bolus dosing of cyclophosphamide 
DLBCL 
diffuse large B-cell lymphoma 
EPOCH 
etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide 
PJP 
Pneumocystis Jiroveci Pneumonia 
PTCL 
peripheral T cell lymphoma 
R-CHOP 
CHOP with rituximab 
SJS 
Stevens-Johnson syndrome 
TEN 
toxic epidermal necrolysis 
VCR 
vincristine 
 
 


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PROTOCOL SUMMARY / SYNOPSIS 
Protocol Title: 
Nivolumab with standard of care chemotherapy for the 
first line treatment of peripheral T cell lymphoma 
 
Objectives: 
 
• Primary Objectives: 
A pilot/feasibility study to evaluate the efficacy of 
nivolumab when given in combination with dose 
adjusted EPOCH for the first line management of 
peripheral T cell lymphoma. 
 
• Secondary Objectives:  
Progression free survival, duration of response, overall 
response rate (CR + PR), toxicity. 
 
Correlative analysis:  Determine immune-related 
predictors of response to nivolumab + EPOCH 
chemotherapy using blood and tumor tissue 
specimens. 
 
 
Endpoint: 
• Primary Endpoints: 
Efficacy (Complete response rate) 
 
• Secondary Endpoint: 
2year progression free survival (Maurer et al. JCO 
2017), duration of response, overall response rate 
(CR+PR), safety/toxicity. 
 
Population: 
 
• Sample size 
o Maximum number of participants that can be 
enrolled is 18 (not including screen failures)  
o Minimum number of participants to be 
enrolled 12 (number of participants needed to 
answer scientific question/aims) 
• Gender Male or Female 
• Age Range 18-80 years old. 
• Demographic group Any 
• General health status ECOG 0-2 
• Geographic location Participating medical center 
 
Phase: 
I/II 
 
 


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Number of 
Participating Sites: 
3 
Description of Study 
Agent: 
PD-1 checkpoint antibody 
Study Duration: 
Patient enrollment is expected to last for 2 years. Patients 
will be followed for outcome measures for up to 2 years 
after enrollment in study. 
 
 
 
 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
PARTICIPATING SITES 
A complete and current listing of investigators, research personnel, research facilities and other 
study centers (if applicable) participating in this study will be maintained throughout the duration 
of this study on a Protocol Contact List form, incorporated herein by reference.  
 
Thomas Jefferson University, Pierluigi Porcu MD 
 
City of Hope, Jasmine Zain MD 
 
 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE                                     
2.1 
BACKGROUND INFORMATION  
Peripheral T cell lymphomas (PTCL) comprise a heterogeneous group of non-Hodgkin 
lymphomas that have consistently demonstrated poor outcomes when treated with anthracycline 
based chemotherapy regimens (e.g. CHOP). When treated with CHOP (cyclophosphamide, 
doxorubicin, vincristine, prednisone), the overall response rate (ORR) for PTCL is 50-70%, with 
a progression free survival (PFS) of 30-40% at 12 months (1, 2) and long term disease free survival 
rates of 20-30% (2). In an attempt to improve upon these outcomes, more intensive combination 
chemotherapy approaches, such as CHOEP (CHOP with etoposide) or DA-EPOCH (dose adjusted, 
continuous infusion etoposide, prednisone, vincristine, doxorubicin, and bolus dosing of 
cyclophosphamide), have been used. Based on retrospective and post-hoc analysis, outcomes 
appear improved in PTCL patients treated with etoposide containing regimens (1, 3, 4). As a result, 
EPOCH has emerged as a first line chemotherapeutic option for patients with PTCL at the 
University of Colorado, as well as other centers (5-8). Nevertheless, long term outcomes in patients 
with PTCL continue to be sub-optimal with current estimates of 5-year survival of 10-30% (9).  
 
Checkpoint blockade is an exciting new therapeutic approach in oncology that has improved the 
standard of care in multiple hematologic and solid tumor malignancies. Less is known about the 
use of checkpoint blockade for the treatment of T cell lymphomas relative to other malignancies.  
Nivolumab had a response rate of 40% in PTCL in a phase 1 study (10). In a heavily pretreated 
advanced stage cutaneous T-cell lymphoma cohort, pembrolizumab showed an ORR of ~40% with 
meaningful durable responses (11). Additionally, 5 out of 7 patients with relapsed/refractory 
NK/T-cell lymphoma after L-asparaginase based therapy had a complete response to 
pembrolizumab (2 PRs) (12).    
 
Mechanistically, there is reason to believe that PD-1 inhibition will be effective for the treatment 
of PTCL. In lung cancer, increased PD-L1 expression is associated with increased response rates 
to PD-1/PD-L1 antibodies (13). In T-cell lymphomas, PD-1 expression on tumor cells is frequent.  
For instance, 93% of angioimmunoblastic T cell lymphomas (AITL) and 62% of PTCL-NOS have 


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increased number of extrafollicular PD-1 positive cells. PD-1 expression can also be used to aid 
in the diagnosis of PTCL (14).  
 
Furthermore, the microenvironment is expected to play a significant role in the etiopathogenesis 
of PTCL (15). The programmed death (PD) pathway serves as a checkpoint to limit T-cell 
mediated immune responses. Blocking the PD-1 receptor on T-cell results in T-cell activation and 
proliferation, inducing a potent immunotherapeutic antitumor effect. Nivolumab inhibits the 
ligation of PD-1 and PD-L1 and would be expected to alter the microenvironment stimulating T-
cell mediated anti-tumor immune responses (16). 
 
 
2.2 
RATIONALE  
Unfortunately, checkpoint blockade as a single treatment modality produces durable responses 
only in a minority of patients with PTCL. As a result, a current major area of interest lies in 
determining how to improve responses to this novel class of therapeutics. One approach that has 
demonstrated promise is via rational combination with other therapeutics with distinct yet 
complementary mechanisms of action. As chemotherapy regimens like EPOCH are effective 
(albeit with modest long-term success) for patients with PTCL, approaches that combine 
chemotherapy with PD-1/PD-L1 antibodies are appealing. Mechanistically, it has been 
demonstrated that chemotherapy-induced apoptotic cells behave as a potent source of 
immunogenic tumor antigens for the stimulation of cytotoxic T lymphocytes (CTL) (17). It has 
subsequently been demonstrated that multiple components of the EPOCH regimen, including 
etoposide, cyclophosphamide, and vincristine increase antigen presentation and MHC expression, 
thus triggering an immune response (18, 19). Further, chemotherapy may increase the activity of 
immune effector cells such as NK cells, while also suppressing the effects of negative regulators 
of an immune response such as T-regulatory cells and myeloid derived suppressor cells (20).  
These immune-modulating effects of chemotherapy may allow for synergism with checkpoint 
blockade. Of note, it has been demonstrated that increased expression of antigens via MHC II has 
been correlated with response to checkpoint blockade in melanoma (21). Similarly, loss of function 
mutations in JAK/STAT and beta-2-microglobulin proteins leading to decreased expression of 
MHC I has been associated with acquired resistance to checkpoint blockade (22). 
 
Patients receiving checkpoint blockade in later lines of therapy tend to be more de-conditioned 
and have weakened immunity after failing prior lines of chemotherapy. In solid tumors, checkpoint 
blockade in combination with standard first line chemotherapy regimens appears to be a safe and 
potentially synergistic combination. For instance, the response rate for pembrolizumab plus 
standard of care pemetrexed/carboplatin in first line lung cancer is 57%; the response rate for 
chemotherapy alone was 30% (23). Of note, the response rate for second line checkpoint blockade 
in unselected non-small cell lung cancer is about 19% (24). Despite a 75% crossover rate to PD-1 
blockade in the chemotherapy alone arm, the hazard ratio for survival in this randomized study 
was 0.69, favoring combination PD-1 blockade with chemotherapy in the first line setting. This 
study led to FDA approval for pembrolizumab plus chemotherapy in the first line treatment of 
non-small cell lung cancer.   
 


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There are currently two ongoing studies combining checkpoint blockade with standard first line 
R-CHOP in B cell lymphomas (Clinicaltrials.gov NCT02541565; and NCT03003520). We are not 
aware of any concerning safety signals that have emerged from these studies; however, there are 
no trials on clinicaltrials.gov combining checkpoint blockade with EPOCH.    
 
Thus, we are conducting a multi-center phase I/II study of standard of care EPOCH in combination 
with nivolumab for the first-line treatment of PTCL. 
 
2.3 
POTENTIAL RISKS AND BENEFITS  
Patients in this study will be offered standard of care first-line chemotherapy (i.e. EPOCH) in 
addition to an experimental drug, nivolumab. As discussed in sections 2.1 and 2.2, nivolumab and 
other checkpoint inhibitors have demonstrated activity in relatively small early studies of patients 
with relapsed refractory T-cell lymphoma. Further, multiple trials are being conducted combining 
PD-1 checkpoint antibodies with first line chemotherapy, including trials in lung cancer (23), 
gastric cancer (25), as well as diffuse large B-cell lymphoma (DLBCL) (26). Importantly, all of 
these studies have demonstrated evidence of therapeutic activity, as well as reasonable toxicity 
profiles when combining chemotherapy with PD-1 antibody immunotherapy. Thus, PD-1 
immunotherapy in combination with first line chemotherapy appears to be an effective and 
tolerable approach in multiple tumor types in preliminary investigations. 
 
Nivolumab has been given to a large number of patients with diverse malignancies. As a result, 
nivolumab has a well characterized toxicity profile, outlined below. Nevertheless, the toxicity 
profile of nivolumab specifically in patients with peripheral T cell lymphoma (PTCL) has not been 
completely characterized given the small number of patients with PTCL who have received 
nivolumab. Further, few if any prior patients with PTCL have been treated with DA-EPOCH in 
combination with nivolumab. Thus, potential interactions of the drug components of DA-EPOCH 
with nivolumab are not yet completely characterized.  
 
Of note, a recent pre-clinical study found that PD-1 may act as a tumor suppressor and PD-1 
inhibition may lead to proliferation of lymphoma cells in a genetic PTCL mouse model (27). This 
pre-clinical model relied on translocation of ITK-SYK, which has been observed in 5/46 cases of 
PTCL (28). Similarly, a recent clinical study of PD-1 immunotherapy for T-cell leukemia 
lymphoma was stopped prematurely due to rapid progression of the initial enrolled patients(29).  
T-cell lymphomas are a heterogenous group of malignancies, and the subset of T-cell leukemia 
lymphoma that demonstrated rapid progression in response to PD-1 immunotherapy will not be 
enrolled in this study. Nevertheless, while it has not been observed clinically to date, it remains 
possible that PD-1 inhibition may lead to rapid progression in other subtypes of T-cell lymphoma. 
Importantly, if PD-1 treatment does lead to enhanced proliferation of malignant cells, the tumor 
would theoretically have increased sensitivity to the intensive chemotherapy component of our 
treatment protocol. Nevertheless, careful stopping rules and patient monitoring have been 
integrated into our protocol to ensure the safety of the enrolled patients.  
 
 
 
2.3.1 KNOWN POTENTIAL RISKS  


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Nivolumab Monotherapy 
MDX1106-01 was a Phase 1, open-label, multicenter, safety and pharmacokinetic dose-escalation 
study of nivolumab (0.3, 1, 3, or 10 mg/kg) in subjects with selected refractory or relapsed 
malignancies. 27 of 39 subjects received a single dose of nivolumab and 15 of those 27 received 
10 mg/kg. All subjects were followed for up to 84 days after the dose of study drug.  
The following are the key safety findings(30):  
24 of 27 (88.9%) subjects had a drug-related AE. The most commonly reported (≥5%) drug- 
related AEs were: fatigue, lymphopenia, proteinuria, dry mouth, fever, decreased weight, pruritus, 
hypocalcemia, anemia, nausea, vomiting, TSH increased, TSH decreased, hypokalemia, myalgia, 
and rash. No drug-related AEs were serious. Most drug-related AEs were Grade 1 or 2. Nine 
(33.3%) subjects had Grade 3 or 4 drug-related AEs; the most commonly reported drug-related 
AEs were CD4 lymphocytes decreased (N=4) and lymphocyte count decreased (N=2)(30). 
7 of 27 (25.9%) subjects had an immune-mediated adverse event. These included rash/erythema 
(N=4), pruritus (N=3), arthritis (N=1), melena (N=1), hypersensitivity (N=1), blood bilirubin 
increased (N=1). No immune-mediated adverse events were serious. All immune-mediated 
adverse events were Grade 1 except for the case of hypersensitivity which was Grade 2(30).  
There was no apparent dose-related pattern with regard to the incidence, severity, or relationship 
of AEs(30).  
 
Nivolumab in Combination with Chemotherapy: 
In CA209012, a completed, multi-arm, Phase 1 safety study of nivolumab in chemotherapy-naive 
NSCLC subjects, 56 subjects were administered nivolumab in combination with chemotherapy 
(gemcitabine/cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel)(31).  
 
The maximum evaluated dose was 10 mg/kg of nivolumab in combination with chemotherapy. No 
dose-limiting toxicities (DLTs) were reported in any subjects receiving nivolumab + platinum-
based chemotherapy during the protocol-defined evaluation period (first 6 weeks of treatment) 
and, thus, no MTD was defined. The safety profile of nivolumab in combination with 
chemotherapy was manageable and consistent with that reported for nivolumab monotherapy and 
platinum-based doublet chemotherapy alone. No new safety concerns were identified.  
 
The following were the key safety findings:  
 
The most frequently reported drug-related AE with nivolumab + chemotherapy was fatigue 
(71.4%)(31).  
 
Drug-related SAEs reported in more than 2 subjects treated with nivolumab in combination with 
chemotherapy included pneumonitis (7.1%), anemia (5.4%), febrile neutropenia (3.6%), and rash 
maculo-papular (3.6%)(31).  
Drug-related AEs leading to discontinuation reported in more than 2 subjects treated with 
nivolumab in combination with chemotherapy included pneumonitis (5.4%) and hypersensitivity 
(3.6%)(31).  


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Most deaths in CA209012 were due to disease progression. There were no deaths reported due to 
study drug toxicity in subjects treated with nivolumab + chemotherapy(31).  
 
PD-1 Immunotherapy in Combination with R-CHOP: 
 
An ongoing study is evaluating the safety of pembrolizumab in combination with R-CHOP 
chemotherapy. The preliminary safety results were presented at ASH 2017(26). Safety results were 
available for the initial 14 patients. Of these, median age is 62 (range 38-72); NCCN-IPI is low, 
low-int, and high-int, and high in 2,6,6, and 0 pts respectively. 2/9 tested are double-expressers 
(MYC IHC >40%, BCL2 IHC>50%), and no patients have double hit (now high-grade B-cell) 
lymphoma. 
 
Eleven grade 3-5 clinically significant adverse have occurred, in 7 unique patients (7/14 patients, 
50%). Eight serious adverse events occurred in 5 patients; none met criteria for reporting as an 
unanticipated event. One death occurred in the first accrued patient who had extensive gastric 
involvement by DLBCL and died during cycle 1 of RCHOP of bleeding from the responding tumor 
bed despite maximal inpatient intervention. Two probable immune-related adverse events were 
seen: grade 3 rash, resolving with steroid and not recurring on continuation of pembrolizumab and 
grade 1 hyperthyroidism. No instances of pneumonitis were observed, and no serious immune-
related adverse events were seen. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Nivolumab has demonstrated evidence of clinical activity in multiple malignancies, including in 
early phase studies of PTCL (10, 12). Nivolumab may increase the likelihood of improved 
outcomes in patients with PTCL, though further studies are needed. 
 
The risks to participants are reasonable in relation to the anticipated benefits to participants and/or 
society, and in relation to the importance of the knowledge that may reasonably be expected to 
result, thereby falling in favor of performing the study: 
 
• To Participant: Potential to improve management of malignancy. 
• To Society: Improved understanding of the role of nivolumab in the 
management of PTCL. 
• Justify the importance of the knowledge gained: PD-1 immunotherapy has led 
to improved outcomes in patients with a large number of malignancies, 
including melanoma, non-small cell lung cancer, Hodgkin’s disease, and others.  
However, there is a relative paucity of information regarding the efficacy of 
PD-1 immunotherapy in patients with PTCL. This protocol will provide 


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valuable insights into the potential role of nivolumab in the management of 
PTCL. 
 
3 
OBJECTIVES AND PURPOSE 
Primary objectives:   
Pilot/feasibility study to measure the efficacy of nivolumab when given in combination with dose 
adjusted EPOCH for the first line management of peripheral T cell lymphoma.  
 
Secondary objectives:  
Progression free survival (PFS), overall response rate (CR + PR), toxicity/safety and duration of 
response. 
 
Correlative analysis:   
Determine immune-related predictors of response to nivolumab plus EPOCH chemotherapy. 
 
Rationale for correlative analysis: Data is rapidly accumulating on baseline factors that predict 
response to checkpoint blockade in patients with solid tumors. Further, dynamic changes in 
peripheral blood and tumor immune profiling also associate with response to immunotherapy; 
however, less is known about predictive correlates associated with T-cell lymphomas, especially 
in patients receiving checkpoint blockade in combination with chemotherapy. 
 
4 STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
Single arm, open-label, Phase I/II interventional study in order to assess the safety and efficacy of 
nivolumab with dose adjusted EPOCH for the treatment of peripheral T cell lymphoma. 
The planned accrual for this study is 18 patients. Patients will all receive nivolumab in combination 
with standard dose-adjusted EPOCH for a planned 6 cycles unless treatment is stopped early for 
disease progression or toxicity. Patients that have already received up to 1 cycle of standard of 
care chemotherapy will also be eligible for this study. Patients that had already received 1 cycle of 
standard of care chemotherapy will receive 5 cycles of experimental nivolumab + DA-EPOCH for 
a total of 6 cycles of chemotherapy. After completion of 6 cycles, patients that had a response will 
have the option of autologous stem cell transplant versus surveillance. This decision will be made 
according to standard of care (e.g. patient and physician preference).   
Study enrollment will continue until stopping endpoints as described below. 
Stopping rules for efficacy:  If 3 or fewer complete responses are observed in initial 10 patients 
trial will be stopped for lack of efficacy. See section 8.5 for statistical calculations. 


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Treatment-related mortality:  If any patient experiences death due to an adverse event that is 
assessed as related to study treatment (by investigator and/or Sponsor), it will lead to temporary 
hold of study pending review by study team. The study will be terminated prematurely if at any 
point 2 patients experience treatment-related death during induction chemotherapy with study 
regimen. 
Toxicities of special interest: The study will be halted prematurely if 3 out of the initial 10 
patients experience the following toxicities: 
 
Grade 3 or higher pneumonitis 
Grade 3 or higher colitis 
Rapid progression, at discretion of investigator, upon initiation of treatment 
Grade 4 hepatitis 
Grade 4 rash 
Grade 4 encephalitis 
Grade 3 or higher myocarditis 
Other grade 4 or unmanageable immune related events attributable to the study treatment. 
 
Transplant-related adverse events of special interest:  For patients undergoing auto-transplant 
the study will be halted prematurely if 3 out of initial 10 patients undergoing auto-transplant 
experience the following toxicities of special interest during period from start of conditioning 
regimen (e.g. BEAM) through 60 days post-transplant: 
Non-relapse related death, 
grade 4 or higher hepatotoxicity 
autograft mobilization failure. 
 
Of note, the study will accrue continuously, and will not stop enrollment of patients while analysis 
of stopping endpoints are underway. 
Patients will continue to receive study therapy until disease progression according to RECIL, 
unacceptable toxicity, death, patient or physician decision to withdraw, pregnancy or completion 
of induction chemotherapy, whichever occurs first. 
The study will end when all patients enrolled have been followed until death, have withdrawn 
consent, have been lost to follow-up, until 2-year follow up, or the Sponsor decides to end the trial, 
whichever occurs first.  
 
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 PRIMARY ENDPOINTS 
  
 
Efficacy:  Complete responses will be assessed by investigator and will be based on PET/CT scan 
to be obtained after 6 cycles of induction chemotherapy (overall response rate, complete response 


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rate, partial response rate, rate of stable disease, and rate of progressive disease according to 
RECIL). We anticipate a complete response rate > 56% for the treatment of nivolumab with DA-
EPOCH for PTCL. Responses will be assessed by the investigator and will be based on PET/CT 
scan to be obtained after 6 cycles of induction chemotherapy. Patients with rapid progression after 
completion of induction chemotherapy, e.g. within 6 weeks following CR, will not be considered 
to have achieved a complete remission but will be considered non-responders. 
 
 
4.2.2 SECONDARY ENDPOINTS 
 
Two-year PFS (32). PFS is defined as time from enrollment to PD or death of any cause. Living 
patients without PD who are lost to follow up will have their information censored at date of most 
recent tumor assessment. Overall response rate is defined as the rate of complete responses + 
partial responses. Minor responses will not count towards the overall response rate. Duration of 
response is defined as time elapsed from initial evidence of either a PR or CR, until patient is found 
to have disease progression or death. Toxicity and tolerability will be monitored, and adverse 
events will be quantified. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Ability to sign and date the consent form. 
2. Stated willingness to comply with all study procedures and be available for the duration of 
the study. 
3. Be a male or female aged 18-80. 
4. Histologically confirmed new diagnosis of Stage II, III or IV Peripheral T-cell Non-
Hodgkin’s lymphoma not otherwise specified (NOS), Anaplastic large cell lymphoma 
(ALK negative) (ALK positive if IPI 3, 4, or 5), Angioimmunoblastic T-cell lymphoma, 
Enteropathy associated T-cell lymphoma (MEITL and EATL), Hepatosplenic T-cell 
lymphoma, γ/δ T-cell lymphoma, Subcutaneous panniculitis like T-cell lymphoma, and 
Nodal T-cell lymphomas with T-follicular helper phenotype. 
5. Available pathology material (fine needle aspirate is inadequate) for review at University 
of Colorado -- see section 7.3.1 for further information. 
6. No prior therapy with the exception of prior radiation therapy and/or 1 cycle of 
chemotherapy (may be any chemotherapy regimen or even prednisone alone) based on 
current diagnosis and clinical condition. If given cytotoxic chemotherapy (one cycle only, 
e.g. CHOP), this cycle of treatment will count toward the 6 cycles of treatment given in the 
study. 


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7. ECOG performance status 0 - 2. 
8. Laboratory status as follows:  
• ANC > 1000 cells/mm3, unless cytopenias due to lymphoma (i.e., bone marrow 
involvement or splenomegaly)  
• Platelet Count > 100,000 /μL, or > 50,000 /μL if bone marrow involvement or 
splenomegaly 
• Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if documented 
hepatic involvement with lymphoma, or ≤ 5 x upper normal limit if history of Gilbert’s 
Disease.  
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper 
normal limit (≤ 5 x upper normal limit if documented hepatic involvement with 
lymphoma).  
• Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min 
(Cockcroft-Gault, Appendix)  
• PT or INR, and PTT ≤ 1.5 x upper limit of normal unless patient is receiving 
anticoagulants. If patient is on warfarin therapy, levels should be within therapeutic 
range.  
9. Patients with measurable disease. Measurable disease is defined as having at least one 
objective measurable disease parameter. A clearly defined, bi-dimensionally measurable 
defect or mass measuring at least 1.5 cm in diameter on the CT portion of a PET/CT or CT 
scan or MRI (if appropriate) will constitute measurable disease. Proof of lymphoma in the 
liver is required by a confirmation biopsy unless there is measurable disease by imaging. 
Skin lesions can be used as measurable disease provided bi-dimensional measurements are 
possible. Patients with non-measurable but evaluable disease may be eligible after 
discussion with the PI. Abnormal PET/CT scans will not constitute evaluable disease, 
unless verified by the CT scan portion, CT scan, or other appropriate imaging.  
10. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use of contraceptive methods that result in a failure rate of < 
1% per year during the treatment period and for at least 180 days after the last study 
treatment. A woman is considered to be of childbearing potential if she is post-menarchal, 
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate 
of < 1% per year include bilateral tubal ligation, male sterilization, hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper 
intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.  
 
11. Patient must be able to adhere to the study visit schedule and other protocol requirements.  
 


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5.2 
PARTICIPANT EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. An additional malignancy treated with palliative intent within the past 2 years. 
Malignancies in patients who have completed definitive treatment with curative intent >1 
year will be permitted after discussion with the PI. Adequately treated basal cell, squamous 
cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer 
of Gleason Grade 6 or less with stable PSA levels are allowed.  
2. Patients with a diagnosis of other PTCL histologies other than those specified in the 
inclusion criteria.  
3. Primary T-cell CNS lymphoma; however, secondary CNS disease is not an exclusion 
criteria. 
4. Pregnant or breastfeeding females.   
5. Contraindication to any of the required concomitant drugs or supportive treatments. 
6. Any other clinically significant medical disease or condition laboratory abnormality or 
psychiatric illness that, in the investigator’s opinion, may interfere with protocol adherence 
or a subject’s ability to give informed consent. 
7. Ejection fraction of <45% by either MUGA or ECHO. 
8. Has immunodeficiency or is being treated with immuno-suppressive therapy (aside from 
medications used to treat lymphoma) within 7 days of first dose of study treatment. Inhaled 
or topical steroids are accepted. Prednisone used to treat adrenal insufficiency in the 
absence of auto-immune disease is also acceptable. 
9. Auto-immune condition requiring immuno-suppressive disease modifying therapy within 
the prior 2 years. Replacement therapy, e.g. levothyroxine for thyroiditis or insulin for 
diabetes are acceptable. 
10. History of non-infectious pneumonitis requiring immuno-suppressive therapy. 
11. Active hepatitis B or C (with measurable virus or antigen in serum) or HIV. Patients who 
are seropositive because of hepatitis B virus vaccine or have a history of hepatitis B (with 
no measurable virus or antigen in serum) are eligible. 
12.  Prior PD-1 or PD-L1 antibody treatment. 
13.  Has received a live virus vaccine in 30 days preceding start of therapy. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Newly diagnosed patients with PTCL at participating institutions will be presented with the options 
of standard of care chemotherapy versus study participation. The study will also be posted on 
clinicaltrials.gov. Given the benefit observed for PD-1 immunotherapy in multiple disease types, 
we anticipate that patients may be referred to participating institutions specifically to enroll in this 
trial. 
 
 


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5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
The subject may withdraw consent at any time for all or certain aspects of the study as follows: 
• Withdraw consent for study treatment, but allow follow-up period assessments and data 
collection on subsequent anti-lymphoma therapy and PFS 
• Withdraw consent for study treatment and follow-up period assessments, but allow data 
collection on subsequent anti-lymphoma therapy and overall survival 
• 
Withdraw all consent 
Note: if a patient chooses to voluntarily withdraw from study, then documentation must be made 
regarding if patient chooses to simply discontinue study treatment, or if patient also no longer 
wants to be followed for treatment outcomes (and thus opts out of study related follow up). 
Investigational study drug MUST be terminated for any of the following reasons: 
• Subject’s request to stop study treatment  
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness, which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject.  
• Termination of the study by the study sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness  
• Disease progression assessed by RECIL criteria 
• Pregnancy or intention to become pregnant 
• Patient non-adherence 
• Initiation of an alternative anti-cancer therapy 
 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Should a patient choose to withdraw voluntarily from the study at any time, study drug will be 
terminated, and the patient will proceed to treatment according to standard of care. Study-related 
information accumulated prior to the patient’s withdrawal of consent will be analyzed according 
to intention to treat analysis.    
 
Subjects that discontinue study drug will remain on study and continue to follow specified follow-
up procedures. If a subject wishes to withdraw consent for all study-related follow up, then the 
patient should notify the investigator of this request. The patient’s request should be in writing if 
possible. The investigator should document in the medical records in detail if the patient’s 
withdrawal is from study treatment or also from all study-related follow up. However, an 
investigator may consult public records, such as those establishing survival status. 
 
 


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5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY (STUDY STOPPING 
RULES) 
Monthly teleconferences will be held with all participating sites to exchange findings and 
unexpected results that may occur in patients participating in this study. Stopping criteria are 
outlined in section 4.1. Efficacy and toxicity will be monitored closely, and study will be 
terminated if criteria for continuation are not met.   
Any new information suggesting the study intervention (addition of nivolumab to standard of care 
chemotherapy for first line treatment of PTCL) may be harmful in study population will be shared 
with IRB of participating sites. The participating principal investigators will discuss any such new 
information via conference, and if warranted may choose to terminate study. 
 
6 
STUDY AGENT 
6.1 
STUDY AGENT AND CONTROL DESCRIPTION 
Nivolumab is currently FDA approved for the management of a variety of solid and hematologic 
malignancies. Other drugs will be administered according to standard of care. 
 
Nivolumab 
Preparation and storage: 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from light 
and freezing. Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 
1.2-micronpore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
protocol-specified doses and infusion times. It is not to be administered as an IV push or bolus 
injection. When the dose is based on patient weight (i.e., mg/kg), nivolumab injection can be 
infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, or 5% Dextrose 
Injection, to concentrations as low as 0.35 mg/mL. When the dose is fixed (e.g., 240 mg, 360 mg, 
or 480 mg flat dose), nivolumab injection can be infused undiluted or diluted so as not to exceed 
a total infusion volume of 120 mL. During drug product preparation and handling, vigorous mixing 
or shaking is to be avoided. Instructions for dilution and infusion of nivolumab injection may be 
provided in the clinical protocol, pharmacy binder, pharmacy manual, or pharmacy reference 
sheet. Care must be taken to ensure sterility of the prepared solution as the product does not contain 
any antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with 
polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and glass bottles. Further 
details regarding preparation and administration of Nivolumab can be located in the current 
investigator brochure or package insert. 
 
Known potential toxicities: 
See section 2.3.1. 
 
Drug procurement:   


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Nivolumab vials of 100mg, 10 mg/mL (10 mL), will be supplied by Bristol-Meyers Squibb 
(BMS).  
 
Nursing guidelines: 
• Severe infusion reactions have been reported in clinical trials of nivolumab. In case of a 
severe or life-threatening infusion reaction, the nivolumab infusion must be discontinued 
and appropriate medical therapy administered. Patients with mild or moderate infusion 
reaction may receive nivolumab with close monitoring and use of premedication according 
to local treatment guidelines for prophylaxis of infusion reactions. Instruct patient to take 
prednisone after and close to meals. To prevent sleep disruption and restlessness, avoid 
taking prednisone at bedtime. A mild sedative may be needed. 
• Monitor for signs/symptoms of adrenal insufficiency, hypophysitis, thyroid disorders, 
immune-mediated colitis, pneumonitis, rash/dermatologic toxicity, and encephalitis 
(changes in neurologic function). 
Concurrent drug therapy issues: 
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose 
or frequency adjustment, additional monitoring, and/or selection of alternative 
therapy. Consult drug interactions database for more detailed information. 
• Potential lack of benefit in treating PTCL, or the addition of nivolumab to standard of 
care chemotherapy may even lead to inferior outcomes. 
• Patients undergoing allogeneic transplant after receiving nivolumab may have 
complications, some of which could be fatal. Such complications including severe 
graft versus host disease, sinusoidal obstructive syndrome, lymphocytic encephalitis, 
and others have occurred. 
• Patients with pre-existing auto-immune conditions may experience flares as a result 
of receiving nivolumab. Such flares may be severe and irreversible, or mild and 
reversible. 
 
Dose Adjusted EPOCH: 
Please refer to CALGB 50303 protocol for detailed instructions regarding preparation and 
administration of EPOCH 
Body Surface Area (BSA) Calculations: 
Dosage calculations will be based on the patient’s BSA at baseline, recommend using Mosteller 
formula. Actual height and weight should be used in determining body surface area. Dose 
adjustments at the beginning of each cycle do not need to be made unless there has been a >10% 
weight gain or loss.  
 
Requirement for Venous Access: 
Central venous access is required for protocol participation. A previously placed central venous 
access device that is functioning properly (free infusion of saline, unimpeded blood return, good 
condition of external appliance, no recent history of device infection or thrombosis) can be used. 
Should the patient need a new central venous access device, an implanted port central venous 


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access device should be placed (e.g. Power Port) or peripherally inserted central venous catheter 
(PICC) after appropriate informed consent has been obtained. Other aspects of catheter/port 
management will be in accordance with standard nursing clinic central venous port procedures.  
 
Prophylaxis:   
Pre and post medications as prescribed by the treating physician.  
 
Intrathecal chemotherapy:  
Treatment or prophylaxis for secondary CNSL is not required by the protocol. Patients should be 
treated per institutional guidelines.   
 
Tumor lysis precaution, per institutional guidelines:  
Patients considered to be at risk for tumor lysis should be well hydrated and treated with allopurinol 
or a suitable alternative for 12-24 hours prior to the first infusion of chemotherapy.  
 
Prophylactic Anti-Emetic Premedication:  
Standard antiemetic prophylaxis will be given per institutional guidelines. Note: EPOCH is 
considered moderately ematogenic and nivolumab has minimal ematogenicity. 
 
 
Cyclophosphamide  
Preparation and storage:  
Injectable powder is stored at room temperature. The temperature is not to exceed 90°F. 
Reconstituted parenteral solutions are stable for 24 hours at room temperature or six days if 
refrigerated. Dissolve the 100 mg, 200 mg, 500 mg, 1 gm, and 2 gm vials in 5, 10, 25, 50, and 100 
mL of sterile water, respectively, resulting in a solution of 20 mg/mL. Shake vials vigorously. The 
lyophilized form is more easily solubilized. Further details regarding preparation and 
administration of cyclophosphamide can be located in the current investigator brochure or package 
insert. 
 
Known potential toxicities: 
Myelosuppression, hemorrhagic cystitis (higher incidence at doses >1250 mg/m2), alopecia, 
nausea, and vomiting are all common; SIADH is dose-related (more common with single doses > 
2 gm/m2) as well as cardiac (if dose level ≥2 gm/m2). Secondary leukemia, liver dysfunction, 
headaches, dizziness, interstitial pulmonary fibrosis, cardiac necrosis may occur. Anaphylaxis is 
rare. 
 
Drug procurement:  
Commercially available for injection in 100 mg, 200 mg, 500 mg, 1 gm and 2 gm vials. 
 
Nursing guidelines: 
• Leukopenia nadir occurs 8-14 days after administration and recovery is usually 18-25 days. 
Monitor CBC. 
• Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following treatment and to 
void frequently, not greater than every three hours to facilitate emptying the bladder of 


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drug. 
• Instruct patient to report any urinary urgency, frequency, dysuria, or hematuria. 
• Advise patient of possible strong metallic taste associated with cyclophosphamide and 
suggest hard candy with a strong flavor (cinnamon, peppermint) to alleviate it. 
• Administer antiemetics as necessary to minimize nausea and vomiting, which usually 
occurs 6-8 hours after administration and can continue up to 5 days. 
• Report and record any complaint of lightheadedness, facial “heat sensation”, or diaphoresis 
during administration. 
• Corticosteroids, phenothiazine, imipramine, and allopurinol may inhibit Cytoxan 
metabolism and modify its effect. They may also increase bone marrow suppression.  
 
Etoposide 
Background:  
Etoposide has been shown to delay transit of cells through the S phase and arrest cells in late S or 
early G2 phase. The drug may inhibit mitochondrial transport at the NADH dehydrogenase level 
or inhibit uptake of nucleosides into HeLa cells. It is a topoisomerase II inhibitor and appears to 
cause DNA strand breaks. Etoposide does not inhibit microtubular assembly. 
 
Formulation:  
Commercially available for injection as: Injection, solution: 20 mg/mL (5 mL, 25 mL, 50 mL)  
 
Preparation, storage, and stability:  
Refer to package insert for complete preparation and dispensing instructions. Store intact vials at 
room temperature of 25ºC (77ºF); do not freeze. Protect from light. Etoposide should be diluted to 
a concentration of 0.2-0.4 mg/mL in D5W or NS for administration (avoid concentrations >0.4 
mg/mL). Diluted solutions have concentration-dependent stability; more concentrated solutions 
have shorter stability times. Precipitation may occur with concentrations >0.4 mg/mL. Following 
dilution 0.9% Sodium Chloride or D5W to concentrations of 0.2-0.4 mg/mL, drug is chemically 
stable for 96 and 24 hours at room temperature, respectively.  
 
Pharmacokinetic information: 
Distribution: Vd: 7-171 L/m2; poor penetration across the blood-brain barrier; CSF 
concentrations <5% of plasma concentrations 
Protein binding: 94% to 98% 
Metabolism: Hepatic via CYP3A4 and 3A5, to various metabolites. 
Half-life elimination: Terminal 4-11 hours 
Excretion: Urine (56%; 45% as unchanged drug) within 120 hours; feces (44%) within 120 
hours 
 
Potential Drug Interactions: 
• Metabolism/Transport Effects: Substrate of CYP1A2 (minor), CYP2E1 (minor), 
CYP3A4 (major), P-glycoprotein; Inhibits CYP2C9 (weak), 3A4 (weak)  
• Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (may increase GI irritation). 
Avoid concurrent St John’s wort; may decrease etoposide levels. 


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• Known potential adverse events: Consult the package insert for the most current and 
complete information.  
U.S. boxed warning:  
Severe dose-limiting and dose-related myelosuppression with resulting infection or bleeding 
may occur. 
 
Known potential toxicities: 
• Common known potential toxicities, > 10%:   
 Dermatologic: Alopecia 
 Gastrointestinal: Nausea/vomiting, anorexia, diarrhea 
 
Hematologic:  Leukopenia, thrombocytopenia, anemia 
• Less common known potential toxicities, 1% - 10%:  
 Cardiovascular: Hypotension 
 Gastrointestinal: Stomatitis, abdominal pain 
 Hepatic: Hepatic toxicity 
 Neuromuscular & skeletal: Peripheral neuropathy 
 Miscellaneous: Anaphylactic-like reaction 
• Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Amenorrhea, blindness (transient/cortical), cyanosis, extravasation, facial 
swelling, hypersensitivity, hypersensitivity-associated apnea, interstitial 
pneumonitis, laryngospasm, maculopapular rash, metabolic acidosis, MI, 
mucositis, optic neuritis, perivasculitis, pruritus, pulmonary fibrosis, 
radiation-recall dermatitis, rash, seizure, Stevens-Johnson syndrome, tongue 
swelling, toxic epidermal necrolysis, weakness 
 
Drug procurement:   
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
 
Nursing guidelines: 
• Monitor CBC. Neutropenia may be severe. Instruct patients to report any sign/symptoms 
of infection to the health care team. 
• Rare myocardial infarctions have been reported in patients who have received prior 
mediastinal XRT. Instruct patient to report any chest pain, or racing of the pulse to the 
health care team immediately.  
• Advise patient of possible mild, reversible alopecia. 
• A rapid infusion may cause hypotension and/or allergic reaction; administer medication 
over at least 30-60 minutes and monitor vital signs during administration. 
• Drug is a radiosensitizer and irritant. Assess IV patency before and throughout infusion.  
Patients who have received prior radiation may experience radiation recall. Assess skin in 
these areas and monitor closely. Instruct patient to report any rash or skin changes to the 
health care team immediately. 
• Anaphylaxis is rare but has been observed. Symptoms may include hypotension, 
bronchospasm, fever, or chills. Have the anaphylaxis tray available. 


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• Nausea and vomiting are usually mild; however, the incidence is increased with oral 
administration. Pre-medicate with antiemetics as ordered and monitor for their 
effectiveness.  
• Instruct patient in importance of maintaining adequate hydration to avoid hyperuricemia. 
• Monitor liver function tests. 
• Etoposide solution is oil based and settles to bottom of bag or drip chamber. Be sure to 
agitate bag to avoid reaction to concentrated solution. Reaction would include flushing, 
shortness of breath, back pain, and anxiety. 
• Advise patient that facial flushing is common and may occur even after administration. 
• Monitor INR closely in patients on warfarin therapy, as etoposide may increase 
prothrombin (PT) time. 
• May increase the toxicity of methotrexate or cyclosporine when given concurrently. 
 
Doxorubicin 
Preparation and storage:  
Doxorubicin vials must be protected from light and kept at room temperature. Doxorubicin PFS 
vials must be refrigerated, 2-8°C. Reconstituted solutions are stable for 24 hours at room 
temperature and 48 hours under refrigeration. The doxorubicin 150 mg multi-dose vial is stable 
after reconstitution for 7 days at room temperatures or 15 days if refrigerated and protected from 
sunlight. It is not necessary to further dilute. This avoids long infusion times and the risk of 
extravasation. Dilution takes place when administered through a rapidly flowing IV line. 
Doxorubicin should be administered according to standard EPOCH regimen. Further details 
regarding preparation and administration of doxorubicin can be located in the current investigator 
brochure or package insert. 
 
Known potential toxicities: 
• Hematologic: Leukopenia (dose-limiting), also thrombocytopenia and anemia. This 
treatment nadir is usually 10-14 days with recovery in 21 days. 
• Dermatologic: Alopecia, usually complete, hyperpigmentation of nail beds and dermal 
creases, radiation recall. 
• Gastrointestinal: Nausea and vomiting, sometimes severe, anorexia, diarrhea, mucositis. 
• Cardiovascular: Arrhythmias, thrombosis/embolism, ECG changes, rarely sudden death. 
Congestive heart failure due to cardiomyopathy related to total cumulative dose, risk is 
greater with doses greater than 550 mg/m2, mediastinal irradiation, preexisting cardiac 
disease, advanced age, risk is reduced with weekly or continuous infusion regimens. 
• Other: Red discoloration of urine, fever, anaphylactoid reaction, may enhance 
cyclophosphamide cystitis or mercaptopurine hepatotoxicity, secondary AML/MDS (risk 
is uncommon, but may be increased when given in combination with an alkylating agent, 
especially if one or both are given at higher than standard doses. 
• Local effects: Vesicant if extravasated; flush along vein, facial flush. 
Availability:  
Commercially available as powder for injection in 10, 20, 50, 100, 150 mg vials, and as 2 mg/ml 
solution for injection in 10, 20, 50, and 200 mg vials. 


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Nursing guidelines:  
• Check CBC and platelet counts. Monitor for signs of infection, bleeding, and anemia. 
• Advise patient that their urine may turn pink in color for approximately 24 hours after 
administration of the drug. 
• Doxorubicin is a vesicant. Check IV potency before and frequently during administration. 
If extravasation occurs, refer to institutional extravasation policy. 
• Hair loss occurs 2-4 weeks after initial injection and can be complete. Regrowth begins 2-
3 months after discontinuation. 
• Beware of doxorubicin “flare” that can occur during administration. The reaction consists 
of an erythematous streak up the vein receiving the infusion. Adjacent veins may also 
demonstrate red streaks. Urticaria and pruritus can be associated with the reaction. The use 
of corticosteroids and/or antihistamines has been helpful. 
• Administer antiemetics to minimize nausea and vomiting. 
• Assess for alterations in mucous membranes. Stomatitis occurs within 7-10 days after 
injection. It begins with burning sensation and can progress to ulceration, which can last 3 
days. Carafate slurry may be useful. Adequate nutritional counseling is important. Topical 
anesthetics such as viscous lidocaine can be used symptomatically. Advise patient that 
there is often significant malaise and fatigue 1-2 weeks after injection. 
• Doxorubicin may potentiate toxicity of other antineoplastic therapies. It has reportedly 
exacerbated cyclophosphamide- induced hemorrhagic cystitis. 
• Assess heart and lung sounds. Monitor vital signs (resting pulse). Be alert to early signs of 
cardiotoxicity (i.e., dyspnea, steady weight gain, nonproductive cough, arrhythmias, 
tachycardia, and pulmonary rales). 
• Document doses, total should not exceed maximum cumulative dose (550 mg/m2 or 450 
mg/m2 if history of mediastinal radiation). 
• Advise patient of probable facial flushing for several hours after drug administration, 
especially if given quickly. 
 
 
Vincristine (VCR) 
Preparation and storage:  
Vincristine is stored under refrigeration, 2-8°C. No dilution is required. Vincristine should be 
administered according to the standard EPOCH regimen. Further details regarding preparation and 
administration of vincristine can be located in the current investigator brochure or package insert. 
 
Known potential toxicities: 
• Hematologic: Rarely leukopenia (mild), rarely thrombocytopenia, and anemia. 
• Dermatologic: Alopecia, skin and soft tissue damage if extravasated (the manufacturer 
recommends subcutaneous injection of hyaluronidase and application of heat to help 
disperse the drug), rash. 
• Gastrointestinal: Nausea, rarely vomiting, constipation, abdominal cramps, anorexia, and 
diarrhea. Fatal ascending paralysis follows intrathecal administration. 
• Hepatic: Elevation of AST and ALT (mild and transient). 


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• Neurologic: Peripheral neuropathy (loss of deep tendon reflexes, paresthesias, paralysis), 
autonomic neuropathy (constipation, paralytic ileus, urinary retention, orthostasis), ataxia, 
myalgias, cortical blindness, headache, seizures. 
• Pulmonary: Bronchospasm (acute shortness of breath), more common when administered 
with mitomycin. 
• Ocular: Diplopia, ptosis, photophobia, cortical blindness (see neurologic), and optic 
atrophy. 
• Other: Severe pain in the jaw, pharynx, bones, back, and limbs following injection, 
syndrome of inappropriate antidiuretic hormone (SIADH), fever, rarely pancreatitis. 
• Cardiovascular: Thrombosis/embolism. 
Availability:  
Commercially available in a concentration of 1 mg/ml in 1, 2, and 5 mg vials and 1 mg and 2 mg 
syringes. 
 
Nursing guidelines: 
• Check IV patency before and frequently during administration. Vincristine is a vesicant. If 
extravasation occurs, refer to agency extravasation policy. 
• Evaluate the patient for numbness and tingling in fingertips and toes, clumsiness of hands, 
and difficulty walking. 
• Monitor bowel function and encourage use of stool softeners. 
• Symptoms of cranial nerve neuropathy may develop several weeks after drug 
administration and take 10–12 months to resolve. 
 
Prednisone 
Storage and Administration:  
The drug is a commercially available table that is intended for oral use and should be stored at 
room temperature in a dry place. Further details regarding administration of prednisone can be 
located in the current investigator brochure or package insert. 
 
Known potential toxicities: 
• Hematologic: Leukocytosis. 
• Gastrointestinal: Nausea, vomiting, anorexia, increased appetite and weight gain, peptic 
ulcer. 
• Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial erythema, and 
ecchymosis. 
• Genitourinary: Menstrual changes (amenorrhea, menstrual irregularities) 
• Neurologic: Insomnia, muscle weakness, euphoria, psychosis, depression, headache, 
vertigo, and seizures. 
• Cardiovascular: Fluid retention and edema, hypertension, hyperkalemia. 
• Ocular: Cataracts, increased intraocular pressure, and exophthalmos. 
• Metabolic: Hyperglycemia decreased glucose tolerance, aggravation or precipitation of 
diabetes mellitus, adrenal suppression, and cushingoid syndrome. 


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• Other: Osteoporosis (and resulting back pain), serious infections including herpes zoster, 
varicella zoster, fungal infections, pneumocystis carinii, tuberculosis, muscle wasting. 
Availability:  
Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg tablets.  
 
Nursing guidelines: 
• Instruct patient to report any abdominal pain, GI bleeding (i.e., tarry stools, vomiting 
coffee-ground material, etc.) to health care team immediately since active peptic ulceration 
is a toxicity that requires dose modification. Antacid therapy may be employed. 
• Instruct patient to take prednisone after and close to meals. To prevent sleep disruption and 
restlessness, avoid taking prednisone at bedtime. A mild sedative may be needed. 
• Monitor CBC and glucose levels. 
• Educate patient concerning potential mood changes. 
• 
Gradual tapering of doses should be employed after long-term use.  
 
6.1.1 DOSING SCHEDULES 
INDUCTION 
 
Patients will receive a planned 6 cycles of therapy (or 5 cycles if patient received a cycle of 
chemotherapy prior to enrollment) before having an autologous stem cell transplant or 
surveillance. 
 
Each cycle is 21 days, +/- 3 days. Nivolumab (360 mg) will be given on day 1 concurrently with 
chemotherapy, including for cycles that are delayed beyond 21 days. Unless there is a planned 
delay (e.g. for low blood counts), the start of chemotherapy should be within 3 days of day 1 of 
each 21-day cycle. Note that the dose of 360 mg of nivolumab was chosen because nivolumab is 
FDA approved at a dose of 240 mg every 2 weeks and 480 mg every 4 weeks. Because the cycles 
of DA EPOCH are every 3 weeks, we will be giving nivolumab 360 mg. 
 
DA-EPOCH will be given according to standard protocols derived from CALGB 50303 with the 
exceptions outlined in this protocol. 
 
All patients will begin treatment at dose level -1. 
 
 
DRUG 
DOSE 
FREQUENCY5 
# of 
CYCLES 
Administration 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Cyclophosphamide1 750 mg/m2 
 
 
 
 
X 
 
6 cycles 
IV 
Doxorubicin2 
10 mg/m2/day 
X 
X 
X 
X 
 
 
6 cycles 
IV 
Vincristine3 
0.4 mg/m2/day 
X 
X 
X 
X 
 
 
6 cycles 
IV 


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Etoposide4 
50 mg/m2/day 
X 
X 
X 
X 
 
 
6 cycles 
IV 
Prednisone 
60 mg/m2 /day 
X 
X 
X 
X 
X 
 
6 cycles 
PO 
Nivolumab7 
360 mg 
X 
 
 
 
 
 
6 cycles5 
IV 
Pegfilgrastim 
(Neulasta or 
OnPro)6 
6 mg 
 
 
 
 
 
X 
6 cycles 
SQ 
 
1. Cyclophosphamide dose may be rounded to nearest 50 mg. 
2. Doxorubicin dose may be rounded to nearest 5 mg. 
3. Vincristine has no cap. 
4. Etoposide dose may be rounded to nearest 5 mg. 
5. Each “day” of the chemotherapy regimen EPOCH represents an approximate 24 hour infusion; however, each day 
may not finish until the subsequent day. (i.e. day 2 chemo may end on day 3, day 3 on day 4, etc.). These alterations 
from schedule should not be considered protocol deviations and are expected.  
6. Within 24-72 hours after completing chemotherapy. Alternatively, can administer filgrastim 480 mcg subcutaneous 
daily from Day 6 until ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 10 days (Days 6-15) if 
the ANC is not being monitored, during every cycle. Substitutions with generic or biosimilar growth factors are 
permitted. 
7. Nivolumab treatment will always be administered first, followed by EPOCH. There is no study-directed window 
between completion of Nivolumab administration and start of EPOCH administration.  
  
Dose adjustments listed in table below (and modified from CALGB 50303) for subsequent cycles 
of EPOCH will be determined by the absolute neutrophil (ANC) or platelet nadir (below 
adjustments are based on twice weekly CBC).   
 
° 
If nadir ANC is greater or equal to 500, increase the EPOCH dose level by 20%.  
° 
If nadir ANC is less than 500 on 1 or 2 measurements, then continue EPOCH at the same 
dose level. 
° 
If nadir ANC is less than 500 on at least 3 measurements (3-4 days apart), then decrease 
the EPOCH dose level 20%. 
 
OR 
 
° 
If nadir platelet count is less than 25,000 on 1 measurement, then decrease the EPOCH 
dose level by 20%. 
 
Begin each cycle of EPCOH chemotherapy when ANC is greater than or equal to 1000 and 
platelets are greater than or equal to 100,000  (unless low due to bone marrow infiltration 
secondary to disease).  
 
For patients whose blood counts are not recovered to ANC > 1000 and platelets > 100,000 by start 
of subsequent cycle: 
- If patient’s counts recover by day 28 or sooner, dose adjustments  for EPOCH should be 
made as outlined above.   
- If patient’s counts recover on day 29 or later, reduce DA-EPOCH to next lower dose level 
and hold nivolumab for subsequent cycle. Then, may resume nivolumab with subsequent 
cycle at the same lower dose level of EPOCH. If delayed count recovery (e.g. by day 29 or 


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later) occurs a second time after patient resumed nivolumab, make standard dose 
adjustments to DA-EPOCH and permanently discontinue nivolumab. 
- If patient’s counts are low (eg. ANC <1000 or platelets <100 at day 21) due to marrow 
involvement by disease, next cycle can resume without delay or dose reduction. EPOCH 
can be delayed or reduced per investigator discretion. 
 
Additional adjustments for severe cytopenias attributed to nivolumab and not EPOCH: For 
hematologic nadirs: ANC<500 for ≥7 days or PLT<25,000 for ≥7 days: For first occurrence hold 
nivolumab with next  cycle and make necessary standard dose reductions. If hematologic recovery 
is not delayed with this cycle, then may resume nivolumab with subsequent cycle. If this occurs a 
second time after patient resumed nivolumab, make standard dose adjustments and permanently 
discontinue nivolumab. 
 
Dose levels, as originally described in CALGB 50303. 
 
 
Dose Levels 
Adjusted Agents 
-3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
Doxorubicin 
(mg/m2/day) 
10 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
29.8 
Etoposide (mg/m2/day) 
50 
50 
50 
50 
60 
72 
86.4 
103.7 124.4 149.3 
Cyclophosphamide 
(mg/m2) 
384 480 600 750 900 1080 1296 1555 
1866 
2239 
 
 
Non-Adjusted Agents 
 
Vincristine (mg/m2/day) 
(No cap) 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
Prednisone (mg/m2/day) 
60 
60 
60 
60 
60 
60 
60 
60 
60 
60 
 
 
*Dose adjustments for dose levels -1, -2, -3 and below apply to cyclophosphamide only. 
  Dose adjustment to dose level -4 and -5 will each include ~20% reduction in   
  cyclophosphamide (i.e. DL-4 = 307 and DL-5 = 245 mg/m2).  
 
Recommendations outlined above are consistent with protocol CALGB 50303 section 9.2.  
However, while rituximab was given in CALGB 50303, no rituximab is given in the current 
protocol. 
 
 


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AUTOLOGOUS STEM CELL TRANSPLANTATION 
Administration of standard preparative regimen (in patients who have a CR or PR, as per 
investigator’s discretion) followed by HSCT (as per institutional guidelines). The choice of the 
conditioning regimen is optional (ex: BEAM). 
Hematopoietic Stem Cell Collection: 
Peripheral blood stem cells will be collected as per the discretion of the treating physician until an 
adequate number of CD34+ cells/kg have been collected (as per existing institutional guidelines). 
The timing of stem cell collection will be at the discretion of the treating physician and as per 
institutional guidelines.  
 
Suggested Optional Preparative Regimen – BEAM: 
 
 
Dose Modifications for Suggested Optional BEAM Regimen: 
The dose of BEAM will remain constant for each subject throughout the study. No adjustments in 
doses for post-screening changes in body surface area will be made. 
NOTE: The preparative regimen above is a suggested option. The exact combination and dosing 
should be as per institutional standards.  
 
Reason as to why patients do not proceed to transplant: 
Physicians will be required to document the reason why patients did not proceed to an autologous 
transplant – i.e., comorbidities, advanced age, inability to mobilize, patient decision, and physician 
decision. 
 
6.1.2 DOSE ADJUSTMENTS FOR TOXICITY 
After the initial two cycles, if it’s felt by the investigator that a dose increase of EPOCH would be 
detrimental to the patient, chemotherapy doses can be maintained without dose escalation. 
Similarly, if the investigator feels it is in the best interest of the patient dose levels can be 
decreased. 
If multiple adverse events are seen, administer dose based on greatest reduction required for any 
single adverse event observed.  
Omit = The current dose(s) during a cycle is skipped. The patient does not make up the omitted 
dose(s) at a later time. 
 


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Hold = Refers to decision made at the beginning of the cycle to delay the start of the cycle until 
the patient meets the protocol criteria to restart drug. 
NOTE: Patients in whom one or more DA-EPOCH plus nivolumab study treatment agents have 
been discontinued will remain on study unless all DA-EPOCH plus nivolumab study treatment 
agents are discontinued. Patients in whom all the study treatment agents were discontinued will 
proceed to event monitoring. 
 
NOTE: For adverse events associated with Nivolumab, based on the severity of the adverse 
reaction, withhold nivolumab and administer systemic corticosteroids. Consider increasing the 
corticosteroid dose (and/or other immunosuppressants) if there is no improvement or if toxicity 
worsens. Begin corticosteroid taper when adverse reaction improves to below grade 1 and continue 
taper over approximately 1 month. For adverse reactions that do not result in permanent 
discontinuation, when improved to grade 1 (or lower) and the corticosteroid dose is reduced to ≤10 
mg/day prednisone (or equivalent), resume nivolumab with subsequent cycles.  
 
 
NIVOLUMAB dose modifications : 
 
Adverse Event 
Severity 
Dose Modification 
Colitis 
Grade 2 or 3 diarrhea or colitis 
Delay or discontinue dose 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 
Delay dose 
Grade 3 or 4 
Discontinue 
Hepatitis 
Aspartate aminotransferase 
(AST) or alanine 
aminotransferase (ALT) >3 and 
≤5 x the upper limit of normal 
(ULN) or total bilirubin >1.5 
and ≤3 x ULN 
Delay dose 
AST or ALT >5 x ULN or total 
bilirubin >3 x ULN 
Delay dose or discontinue 
Hypophysitis 
Grade 2 or 3 
Withhold dose 
Grade 4 
Permanently discontinue 
Adrenal insufficiency 
Grade 2 
Withhold dose 
Grade 3 or 4 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold dose 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal dysfunction 
Serum creatinine >1.5 and ≤6 x 
ULN 
Delay dose 
Serum creatinine >6 x ULN 
Discontinue dose 


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Adverse Event 
Severity 
Dose Modification 
Skin  
Grade 3 rash or suspected 
Stevens-Johnson syndrome 
(SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold dose 
Grade 4 rash or confirmed SJS 
or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe 
neurologic symptoms 
Withhold dose 
Immune-mediated encephalitis 
Permanently discontinue 
Cardiac 
Grade 3 myocarditis 
Permanently discontinue 
Infusion reactions 
Grade 1 or 2 
Grade 3 or 4 
Interrupt or slow infusion 
Permanently discontinue  
 
• 
For all immune-related adverse reactions, consider administering systemic glucocorticoids per 
institutional guidelines. 
 
• 
For neurological adverse reactions of any grade, discontinue for myasthenia gravis, Guillain-
Barre syndrome, treatment-related myelitis, or encephalitis. 
 
• 
For suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug 
Reaction with Eosinophilia and Systemic Symptoms (DRESS), withhold immune-oncology 
treatment and refer patient for specialized care. 
 
• 
For other Grade 3 adverse reactions suspected to be attributable to nivolumab: First occurrence, 
withhold dose. For recurrence of same Grade 3 adverse reactions, permanently discontinue. 
 
• 
For other life-threatening or Grade 4 adverse reactions attributable to nivolumab, permanently 
discontinue nivolumab. 
 
• 
Discontinue nivolumab for requirement of 10 mg per day or greater prednisone or equivalent for 
more than 12 weeks. 
 
• 
Permanently discontinue nivolumab for persistent Grade 2 or 3 adverse reactions that last for at 
least 12 weeks. 
 
 
Dose modifications for adverse events associated with chemotherapy: 
 


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Use Common Terminology Criteria for Adverse Events (CTCAE) v5.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Cardiac General 
Left ventricular 
systolic dysfunction ≥ 
grade 3 
doxorubicin 
 
 
Discontinue doxorubicin.  
 
 
 
Renal/ 
Genitourinary 
Cystitis ≥ grade 2 
 
 
 
 
 
cyclophosphamide 
 
 
 
 
 
 
Omit until resolution of cystitis. 
Decrease 50% of preceding dose for 
next cycle of treatment. If subsequent 
cycle is well tolerated and there is no 
grade ≥2 renal/GU adverse events, 
increase to 100% of the original dose. 
Neurology 
Neuropathy – motor 
Grade 2 
 
Neuropathy – motor 
Grade ≥ 3  
 
Neuropathy – sensory 
Grade 2 
 
Neuropathy – sensory 
Grade 3  
 
Neuropathy – sensory 
Grade 4 
VCR 
 
 
 
 
 
 
 
 
 
 
 
 
 
Omit VCR until neuropathy < grade 2 
and resume at 50% dose reduction.  
 
Discontinue VCR. 
 
 
Reduce VCR by 25%. 
 
 
Omit VCR until neuropathy <grade 2 
and resume at 50% dose reduction. 
 
Discontinue VCR. 
 
Gastrointestinal 
Nausea/Vomiting ≥  
Grade 3 
Nivolumab DA-
EPOCH 
 
Maximize antiemetic therapy; if 
maximized antiemetic treatment 
ineffective, reduce doses at physician 
discretion.  
 
Mucositis/Stomatitis ≥ 
Grade 2  
 
doxorubicin 
 
If attributable to prolonged cytopenias, 
follow dose reduction according to 
section 6.1.1 If not due to prolonged 
cytopenias, decrease doxorubicin by 
25% of preceding dose for next cycle. If 
no grade ≥3 GI toxicities in subsequent 
cycle, increase doxorubicin to 100% of 
original dose. 
Constipation grade 2 
 
 
Constipation ≥ grade 3 
VCR 
 
Initiate bowel regimen and continue 
VCR. 
 
Decrease VCR by 25%. 
 


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Use Common Terminology Criteria for Adverse Events (CTCAE) v5.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Infection 
 
Infection with 
ANC ≥ 1,000/μL 
 
Nivolumab DA-
EPOCH 
 
Hold drugs in case of an infection 
requiring IV antibiotics or 
hospitalization and restart when 
infection is controlled. If dosing is held 
≥ 21 days call study chair.  
 
If adverse event recurs on subsequent 
cycles, decrease DA-EPOCH to next 
lower dose level and consider 
prophylactic antibiotics. If AE recurs at 
this dose level call study chair. 
Infection with 
ANC < 1,000/μL 
Hold drugs in case of an infection 
requiring IV antibiotics or 
hospitalization and restart when 
infection is controlled. Decrease DA-
EPOCH to next lower dose level and 
consider prophylactic antibiotics. If AE 
re-occurs at this dose level call study 
chair. 
New or reactivation of 
viral hepatitis  
Discontinue treatment, treat hepatitis.  
VCR = vincristine 
 
 
Dose modifications for adverse events associated with chemotherapy or nivolumab (and not 
due to bone marrow infiltration secondary to disease): 
 


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Use Common Terminology Criteria for Adverse Events (CTCAE) v5.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Blood/Bone marrow 
Hematologic nadirs: 
ANC<500 for ≥7 days 
or 
PLT<25,000 for ≥7 
days  
 
Or delayed count 
recovery to ANC > 
1000 and platelets > 
100,000 on day 29 or 
later   
cyclophosphamide 
/ doxorubicin / 
etoposide/ 
nivolumab 
 
 
 
 
Dose adjustments as described in section 
6.1.1. 
 
 
 
Note:  For other adverse events, or where attribution of cause of adverse event is unclear, please discuss 
with study chair for guidance with dose modifications. In general, maintenance of adequate dose intensity 
of DA-EPOCH will be prioritized given the uncertain benefit of nivolumab in management of PTCL. 
 
 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Nivolumab will be provided by BMS to the participating institution. The investigator, or a 
responsible party designated by the investigator, must maintain a careful record of the receipt, 
dispensing and final disposition of all agents received from BMS in a Drug Accountability Log.  
The Drug Accountability Log will record the study drugs received, dosages prepared, time 
prepared, doses dispensed and doses/vials destroyed. The Drug Accountability Log will be 
reviewed during any site visits and at the completion of the study.   
 
Nivolumab will be kept in an appropriate, secure locked area and stored in accordance with the 
conditions specified on the label.   
 
6.3 
POST-STUDY ACCESS 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care or other 
appropriate treatment in the independent medical judgement of the Investigator to treat the 
condition under study. 
 


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7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
• 
PET/CT: A PET/CT scan is done at baseline as part of the initial staging evaluation, and 
at the end of therapy to confirm the response. For patients that had already been treated 
with 1 cycle of standard of care chemotherapy prior to study enrollment, if the patient had 
baseline PET-CT within 6 weeks prior to C1D1 of standard of care chemotherapy then 
another PET-CT is not required prior to initial cycle of study therapy. Otherwise, repeat 
CT or PET/CT is required within 28 days of C1D1 of study therapy. A dedicated CT or 
PET/CT response assessment will also be done between cycle 2 and cycle 3 of EPOCH + 
nivolumab (if the patient received 1 cycle of standard of care chemotherapy prior to 
enrollment in the study, then the scan should be performed between the 3rd and 4th cycles 
of all chemotherapy, and between cycles 2 and 3 of EPOCH + nivolumab). PET-CT should 
also be performed within 6 weeks of cycle 6 day 1 of chemotherapy.  
 
If the patient elects to undergo autologous transplant, response evaluation is required with 
CT or PET/CT (per investigator’s discretion) at D+100 (+/- 14 days), but PET/CT would 
be preferred if not in a CR after cycle 6. 
 
• 
Bone Marrow Biopsy: A restaging bone marrow biopsy may be done if a staging bone 
marrow biopsy was previously positive or if symptoms suggest involvement. Restaging 
may also include MRI, if clinically indicated.  
 
• 
Autologous Hematopoietic Cell Transplantation: After 6 courses, and if transplant 
eligible, patients can proceed to autologous hematopoietic cell transplantation per 
investigator’s discretion. Auto-HCT will be performed per institutional guidelines.  
 
• 
Post-Trial Assessments: Patients who go off study treatment at any time during the trial 
will complete end of treatment assessments per section 7.3.6. For all patients, drug-related 
SAEs and AEs will be followed until baseline or ≤ grade 1 levels. Patients who responded 
or maintained stable disease during the study will be followed for date of disease 
progression. Patients will be assessed after cycle 2 and 6 as outlined in treatment plan as 
well as at 100 days post-transplant according to standard of care for patients undergoing 
transplant. Patients may refuse to participate in the post-trial assessments. 
 
• Clinical Evaluations: Patients should be seen and evaluated by provider no more than 7 
days prior to start of every chemotherapy cycle, and patients should be evaluated by a 
provider or nurse no more than 48 hours prior to every chemotherapy cycle.   
 
7.1.1 RESPONSE ASSESSMENT 
Response to therapy will be classified as complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), early death, or not evaluable. Response assessment will be 
obtained between cycle 2 and cycle 3 of EPOCH + nivolumab and after cycle 6 as outlined in 


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treatment plan (For patients that got 1 cycle of standard of care chemotherapy prior to enrolling in 
study, then response assessment is between cycles 3 and 4 of all induction chemotherapy and 
between cycles 2 and 3 of study EPOCH + nivolumab). If patients discontinue therapy due to a 
toxic event this will not also be counted towards the efficacy endpoint unless objective progressive 
disease is documented. Patients with a complete response based on end of treatment imaging 
assessment, but subsequently develop rapid progression within 6 weeks, will not be considered a 
complete responder, rather instead progressive disease.  
Definitions for clinical response for patients with lymphoma are from the Younes et al, Annals of 
Oncology, 2017, the RECIL criteria. Measurable disease lesions will be determined from CT, CT 
portion of the PET/CT if possible, or MRI scans where applicable. Measurement of disease burden 
will be from sum of longest diameters (SLD). A maximum of three target lesions will be followed.  
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only assessable 
– but not measurable by RECIL criteria (e.g., pleural effusions, bone lesions) – will be recorded 
as present or absent only, unless, while an abnormality is still noted by imaging studies or physical 
examination it is found to be histologically negative. Response is based on the CT component of 
PET/CT (as below), CT alone, or MRI where applicable. Response assessment will be performed 
by treating provider and will not be performed centrally at the University of Colorado. 
 
 
Response 
Category 
Definition 
PET-CT 
New Lesions 
Bone Marrow 
Complete 
Response 
Complete 
disappearance of all 
target lesions. All 
nodes have long 
diameter <10 mm. 
 
≥30% decrease in the 
sum of longest 
diameters of target 
lesions (PR) with 
normalization of 
FDG-PET 
Normalization of 
FDG-PET 
(Deauvile score 1- 
3) 
  
No 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
Partial Response 
≥30% decrease in the 
sum of longest 
diameters of target 
lesions but not a CR 
Positive (Deauville 
score 4-5) 
 
No 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
Stable Disease 
<30% decrease or ≤ 
20% increase in the 
sum of longest 
diameters of target 
lesions 
Any 
No 
Any 


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Response 
Category 
Definition 
PET-CT 
New Lesions 
Bone Marrow 
Progressive 
Disease 
>20% increase in the 
sum of longest 
diameters of target 
lesions 
 
For small lymph 
nodes measuring < 
15 mm post-therapy, 
a minimum of 5 mm 
increase in longest 
diameter to > 15 mm   
 
New lesion 
Any  
Yes or No 
Any 
FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose 
(All response criteria modified from Younes et al, Annals of Oncology, 2017) 
 
Note:   
A minimum of 1 cm in largest diameter of new extra-nodal lesions is required to 
assign PD directly. New smaller but suspicious lesion should be designated as 
equivocal, and if later confirmed (by CT or biopsy) as being due to lymphoma, the 
documented date of progression should be the date of when it was first identified 
as equivocal. 
 
Complete Response (CR)  
CR is defined as a complete resolution of all target lesions by CT scans with 
complete normalization of FDG-PET uptake in all areas (Deauville score of 1–3), 
and bone marrow biopsy negativity (if it was positive or unknown at baseline). If 
pretreatment PET scan was negative, lymph nodes that measured 15 mm in the long 
axis should regress to < 10 mm. CR is also defined as achievement of a partial 
remission by CT scan criteria (reduction in sum of longest diameters by CT imaging 
by >30%) with normalization (Deauville score 1–3) of FDG-PET activity in FDG-
avid lymphoma. 
 
 
Normalizing of FDG-PET imaging alone is not sufficient by itself to determine CR 
status unless accompanied with a significant (>30%) decrease in the sum of 
diameters. Accordingly, a reduction in the sum of diameters by ≤ 30% with 
normalization of FDG-PET uptake should not be considered a CR unless 
documented by a negative tissue biopsy.  
 
 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry but 
that demonstrates a small population of clonal lymphocytes by flow cytometry will 


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be considered a CR until data become available demonstrating a clear difference in 
patient outcome.  
 
In cases where pretreatment baseline tumor burden is low, with only a few lesions 
measuring around 2 cm in longest diameter, treatment effect may shrink the long 
axis of a target lymph node to a normal value of <10 mm. However, even though 
the lymph node is now within normal size range, consistent with CR, the percentage 
of diameter reduction may be <30% (less than a PR). In these cases, a normalized 
diameter of “0, or resolved” should be used to calculate the sum of diameters, and 
therefore ensuring accurate response designation. Patients in CR but with rapid 
progression within 6 weeks of end of treatment scan will not be considered a CR, 
but rather will be considered a PD. 
 
Criteria for Partial Response (PR) – the designation of PR requires all of the following: 
PR is defined as a reduction of the sum of longest diameters of target lesions by 
30%, but without meeting the definition of CR described above. If one or more 
target lesions grew in size but the sum of the diameters remains ≤ 30% of the 
baseline measurement, and no new lesions appear, the response should be 
designated PR. This definition will eliminate the false interpretation of disease 
progression due to treatment-related inflammatory flares. Patients in CR but with 
rapid progression within 6 weeks of end of treatment scan will not be considered a 
CR, but rather will be considered a PD. 
 
Criteria for Stable Disease (SD) 
  
A patient is considered to have SD when he or she fails to attain the criteria needed 
for a CR or PR (see above) but does not fulfill those for progressive disease (see 
below).   
Progressive Disease (PD) 
 
 
Consistent with Deauville criteria, and using a unidimensional tumor measurement, 
PD after initiating a new therapy is defined as an increase in the sum of longest 
diameters of target lesions by >20%, and/or appearance of a new lesion (lymph 
node or a soft tissue mass 10 mm of the longest diameter), irrespective of FDG-
PET results. Whenever possible, questionable small FDG-PET avid lesions should 
be confirmed by a histologic or cytologic analysis. Appearance of a new FDG-PET 
avid lesion that is smaller than the above thresholds should be closely monitored, 
and whenever possible, a biopsy should be performed to determine its nature. An 
increase in the size of previously involved small lymph nodes by >20% while other 
lesions are decreasing, especially at the beginning of treatment with investigational 
agents, may represent a tumor flare and should not be designated a PD, unless there 
is continued increase in size on subsequent imaging studies. Patients should be 
allowed to remain on trial at investigators and patient discretion (eg if patient is not 
showing signs of symptomatic progression or deterioration) until the response or 
lack thereof is clarified on subsequent imaging. When treating clinicians are 
suspicious of tumor flare, repeat imaging should be obtained 4-8 weeks after initial 
indeterminate scan to help make the diagnosis of flare versus PD. 


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Relapsed Disease 
 
 
 
 
After an initial response, and in the absence of appearance of new lesions, PD is 
defined as an increase of the nadir sum of diameters by >20%. Consistent with 
Deauville criteria, patients who achieve a CR (normalization of all lymph node 
measurements and disappearance of extranodal lesions), at least one previously 
involved lymph node should increase in size to measure 15 mm in the long 
diameter, with a minimum absolute increase of at least 5 mm from nadir.  
Accordingly, an increase in a lymph node longest diameter from 8 to 13 mm is not 
considered a PD, even though there is 38% increase in the measurement, since the 
lesion did not exceed 15 mm. Similarly, a change from 12 to 16 mm does not qualify 
as a PD even though the new measurement exceeds 15 mm, since the absolute 
increase was < 5 mm. 
 
Patients will be analyzed with respect to progression-free survival (PFS). Progression-free survival 
is defined as time from therapy until relapse, progression, or death from any cause.  
 
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
Local laboratory assessments as specified on the schedule of events table will include the 
following: 
• Hepatitis B virus (HBV) testing will include hepatitis B surface antigen (HBsAg), antibody 
to the hepatitis B surface antigen (anti-HBs), and antibody to the hepatitis B core antigen 
(anti-HBc). If a subject is anti-HBc or HBsAg positive, then a quantitative polymerase 
chain reaction test to measure viral DNA load will be done. 
• Testing for HCV (testing for antibody; if positive then quantitative polymerase chain 
reaction test to measure viral DNA load), HIV, and HTLV will be performed per 
institutional guidelines. 
• EBV PCR will be performed in EBV+ subset. 
• Hematology: Complete Blood Count (CBC) with absolute differential, including 
hematocrit, hemoglobin, white blood cell count (WBC) with differential, and platelet 
count. 
• Chemistry: Comprehensive Metabolic Panel including albumin, alkaline phosphatase, 
alanine aminotransferase (ALT/SGPT), aspartate transaminase (AST/SGOT), bilirubin 
(total and direct), calcium, chloride, creatinine, glucose, phosphorous, potassium, sodium, 
total protein, serum urea/blood urea nitrogen (BUN), LDH and uric acid. 
• Thyroid function tests will include thyroid stimulating hormone (TSH) and free 
thyroxine (fT4). 
• Calculated creatinine clearance (CrCl) will be estimated using the Cockcroft-Gault 
formula by central laboratory: CrCl (mL/min) = (140 – age) (weight [kg]) / 72 (serum 
creatinine [mg/dL]; for females, the formula is multiplied by 0.85 (Cockcroft, 1976). 


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o Ideal body weight (IBW) will be used in the Cockroft-Gault equation to calculate 
estimated creatinine clearance for all patients with a total body weight ≤120% of 
their IBW. 
o Adjusted body weight will be used in the Cockroft-Gault equation for all patients 
with a total body weight >120% of their total body weight 
• Coagulation tests will include prothrombin time, international normalized ratio (INR) and 
partial thromboplastin time (PTT or activated PTT). 
• Urinalysis (a urine dipstick may be used) will include color, appearance, specific gravity, 
pH, glucose, ketones, blood, bilirubin, and protein. A microscopic examination will be 
performed if urinalysis result is abnormal. 
• 
Pregnancy testing (serum or urine) will be performed for patients of child-bearing potential 
at screening only. Pregnancy test must be done ≤14 days of starting treatment. 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS (RESEARCH PROCEDURES) 
 
Pathology 
 
Baseline standard of care diagnostic pathology samples will be performed as clinically indicated. 
Pathological materials including H&E stain, all IHC slides, and any leftover FFPE tissue block 
along with the pathology report from initial diagnosis should be sent to be reviewed, and the 
diagnosis confirmed by the University of Colorado pathology department (retrospective diagnostic 
review: treatment may commence prior to the University of Colorado review).  
 
Obtaining pathology samples is not required prior to enrollment, but confirmation of availability 
IS required prior to enrollment. 
 
Initial diagnostic materials should be submitted within 30 days of patient registration. A copy of 
the pathology report should be sent when the sample is shipped.  
 
Please refer to the Lab Manual for detailed instructions on acquisition and shipping. 
 
The diagnostic slides and any leftover material will be returned after review. 
 
7.2.2 OTHER ASSAYS OR PROCEDURES (RESEARCH) 
 
Correlative analysis blood samples. 
 
Peripheral blood will be collected at the following time points (see lab manual for specifics): 
° 
Baseline—Within 28 days prior to first day of first cycle of study treatment.  
° 
Prior to cycle 2 on study—within 7 days prior to C2D1 of nivolumab + EPOCH.  
° 
Prior to cycle 3 on study—within 7 days prior to C3D1 of nivolumab + EPOCH.  
° 
At the end of induction treatment—within 14 days of EOT imaging response assessment. 
° 
At the end of treatment (D+100 post auto-transplant). 
° 
At time of recurrence/progression, or if patient is taken off study. 


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Please refer to the Lab Manual for detailed instructions on acquisition and shipping. 
 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Pathology 
H&E stain, IHC slides, and any leftover FFPE tissue block along with the pathology report from 
initial diagnosis should be sent to be reviewed, and the diagnosis confirmed by the University of 
Colorado. 
NOTE: the diagnostic H&E slide and IHC slides will be returned after review. Specimens from 
the tissue block will be stored in the Lymphoid Malignancy Tissue Bank (LTB) for potential 
further correlative studies at a later time. 
 
Research Blood Samples 
 
Research blood samples will be banked in the LTB and subject to further correlative analysis. 
 
7.2.4 SPECIMEN SHIPMENT 
 
Please reference Lab Manual for full details on specimen collection, requisition forms and details 
on shipment supplies and specifications. 
 
 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
 
Informed Consent must be obtained prior to beginning any assessments solely for the purpose of 
this study. Informed consent will be reviewed with patient in detail with the physician, with the 
physician addressing all questions and concerns of the patient. Informed consent will be signed by 
patient and authorized consenting personnel should risks/benefits be deemed acceptable to patient. 
 
Screening evaluations will be performed for all subjects to determine study eligibility after signing 
the informed consent form. These evaluations must be completed within 28 days of administration 
of the first dose (Cycle 1 Day 1 [C1D1]) unless noted otherwise below. 
 
The following will be performed or assessed at screening as specified in section 7.4: 
 
• Complete medical history will be documented by a qualified clinician at the time of the 
Screening Visit. The medical history will be general enough to document common 
comorbid conditions as well as specific enough to confirm any condition against the 
eligibility criteria, and will document whether the identified conditions are active or 


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inactive at the time of enrollment. Disease history will include specific information 
regarding diagnosis and histology including grade. 
 
• Physical examination including evaluation of lymph nodes, spleen and liver will be 
performed. 
 
• Demographics will include date of birth, sex, race, and ethnicity (if allowed by local 
regulations). 
 
• Adverse Event assessment (baseline AEs) 
 
• Concomitant medications reviewed and documented 
 
• ECOG performance status will be recorded. 
 
• Vital signs will include blood pressure, pulse, and body temperature. 
 
• Body weight and height (height at the screening only) will be measured. 
 
• Body surface area (BSA) will be calculated using the subject’s height and weight 
according to local pharmacy practice. 
 
• Pregnancy testing (in WOCBP) ≥14 days of starting treatment 
 
• Counseling about pregnancy precautions and the potential risks of fetal exposure will be 
given to patients of child-bearing potential. 
 
• Tumor tissue sample for confirmation of diagnosis and correlative research (submitted 
within one month after registration – confirmation of availability is required). H&E stain 
and IHC slides or a representative FFPE tissue block along with the pathology report from 
initial diagnosis, should be sent to be reviewed and have the diagnosis confirmed at 
University of Colorado. Patients whose tissue is not available may still be eligible to go on 
trial only if they choose to have a SOC biopsy prior to treatment. In either case, patients 
may commence treatment prior to pathologic review of tissue and the diagnosis confirmed 
at the University of Colorado. Tissue must be a core needle, excisional, or incisional 
biopsy. Fine needle aspirations are not adequate. If patient does not have adequate tissue 
for biomarker analysis, then an additional biopsy may be performed as per standard of care.   
 
• Hematology (as outlined in section 7.2) 
 
• Chemistry (as outlined in section 7.2)  
 
• Urinalysis (as outlined in section 7.2)  
 
• TSH and free T4 


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• PT/INR and PTT 
 
• HIV, HBV, HCV, HTLV screen (as outlined in section 7.2)* 
 
• EBV PCR (in EBV+ subset)* 
 
• PET-CT will be performed ≤ 6 weeks of C1D1 of treatment* 
 
• 12-lead single electrocardiogram (ECG) will be recorded 
 
• Left ventricular function assessment via MUGA or echocardiogram* 
 
• Bone marrow biopsy and/or CSF analysis will be performed if clinically indicated (must 
be performed ≤6 weeks prior to study registration)* 
 
• Research blood tubes will be collected for biomarker/correlative analysis 
 
*For patients that received 1 cycle of standard of care chemotherapy prior to enrollment: If these 
tests were performed within 28 days prior to C1D1 of standard of care chemotherapy, they do not 
need to be repeated prior to first cycle of study nivolumab + EPOCH. 
 
Inclusion/exclusion criteria will be reviewed in detail to ensure that the patient is a study candidate 
prior to enrollment and subsequent treatment. If it is not clear if patient qualifies for study, the 
principal investigator should be notified for review of patient candidacy.  
  
 
7.3.2 INDUCTION TREATMENT WITH NIVOLUMAB + CHEMOTHERAPY 
 
Cycle 1 – Cycle 6 
 
Chemotherapy should be started within 3 days of day 1 for each 21-day cycle. 
  
NOTE: If patient has been given one cycle of cytotoxic chemotherapy (e.g. CHOP) prior to 
enrollment, this cycle of treatment will count toward the 6 cycles of treatment given in the study, 
and thus would be starting at Cycle 2. Thus, patients will receive no more than 6 total cycles of 
induction treatment. 
 
If screening assessments are performed within 48 hours of Cycle 1 Day 1, safety laboratory and 
physical examinations need not be repeated at Cycle 1 Day 1. 
 
Upon starting treatment, patients will be seen and evaluated by treating provider within 7 days 
prior to day 1 of every cycle. All laboratory, safety, and physical examinations should be 
performed by a provider or nurse within 48 hours of the start of every cycle (e.g. within 48 hours 
of the start of chemotherapy).   


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The following evaluations will be performed at scheduled follow up visits: 
 
• Physical examination with vital signs and weight 
 
• Adverse Event assessment 
 
• Concomitant medications 
 
• Hematology (as outlined in section 7.2) 
 
• Chemistry (as outlined in section 7.2) 
 
• Urinalysis (as outlined in section 7.2)  
 
• TSH and free T4 (as outlined in section 7.2) 
 
• EBV PCR (as outlined in section 7.2) 
 
• Tumor response assessment (PET/CT or CT according to investigator preference). Note 
that we generally recommend interim scan be performed between the 2nd and 3rd cycle of 
EPOCH + nivolumab. For patients that received 1 cycle of standard of care chemotherapy 
prior to enrollment in study, we suggest interim scan be performed between cycle 2 and 
cycle 3 of EPOCH + nivolumab (i.e. between the 3rd and 4th cycles of all chemotherapy).  
 
• Bone marrow biopsy and/or CSF assessment (as clinically indicated) or to confirm CR. 
 
• Research blood tubes will be collected for biomarker analysis prior to Cycle 2 and Cycle 
3 of nivolumab + EPOCH. 
 
Hematology Blood Collection between Induction Cycles 
 
Hematology (as outlined in section 7.2) is to be collected 2 times per week during Cycles 1 through 
6.  These two hematology blood draws must be at least one day apart. 
 
7.3.3 END OF INDUCTION VISIT 
The End of Induction Visit will occur after completion of 6 cycles of chemotherapy (3-6 weeks 
after C6D1 of nivolumab + chemotherapy) and will include the following assessments: 
 
• History and physical examination with vital signs and weight  
 
• Adverse Event assessment 
 
• Concomitant medications 


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• ECOG performance status will be recorded 
 
• Hematology (as outlined in section 7.2) 
 
• Chemistry (as outlined in section 7.2) 
 
• Urinalysis (as outlined in section 7.2)  
 
• TSH and free T4 (as outlined in section 7.2) 
 
• EBV PCR (as outlined in section 7.2) 
 
• End of induction treatment PET-CT (within 6 weeks of cycle 6 day 1 of chemotherapy) 
and tumor response assessment. 
 
• If PET positive after the completion of cycle 6, a biopsy of PET positive area may be done 
at investigator discretion. 
 
• Bone marrow biopsy and CSF assessment (as clinically indicated) or to confirm CR. 
 
• Survival status will be assessed. 
 
• Discussion of candidacy and risks/benefits of consolidation autologous transplant. 
 
• Research blood tubes will be collected for biomarker analysis. 
 
 
7.3.4 AUTOLOGOUS HEMOPOEITIC CELL TRANSPLANT & POST-TRANSPLANT 
 
Patients undergoing autologous transplant will undergo clinical and laboratory evaluation 
according to standard of care subsequent to end of induction treatment visit. A CT or PET/CT 
should be obtained according to standard of care every 3 months (+/- 14 days) until 1 year post 
transplant. While encouraged, it is not mandatory to obtain imaging every 3 months if patients 
achieve complete metabolic response after completion of cycle 6. The end of treatment visit will 
be at D+100 (+/- 14 days) after the transplant date. Patients will then enter LTFU.  
 
 
7.3.5 END OF TREATMENT (FOR PATIENTS UNDERGOING TRANSPLANT OR THOSE WHO 
DO NOT COMPLETE 6 CYCLES OF TREATMENT) 
 
This visit will be completed for subjects who are withdrawn from treatment for any reason as 
soon as possible after the decision to permanently discontinue treatment has been made. This visit 
applies to patients who stop treatment for any reason prior to completing all treatment OR if a 
patient goes on to get an autologous stem cell transplant, then they would complete the End of 


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Treatment visit 100 days after their transplant (see calendar for details). If a patient decision to 
withdraw the patient from treatment occurs at a specific time point in the protocol (ex: at the 
scheduled End of Induction visit a patient comes off treatment due to PD) then that time point 
would be considered the EOT visit.  
 
The following evaluations will be performed at the EOT visits: 
 
• History and physical examination with vital signs and weight  
 
• Adverse Event assessment 
 
• Concomitant medications 
 
• ECOG performance status 
 
• Hematology (as outlined in section 7.2) 
 
• Chemistry (as outlined in section 7.2) 
 
• Urinalysis (as outlined in section 7.2)  
 
• TSH and free T4 (as outlined in section 7.2) 
 
• EBV PCR (as outlined in section 7.2) 
 
• End of treatment PET-CT and tumor response assessment (unless patient has had a scan 
within the past 21 days).)  
 
• Bone marrow biopsy and CSF assessment (as clinically indicated) 
 
• Survival status will be assessed 
 
• Research blood tubes will be collected for biomarker analysis 
 
 
7.3.7 LONG-TERM FOLLOW-UP 
 
The follow-up period begins upon all study treatment discontinuation or completion as per 
protocol. This includes subjects who complete the full course of treatment and who discontinue 
treatment due to toxicity. All subjects will be followed for AEs and concomitant 
medications/procedures for 100 days after the last dose of nivolumab. In addition, after end of 
induction or end of treatment visit/labs, patients will be contacted via telephone every 3 months 
(+/- 1 month) for 2 years for the following endpoints: death, first progression, and new anti-
lymphoma treatment. If at any point a patient decides to withdraw from long term follow-up, there 
must be documentation of this decision by the provider, nurse or coordinator. 


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7.3.8 EARLY TERMINATION VISIT 
 
Early termination visits will be performed with the same requirements as the end of treatment visit 
(see section 7.3.6). 
 
Note that if a patient chooses to voluntarily withdraw from study, then documentation must be 
made regarding if patient chooses to simply discontinue study treatment, or if patient also no longer 
wants to be followed for treatment outcomes (and thus opts out of study related follow up). 
 
7.3.9 UNSCHEDULED VISIT 
 
The following evaluations will be performed all unscheduled visits: 
 
• History and physical exam including vital signs  
 
• Laboratory evaluation and imaging as clinically indicated 
 


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7.4 
SCHEDULE OF EVENTS TABLE 
 
Active Monitoring Phase 
Off Treatment 
 
Screening 
 
≤ 28 days prior 
to C1D1 
(exceptions 
noted) 
Induction Treatment with  
Nivolumab + Chemotherapy 
Post-Induction 
End of 
Treatment26 
Long Term 
Follow-Up28 
Tests and procedures 
C1 – C6 
Treatment15, 16  
Hematology 
during 
Induction21 
End of Induction Visit 
 (3-6 weeks after C6D1) 
Autologous Transplant & 
Post-Transplant24,26 
 
 
+/-3 days 
 
 
 
 
 
History and exam 
X 
X17 
 
X 
 
X 
 
Adverse event assessment 
X 
X17 
 
X 
 
X 
X29 
Concomitant medications 
assessment 
X 
X17 
 
X 
 
X 
X29 
ECOG 
X 
 
 
X 
 
X 
 
Vital signs1 including weight and 
height2 
X 
X17 
 
X 
 
X 
 
Serum or urine pregnancy test3 
X3 
 
 
 
 
 
 
Tumor tissue sample for 
confirmation of diagnosis and 
research purposes or SOC biopsy 
X4 
 
 
X22 
 
 
 
Hematology (see section 7.2) 
X 
X17 
2x per week21 
X 
 
X 
 
Chemistry (see section 7.2) 
X 
X17 
 
X 
 
X 
 
Urinalysis 
X 
 
 
X 
 
X 
 
TSH and free T4 
X 
X17 
 
X 
 
X 
 
PT/INR5, PTT 
X 
 
 
 
 
 
 
HIV, HBV, HCV, HTLV screen 
X6, 30 
 
 
 
 
 
 
EBV PCR (in EBV+ subset) 
X30 
 
 
X 
X 
X 
 
Tumor Measurement/Evaluation of 
indicator lesions (CT chest, 
abdomen, pelvis; other CT and/or 
MRI when indicated) 
X8, 30 
Before C37, 18 
 
X 
 
X24,25 
 
X27 
 
PET/CT scan7 
X8, 30 
Before C37 
 
X22 
X24,25 
X27 
 
Bone marrow aspirate and biopsy 
(unilateral or bilateral)9 
X10, 30 
Before cycle 319 
 
X19 
 
 
X9 
 
Electrocardiogram11 
X 
 
 
 
 
 
 
Left ventricular function 
measurement12 
X30 
 
 
 
 
 
 
Cerebrospinal fluid analysis10,13 
X30 
X 
 
X 
 
X13 
 
Research blood samples 14 
X 
Before C2 and 
C314 
 
X 
X14,23 
X14,23 
 
Dosing20 
 
X 
 
 
 
 
 
Survival status 
 
 
 
X 
 
X 
X28 


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1. 
Vital signs include blood pressure, pulse and temperature. 
2. 
Height will be measured at screening only.  
3. 
Pregnancy tests for females of childbearing potential must be done ≤14 days of treatment start date. A female of 
childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months).  
4. 
Central review of pathology is required for confirmation of diagnosis. Completion of central pathology review is not 
required prior to registration for patients; however, materials for central review must be submitted within 30 days after 
registration. Pathology material: H&E stain and IHC slides or a representative FFPE tissue block from initial diagnosis, 
including additional material for correlative analysis. Please NOTE: the diagnostic H&E slide and IHC slides will be 
returned after review. In addition, patients whose tissue is not available may still be eligible to go on trial if they choose to 
have an SOC biopsy prior to treatment. 
5. 
PT/INR assessment frequency (for patients on Coumadin) is per investigator discretion to keep within therapeutic range. 
6. 
Patients who are seropositive because of hepatitis B virus vaccine are eligible.   
7. 
Imaging should be obtained per standard of care and NCCN guidelines. PET/CT is mandatory pre- and post-treatment. 
Interim CT may be adequate to assess disease response; however, PET/CT is preferred. Note that we generally 
recommend interim scan be performed prior to 3rd cycle of study chemotherapy; for patients that got 1 cycle of standard 
of care chemotherapy prior to enrollment in study, we suggest interim scan be performed prior to cycle 3 of EPOCH + 
nivolumab (Thus, for patients who received 1 cycle of standard of care chemotherapy prior to study enrollment, scan will 
be prior to 4th cycle of all induction chemotherapy and prior to 3rd cycle of nivolumab + EPOCH).  
8. 
Imaging must be done ≤ 6 weeks prior to study registration, unless patient received 1 cycle of standard of care 
chemotherapy prior to enrollment in study, in which case imaging must have been obtained within 6 weeks of C1D1 of 
standard of care chemotherapy. 
9. 
Bone marrow biopsies will be done according to standard of care and only mandatory in the setting of unexplained 
cytopenias. However, bone marrow biopsies are highly encouraged, especially in the setting of cytopenias. If screening 
bone marrow biopsy is indicated, it should be done ≤ 6 weeks prior to study registration. 
10. Screening bone marrow biopsy and/or CSF analysis will be performed if clinically indicated (for screening: must be 
performed ≤6 weeks prior to study registration). Since the chemotherapy requires dose adjustment based on hematologic 
toxicity it is strongly encouraged to obtain a bone marrow biopsy prior to treatment but can be omitted in select situations 
after discussion with the study chair. 
11. 12-lead single electrocardiogram (ECG) will be recorded. 
12. MUGA or ECHO. 
13. A lumbar puncture and cytologic examination of the cerebrospinal fluid is not required but should be performed if clinically 
indicated. (Secondary CNSL is not an exclusion criteria). 
14. Research blood samples: Blood samples will be drawn at screening, prior to 2nd, and 3rd cycles of nivolumab + EPOCH 
(on trial), and at end of induction visit. See requisition form for further detail. For patients who have not progressed, the 
end of treatment samples will be D+100 post auto-transplant. End of treatment tubes should also be drawn for any patient 
that is taken off treatment early. See section 7.2.2 for full details of blood draws 
15. If patient has been given one cycle of cytotoxic chemotherapy (e.g. CHOP) prior to enrollment, this cycle of treatment will 
count toward the 6 cycles of total treatment given, and thus would be starting at Cycle 2. 
16. All assessments must be done prior to treatment – may be done up to 2 days prior. 
17. If screening assessment are performed within 48 hours of C1D1, safety laboratory and physical examinations need not be 
repeated at Cycle 1. 
18. Measurements can be done off the CT images of a PET/CT. 
19. If bone marrow positive at diagnosis, a repeat bone marrow biopsy must be done to confirm CR. Can be delayed to end of 
treatment response assessment or done in parallel with interim response assessment. If interim bone marrow biopsy is 
negative for disease, it will be repeated at the discretion of the treating physician. 
20. During the induction treatment, patients will dose according to section 6.1.1 Dosing Schedule. 
21. Hematology blood draws must be done 2 times per week (i.e., twice during every 7-day period, starting with Day 1) at 
least one day apart, but ideally 2 days apart. 
22. If PET positive after the completion of cycle 6, a biopsy of PET positive area may be done at investigator discretion.  PET 
should be done within 6 weeks of cycle 6 day 1 of chemotherapy. 
23. At relapse. 
24. For patients who have undergone an autologous transplant, a CT or PET/CT should be obtained according to standard of 
care every 3 months (+/- 14 days) until 1-year post-transplant. While highly encouraged, it is not mandatory to obtain 
imaging every 3 months if patients achieve complete metabolic response after completion of cycle 6. 
25. If the patient elects to undergo autologous transplant, at D+100 (+/- 14 days) response evaluation is required with CT or 
PET/CT (per investigator’s discretion), but PET/CT would be preferred if not in a CR after cycle 6. This visit will also be 


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considered the end of treatment visit for patients who have undergone autologous transplant, and as such all 
assessments should be done accordingly.  
26. An end of treatment visit will be completed for the subjects who are withdrawn from treatment early, for any 
reason, as soon as possible after the decision to permanently discontinue treatment has been made. For 
patients who undergo autologous transplant, the end of treatment visits will be D+100 (+/- 14 days) post auto-
transplant. 
27. Patients who have had a PET-CT within the last 21 days will not require a repeat scan. 
28. The long-term follow-up (LTFU) period begins after the EOT visit. All patients on LTFU will be contacted via phone every 3 
months (+/- one month) until first progression, subsequent anti-lymphoma therapy, and survival for up to 2 years after 
enrollment, unless they have withdrawn consent. Patients will also continue SOC follow-up as dictated by institutional 
guidelines. 
29. All subjects will be followed for AEs and concomitant medications/procedures for 100 days after the last dose of 
nivolumab or until start of new anti-lymphoma treatment. 
30. For patients that had 1 cycle of standard of care chemotherapy prior to enrollment in study: Patients that had these tests 
prior to cycle 1 of standard of care chemotherapy do not have to repeat these tests prior to start of nivolumab + EPOCH. 
 


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7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
All concomitant prescription medications taken during study participation will be recorded on the 
case report forms (CRFs). For this protocol, a prescription medication is defined as a medication 
that can be prescribed only by a properly authorized/licensed clinician. Medications reported in 
the CRF are concomitant prescription medications, over-the-counter medications, and non-
prescription medications. 
 
In addition, examples of acceptable methods of contraception include the following (also listed in 
section 5.1): 
° 
Bilateral tube ligation 
° 
Male sterilization 
° 
Hormonal contraceptives that inhibit ovulation 
° 
Hormone-releasing intrauterine devices 
° 
Copper intrauterine devices 
NOTE: Periodic abstinence (e.g. calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are NOT acceptable methods of contraception. 
 
Involved site radiation therapy (ISRT): ISRT does not have a proven role for the management of 
PTCL and will not be allowed during induction(33) or as consolidation for patients in complete 
response treated in this protocol. If patients have residual disease after induction chemotherapy 
and opt not to undergo an autologous transplant, consolidative radiation will be permitted after 
discussion with the study chair. 
   
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
° 
Antiemetics may be used at the discretion of the attending physician. 
° 
Tumor lysis syndrome prophylaxis will be used at the discretion of the treating physician.  
° 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. Pegfilgrastim support will be given with each 
cycle. Treat as needed. 
° 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions.  
° 
All blood products and concomitant medications such as anti-diarrheals, analgesics, and/or 
antiemetics received from the first day of study treatment administration until 30 days after 
the final dose will be recorded in the medical records. 
 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
The following medications are prohibited while on study treatment (exceptions noted): 


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° 
Treatment with immuno-suppressive medications, except as used to treat drug-related 
adverse events, will not be permitted unless discussed with and approved by the study 
principal investigator.   
° 
Patients will also not be allowed to be treated with any concurrent anti-neoplastic therapy, 
including chemotherapy, non-palliative radiotherapy, and Chinese medications used for 
cancer treatment.   
° 
Topical, inhaled, articular, intra-nasal corticosteroids are permitted. A brief (<3 weeks) 
course of steroids is permitted for purposes of prophylaxis (e.g. contrast) or treatment of 
non-auto-immune conditions (e.g. anaphylaxis). 
 
Treatment needs to be administered in collaboration with an oncology trained pharmacist.  
Drugs that have interactions with standard of care EPOCH or nivolumab should be used 
with caution or avoided as per institutional guidelines.  
 
 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prophylactic medications, treatments and procedures should be performed according to 
institutional guidelines. This includes prophylactic antibiotics, anti-fungals, or PJP prophylaxis. 
We strongly encourage prophylactic antibacterial and antifungal for 10 days after EPOCH (e.g. 
levofloxacin 500 mg daily and fluconazole 400 mg daily) and continuous antiviral prophylaxis 
(e.g. acyclovir 400 mg BID or valacyclovir 500 mg daily) for 6 months post induction. 
 
   
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Patients with adverse events while on study drug should be treated as indicated in section 6 of 
protocol. Other medical conditions that arise while patients are on study should be treated 
according to standard of care. The principal investigator should be made aware of serious adverse 
events occurring while patients are on study. Inquiries regarding handling of adverse events 
occurring while on study that are not described in this protocol should be directed towards the 
principal investigator. 
 
  
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study 
drug to subjects/investigators unless the Sponsor-Investigator chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care or other 
appropriate treatment in the independent medical judgement of the Investigator to treat the 
condition under study. 
 


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8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
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 (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
A non-serious adverse event is an AE not classified as serious.  
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 (e.g., anemia versus low hemoglobin value). 
 
 
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.  
 


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8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
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 (e.g. 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 (e.g. death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
The following are NOT considered serious adverse events: 
° 
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) 
° 
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 


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° 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
° 
Admission for administration of anticancer therapy in the absence of any other SAEs 
 
 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UAP) 
 
The Office of Human Research Protection (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied. 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research). 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
This study will use the OHRP definition of UAP. 
 
   
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
For AEs not included in the protocol-defined grading system, the following guidelines will be used 
to describe severity. 
• Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating. 
  


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8.2.2 RELATIONSHIP TO STUDY AGENT 
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.) 
 
8.2.3 EXPECTED ADVERSE EVENTS 
The study investigators will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the risk information previously described for the study agent. 
 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/ stabilization of the event. 
All AEs occurring while on study must be documented appropriately regardless of relationship. 
All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE. UAPs will be recorded in the data 
collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 


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The investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained (for SAEs) or from initiation of study treatment (AEs) until 100 days after the 
last day of study treatment. At each study visit, the investigator will inquire about the occurrence 
of AE/ SAEs since the last visit. Events will be followed for outcome information until resolution 
or stabilization. 
 
 
8.4 
REPORTING PROCEDURES 
8.4.1 ADVERSE EVENT REPORTING  
ADVERSE EVENTS 
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.) 
Adverse events will be documented in clinic notes at all scheduled visits. Adverse events will be 
graded by investigator according to CTCAE v5.0. 
 
NON-SERIOUS ADVERSE EVENTS 
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 [e.g., IND US trial] as 
part of an annual reporting requirement. The collection of non-serious AE information should 
begin at initiation of the study. 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.  
 
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and new cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
1) Potential drug induced liver injury is defined as:  
i) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
ii) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
iii) 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. 


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Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
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 reported to BMS Worldwide 
Safety, whether related or not related to study drug. All SAEs must be collected that relate to 
participation in the study. This includes SAEs associated with study drug or other protocol-
specified procedure (e.g., a follow-up skin biopsy). 
  
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours / 1 Business Day of becoming aware of the event. SAEs must be 
recorded on either CIOMS, MedWatch, or approved site SAE form. BMS Protocol number 
must be included on the SAE form or on the cover sheet with the SAE form transmission. 
o The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
 
To submit an SAE (or other immediately reportable event):  
∙ write in the expectedness, relationship and severity at the bottom of the CIOMS form 
∙ have the investigator sign and date the bottom of the form 
∙ then attach and email, including ALL of the following: 
 
Email SAE Form To:  
Worldwide.Safety@BMS.com  (or fax to +1 609-818-3804) 
 
 
 
 
CPDM.IIT@CUAnschutz.edu   
 
 
 
 
Bradley.Haverkos@CUAnschutz.edu    
 
 
 
 
DSMC@CUAnschutz.edu   
 
Subject: 
 
 
18-0708 SAE Report Form 
 
Body of Email: 
 
List the following information as assessed by the Investigator  
• 
whether the event is expected or unexpected 
• 
causality of events in relation to all study medications 
• 
whether the SAE is related to disease progression 
• 
CTCAE grade 
 
 
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 \ 1 Business Day to 
BMS using the same procedure used for transmitting the initial SAE report.  
Following the subject’s written consent, all SAEs including those thought to be associated with 
protocol-specified procedures, need to be reported to BMS and others as above. The investigator 
should report any SAE 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;  


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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. 
The sponsor must notify FDA and all participating PIs in an IND safety report of potential serious 
risks as soon as possible, but in no case later than 15 calendar days after the sponsor determines 
that the information qualifies for reporting (21 CFR 312.32(c)(1)). 
 
The sponsor must notify FDA of any unexpected fatal or life-threatening adverse reactions as soon 
as possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information (21 CFR 312.32(c)(2)). 
 
The study clinician will complete an SAE Form within the following timelines: 
• All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded on the SAE Form and submitted to the study sponsor within 24 hours of site 
awareness. See Study Contact Listing for contact information. 
• Other SAEs, regardless of relationship, will be submitted to the study sponsor within 72 
hours of site awareness. 
All SAEs will be followed until satisfactory resolution or until the site PI deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be 
requested by the study sponsor and should be provided as soon as possible.  
 
The study sponsor will be responsible for notifying FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the 
sponsor’s initial receipt of the 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. 
 
 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the OHRP criteria for UAPs require the creation and completion of 
a UAP report form. It is the site PI’s responsibility to report UAPs to their IRB, using the IRB’s 
standard UAP form. The Lead PI is responsible for reporting the UAP to the UCCC DSMC, if 
applicable. If an IRB UAP form is not provided, the UAP report will include the following 
information: 
• Protocol-identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome; 


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• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents a UAP; 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UAP. 
 
To satisfy the requirement for prompt reporting, UAPs will be reported using the following 
timeline: 
• UAPs that are SAEs will be reported to the IRB and to the DSMC within 5 calendar 
days of the investigator becoming aware of the event. 
• Any other UAP will be reported to the IRB and to the DSMC within 5 calendar days 
of the investigator becoming aware of the problem. 
 
8.4.4 REPORTING OF 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 the last dose of a potentially fetotoxic, non-genotoxic 
therapy) the investigational product will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either the 
CIOMS in accordance with SAE reporting procedures, as listed in section 8.4.2. 
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, BMS Pregnancy Surveillance Form, or approved site SAE form. A BMS Pregnancy 
Surveillance Form may be provided upon request. 
8.5 
STUDY HALTING RULES  
Toxicity 
If any patient experiences death due to an adverse event that is assessed as related to study 
treatment (by investigator and/or Sponsor), it will lead to temporary hold of study pending review 
by study team. 
Toxicities of special interest: The study will be halted prematurely if 3 out of the initial 10 patients 
experience the toxicities of special interest, listed in 4.1. 
 
Transplant-related adverse events of special interest: For patients undergoing auto-transplant 
the study will be halted prematurely if 3 out of initial 10 patients undergoing auto-transplant 


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experience any of the following toxicities of special interest during period from start of 
conditioning regimen (e.g. BEAM) through 60 days post-transplant: 
• 
Non-relapse related death 
• 
grade 4 or higher hepatotoxicity 
• 
autograft mobilization failure 
 
Treatment-related mortality: If any patient experiences death due to an adverse event that is 
assessed as related to study treatment (by investigator and/or Sponsor), it will lead to temporary 
hold of study pending review by study team. The study will be terminated prematurely if at any 
point 2 patients experience treatment-related death during induction chemotherapy with study 
regimen. 
Efficacy 
The study will be suspended pending further review if, at any time, there is sufficient evidence to 
suggest that the true probability of achieving a complete response falls below 30% while assuming 
the treatment drug will elicit a 56% complete response rate. Statistically significant evidence for 
this low complete response rate is defined as an observed complete response rate whose upper one-
sided 90% confidence limit is lower than 30%. Sample size calculations were made assuming 80% 
power. In practice, the study will be suspended if too few complete responses are observed in 
participants. Table 3 displays the total number of subjects needed for a complete response endpoint 
for this study and the number of subjects to be accrued in each of two stages in Simon’s two-stage 
procedure (n1 and n2). If r1 or fewer complete responses are observed during stage 1, the trial is 
stopped early for futility. If r2 or fewer complete responses are observed by the end of stage 2, 
then no further investigation of this treatment regimen is warranted. While 17 samples are needed 
to achieve 80% power, 18 total patients will be enrolled in the study to account for possible drop-
out/loss to follow-up. 
 
Table 2.  Simon Two-Stage Design Stopping Rules for Efficacy 
n1 
r1 
n2 
n 
(Total 
Sample 
Size) 
r2 
Assumed 
response 
rate of 
treatment 
drug 
Type I 
error 
Power 
10 
3 
7 
17 
7 
56% 
0.096 
0.813 
 
8.6 
SAFETY OVERSIGHT 
Monitoring and Oversight 
The sponsor investigator will be responsible for monitoring the trial per the trial monitoring plan, 
in addition to overseeing the safety and efficacy of the trial including any specimens collected, 
executing the data and safety monitoring (DSM) plan, and complying with all reporting 
requirements to local and federal authorities. This oversight will be accomplished through 
additional oversight from the Data and Safety Monitoring Committee (DSMC) at the University 
of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for ensuring data 


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quality and study participant safety for all clinical studies at the CU Cancer Center, which is the 
coordinating institution of this trial. A summary of the DSMC’s activities is as follows:  
 
• Conduct of internal audits  
• Ongoing review of all serious adverse events (SAEs) and unanticipated problems (UAPs)  
• Has the authority to suspend trials for safety or trial conduct issues  
• May submit recommendations for corrective actions to the CU Cancer Center’s Executive 
Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to the DSMC, 
IRB and the sponsor investigator per protocol. All SAEs and UAPs are to be reported to the DSMC 
within 7 (for fatal or life-threatening events) or 15 (non-life-threatening events) calendar days of 
the sponsor investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at regularly 
scheduled meetings. Data regarding number of subjects, significant toxicities, dose modifications, 
and treatment responses will be discussed. 
 
The sponsor investigator is responsible for organizing and conducting regularly scheduled 
teleconferences with all participating sites. The sponsor investigator will also be responsible for 
including data from all the participating sites to include the minutes from these regularly scheduled 
teleconferences between the sponsor investigator and the sites within the overall trial’s DSM 
progress report.  
 
The sponsor investigator will provide a DSM progress report to the CU Cancer Center DSMC on 
a recurring basis (either every six or twelve months based on DSMC vote). The DSM report will 
include a protocol summary, current enrollment numbers, summary of toxicity data to include 
specific SAEs, UAPs and AEs, any dose modifications, all protocol deviations, and protocol 
amendments. The DSM report submitted to the DSMC will also include, if applicable, the results 
of any efficacy data analysis conducted. Results and recommendations from the review of this 
progress report by the DSMC will then be provided to the sponsor investigator in a DSMC review 
letter. The sponsor investigator is then responsible for ensuring this letter is submitted to the site’s 
IRB of record at the time of IRB continuing review.  
 
Quality Control and Quality Assurance 
Site monitoring visits will be performed by the sponsor investigator’s authorized representative on 
a regular basis, pursuant to the Monitoring Plan. During these visits, information recorded on the 
CRFs will be verified against source documents. As necessary, requests for data clarification or 
correction will be sent to the appropriate site PI. 
 
Independent auditors from the sponsor investigator’s authorized representative will be allowed by 
the site’s PI to audit. In addition, audits may be conducted at any time by appropriate regulatory 
authorities and/or the IRB. 
 
 


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9 
CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of human 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol/ amendment(s), 
with GCP, and with applicable regulatory requirement(s).  
 
Monitoring for this study will be performed by CU Cancer Center Clinical Monitor in accordance 
with the clinical monitoring plan (CMP), incorporated herein by reference. The CMP describes in 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
of detail monitoring will be performed, and the distribution of the monitoring reports. 
 
Independent audits will be conducted by the CU Cancer Center DSMC to ensure monitoring 
practices are performed consistently across all participating sites, if applicable, and that monitors 
are following the CMP. 
 
10 
STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL AND ANALYTICAL PLANS 
Using standard of care first-line treatment of PTCL, as low as 40% of patients will achieve a 
complete response. We hypothesize that treating patients with standard of care EPOCH in 
combination with nivolumab that we can improve complete response rate to 56% by combining 
standard of care treatment with nivolumab. Safety will be tested by noting the number of toxicities 
and SAEs experienced in the treatment cohort. Simon’s two-stage design (Simon, 1989) will be 
used to test the efficacy of combination treatment. Efficacy will be assessed using the proportion 
of patients who achieve a complete response. See 8.5 for further details. 
 
10.2 STATISTICAL HYPOTHESES 
Primary endpoint 
 
Complete response rates will be formally assessed as the primary endpoint. With standard of care 
treatment, the majority of studies suggest complete response rates of approximately 40% (Maeda 
et al. Haematologica. 2017; Gleesen et al. Leuk & Lymphoma. 2018; Schmitz et al. Blood 
& Vose et al. JCO). Of note, these prior studies include favorable subsets (low risk ALK+ ALCL 
and Stage I disease), which we have excluded from our study. Additionally, in our study we have 
included poor risk subsets (EATL, MEITL, γ/δ TCL, and secondary CNS disease), which are 
commonly excluded from PTCL studies. In this current study investigating nivolumab + EPOCH, 
we hope to achieve an observed complete response rate of >56% and if fewer than 30% of patients 
experience a complete response to treatment, then the treatment approach is considered a failure.   
 


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A sample size of 17 was determined assuming a Simon Two-Stage design with a Type I error of 
0.096 and a power of 0.813—given an assumed complete response rate of 56% compared to a 30% 
complete response rate of the treatment population under standard of care (with realization that 
this treatment population excludes favorable subsets of the overall disease population). An 
additional patient will be enrolled to account for potential loss-to-follow-up, etc.   
 
For the experimental treatment, we define failure as an observed complete response rate less than 
30%, and we define the null hypothesis as follows: H0: p0 ≤ 0.30. Under the assumption that 
standard of care in combination with nivolumab will result in an observed complete response rate 
of at least 56%, we define the following alternative hypothesis: H1: p1 ≥ 0.56. Formal calculation 
of the p-value associated with the observed data (as well as calculation of a 90% two-sided 
confidence interval for the complete response rate) will be made using the method outlined by 
Koyama and Chen (2007). 
 
Secondary endpoints 
 
The following secondary endpoints will be descriptive in nature (no formal statistical analyses 
will be conducted.) They are: 
2-year Progression-free survival 
Toxicity/safety 
Overall response rate (CR + PR) 
Duration of response. 
Correlative Analysis: determine immune-related predictors of response to 
nivolumab + EPOCH 
 
 
10.3 ANALYSIS DATASETS 
The primary efficacy analyses will be performed on the Intent-to-treat (ITT) population, which 
will include all subjects who have been enrolled for the study.  
 
 
10.4 DESCRIPTION OF STATISTICAL METHODS 
10.4.1 
GENERAL APPROACH 
 
 
 
To assess efficacy, this study will be guided by a Simon Two-stage design. 
 
The proportion of patients achieving a complete response also will be calculated for the patients 
being treated in this study. This proportion will be formally compared to a null proportion of 30%.  
Calculation of the p-value for the observed data and a two-sided 90% confidence interval will be 
made using the method outlined by Koyama and Chen (2007). 
 
 
10.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 


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The proportion of patients achieving a complete response will be calculated for the patients being 
treated in this study. This proportion will be formally compared to a null proportion of 30%. The 
population proportion for complete response rate and associated p-value and 90% confidence 
intervals for the complete response rate will be calculated at study completion. 
 
 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINTS 
 
Secondary endpoints will be descriptive in nature, and no formal statistical analyses will be 
conducted on them. 
 
Progression-free survival (PFS) will be summarized by the proportion of patients without objective 
or symptomatic progression or death within the first 24 months of therapy.   
 
Overall response rate is defined as complete response rate + partial response rate. 
 
Duration of response is defined as time from first evidence of response until progressive disease 
or death. 
 
Safety and toxicity: Adverse events will be monitored and quantified. 
 
Correlative Analysis will be descriptive in nature and will investigate immune-related predictors 
of response to nivolumab + EPOCH. 
 
 
10.4.4 
SAFETY ANALYSES 
 
Regimen toxicities, as defined by CTCAE v5.0 will be summarized using tables and descriptive 
statistics. 
 
 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
 
The PI will provide a DSM report to the UCCC DSMC on a six-month basis. The DSM report will 
include summaries of minutes taken at monthly meetings, the participants’ demographic 
characteristics, expected versus actual recruitment rates, treatment retention rates, any quality 
assurance or regulatory issues (including a summary of any protocol deviations). 
 
 
10.4.6  
BASELINE DESCRIPTIVE STATISTICS 
 
Demographic data will be compiled for participants in the study at baseline, including age, gender, 
ethnicity, disease status, and comorbid conditions. 
 


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10.4.7 
PLANNED INTERIM ANALYSES  
 
No interim analyses are planned for this study. A stopping rules are described in 4.1. 
 
 
10.4.8 
SAFETY REVIEW 
 
10.4.8.1  
TOXICITY REVIEW 
Data will be monitored continuously, and study will be halted prematurely if at any point 
stopping criteria as described in 4.1 are met. 
 
10.4.8.2  
EFFICACY REVIEW 
A Simon 2 stage design will be used to assess efficacy of the regimen using complete 
response rate as the primary outcome. 
 
 
10.4.9 
EXPLORATORY ANALYSES 
 
Secondary endpoints may lead to exploratory analyses outlined in 10.4.3. 
 
 
10.5 SAMPLE SIZE 
The study will enroll 18 patients. 
 
 
10.6 MEASURES TO MINIMIZE BIAS 
In this non-blinded phase I-II study and outcomes will be assessed by investigators. 
 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
To ensure the privacy and confidentiality of data for this protocol, the data will be stored on a 
restricted access server. Access to the project directory containing the data will be limited to the 
investigators and research staff. Information about data security awareness is promoted through 
user training and education and supplemented by policies and procedures. Password protection 
will be used for all transactions that involve viewing, editing, and analyzing the data or that provide 
access to data fields derived from the original source documents.   
 


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12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality Control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/ resolution. 
 
Following written SOPs, the study monitor will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). 
 
The investigational site will provide direct access to all trial-related sites, source data/ documents, 
and reports for the purpose of monitoring and auditing by the DSMC audit team, and inspection 
by local and regulatory authorities. 
 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 ETHICAL STANDARD  
The PI will ensure that this study is conducted in full conformity with regulations for the Protection 
of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56. ICH 
E6 may also be followed to the extent it has been adopted by and is in accordance with FDA 
regulations. 
 
13.2 INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Colorado Multiple Institutional Review Board (COMIRB) for review and 
approval. Approval of both the protocol and the consent form must be obtained before any subject 
is enrolled. Any amendment to the protocol will require review and approval by COMIRB before 
the changes are implemented to the study. All changes to the consent form will COMIRB 
approved; a determination will be made regarding whether previously consented participants need 
to be re-consented. 
 
13.3 INFORMED CONSENT PROCESS  
The Consent Forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
 


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The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate. 
The final revised IRB/EC-approved Consent Forms must be provided to BMS for review. 
 
Patients must be re-consented to the most current version of the Consent Forms (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/EC policy) 
during their participation in the study. For any updated or revised Consent Forms, the case history 
or clinical records for each patient shall document the informed consent process and that written 
informed consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s study 
file or in the site file and must be available for verification by study monitors at any time. 
 
Consent Form may also include patient authorization to allow use and disclosure of personal health 
information in compliance with the U.S. Health Insurance Portability and Accountability Act 
(HIPAA) of 1996. If the site utilizes a separate Authorization Form for patient authorization for 
use and disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
 
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/ administering study product.  
 
 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent process will be initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of participation will be provided to the participants and their families.  
 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent 
form and ask questions prior to signing. The participants will have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The participant will 
sign the informed consent document prior to any procedures being done specifically for the study.  


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The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
The study allows the inclusion of non-English speaking and non-reading participants. Witnesses 
to these consent processes will be individuals not associated with the trial and will not have a 
conflict of interest. 
 
 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY  
Participant confidentiality is strictly held in trust by the participating PIs, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records (office, clinic, 
or hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the University of Colorado Cancer Center. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry and 
study management systems used by clinical sites and by the University of Colorado Cancer Center 
research staff will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the University of Colorado Cancer Center. 
 
 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
 
Intended Use:  
Samples and data collected under this protocol may be used to assess biomarkers associated with 
response to chemo-immunotherapy. No genetic testing will be performed. 
 


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Storage: 
Access to stored samples will be limited to research personnel only. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. 
 
Disposition at completion of the study:  
Consent will be obtained from all patients for tumor tissue banking. Patients can withdraw consent 
for tumor banking at any time. All stored samples will be sent to the University of Colorado HCTU 
bank. Study subjects who request destruction of samples will be notified of compliance with such 
request and all supporting details will be maintained for tracking. 
 
 
13.5 FUTURE USE OF STORED SPECIMENS  
Data collected for this study will be analyzed and stored within the University of Colorado 
Hematology Clinical Trials Unit. After the study is completed, the de-identified, archived data will 
be transmitted to and stored at the, under the supervision of the primary investigator of Hematology 
Lymphoid Malignancy Tissue Bank (LTB) for use by other researchers including those outside of 
the study. Permission to transmit data to the LTB will be included in the informed consent. 
 
With the participant’s approval and as approved by local IRBs, de-identified biological samples 
will be stored at the LTB with the same goal as the sharing of data with the LTB. These samples 
could be used for research into the causes of PTCL its complications and other conditions for 
which individuals with PTCL are at increased risk, and to improve treatment. The LTB will also 
be provided with a code-link that will allow linking the biological specimens with the phenotypic 
data from each participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, and individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. 
 
When the study is completed, access to study data and/ or samples will be provided through the 
LTB. 
 
 
14 
DATA HANDLING AND RECORD KEEPING  
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and timelines of 
the data reported. 
 
 


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Source Documentation: 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, 
laboratories, and medico-technical departments involved in a clinical trial. 
 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Clinical Monitoring Plan. This includes any protocol data to be entered directly into 
the eCRFs (i.e., no prior written or electronic record of the data) and considered source data. 
 
Source documents that are required to verify the validity and completeness of data entered into the 
eCRFs must not be obliterated or destroyed and must be retained. 
 
The study site must also allow inspection by applicable health authorities. 
 
When clinical observations are entered directly into a study site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. 
 
An acceptable computerized data collection system allows preservation of the original entry of 
data. If original data are modified, the system should maintain a viewable audit trail that shows the 
original data as well as the reason for the change, name of the person making the change, and date 
of the change. 
 
Electronic Case Report Forms (eCRF): 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into an electronic data capture system provided by the 
University of Colorado. 
 
eCRFs are to be completed through use of a Sponsor-Investigator designated EDC system. Sites 
will receive training and have access to a manual for appropriate eCRF completion. The data 
system includes password protection and internal quality checks, such as automatic range checks, 
to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. All eCRFs should be completed by designated, trained site 
staff.   
 


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At the end of the study, any hard copy of patient data received by the investigator for his or her 
site must be stored safely with the study records. Acknowledgement of receipt of the compact disc 
is required. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained 
for recording data for each subject enrolled in the study. Data reported in the eCRF derived from 
source documents should be consistent with the source documents or the discrepancies should be 
explained and captured in a progress note and maintained in the subject’s official electronic study 
record. 
 
Data Quality Assurance: 
The Sponsor-Investigator will be responsible for data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC through use of eCRFs. Site 
will be responsible for data entry into the EDC system. 
 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. System 
backups for data stored by the Sponsor-Investigator and records retention for the study data will 
be consistent with the Sponsor-Investigator’s standard procedures.  
 
14.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of an 
investigational marketing application and until there are no pending or contemplated marketing 
applications or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period, however, if required by local regulations, or institution policies. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the PI when these documents no longer need to be retained.  
 
 
14.3 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or SOP 
requirements. The noncompliance may be either on the part of the subject, the investigator, or the 
study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. These practices are consistent with ICH E6, sections: 
 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
• 5.1 Quality Assurance and Quality Control, section 5.1.1. 
• 5.20 Noncompliance, sections 5.20.1 and 5.20.2. 
 
It is the responsibility of the study team to use continuous vigilance to identify and report 
deviations. Deviations will be reported to the DMSC and IRB according to UCCC DSM plan and 
institutional policy. 
 


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14.4 PUBLICATION AND DATA SHARING POLICY 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH-funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human participants to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include any 
biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 801 of the Food 
and Drug Administration Amendments Act of 2007 requires that all clinical trials be registered in 
a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 
responsibility to register the trial in an acceptable registry, so the research results may be 
considered for publication in ICMJE member journals. The ICMJE does not review specific 
studies to determine whether registration is necessary; instead, the committee recommends that 
researchers who have questions about the need to register err on the side of registration or consult 
the editorial office of the journal in which they wish to publish. 
  
FDAAA mandates that a “responsible party” (i.e., the sponsor or designated PI) register and report 
results of certain “applicable clinical trials”. 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric post-market surveillance 
studies. 
 
 
16 
CONFLICT OF INTEREST POLICY 
Independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed.by the 
University of Colorado Denver’s (UCD) Office of Regulatory Compliance Conflict of Interest and 
Commitment Management (COIC) program. Persons with a perceived conflict of interest will have 
such conflicts managed in a way that is appropriate to their participation in the trial. Conflict of 


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Interest management plans are project-specific and are reviewed at least annually. UCD has 
integrated the institutional conflict of interest management program with its existing program. 
 
 
17  
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Page 1 of 26
Consent and Authorization Form
Principal Investigator:
Bradley Haverkos, MD, MPH, MS 
COMIRB No:
18-0708
Version Date:
10/08/2020
Study Title:
Nivolumab with standard of care chemotherapy for the first 
line treatment of peripheral T cell lymphoma
You are being asked to participate in a research study. A member of the research team will 
explain what is involved in this study and how it will affect you. This consent form 
describes the study procedures, the risks and benefits of participation, as well as how your 
confidentiality will be maintained. Please take your time to ask questions and feel 
comfortable making a decision whether to participate or not. This process is called 
informed consent. If you decide to participate in this study, you will be asked to sign this 
form.
Why is this study being done?
The purpose of this study is to learn more about a combination of the standard 
chemotherapy regimen with one additional drug and how well they might work to treat 
peripheral T cell lymphoma (PTCL). The chemotherapy drugs together are commonly 
called DA-EPOCH and include the following: Etoposide, Prednisone, Vincristine, 
Doxorubicin, and Cyclosphosphamide. ‘DA’ stands for dose-adjusted. The additional drug 
that you will receive is called Nivolumab.
You are being asked to be in this research study because you have been newly diagnosed 
with PTCL.
The drugs in EPOCH regimen are approved by the U.S. Food and Drug Administration 
(FDA) to treat PTCL. Nivolumab is approved by the FDA to treat several different types of 
cancer, including other blood cancers, but is not approved to treat your specific type of 
cancer. This combination is therefore considered to be experimental.
Throughout the rest of this consent form, the DA-EPOCH regimen and Nivolumab will be 
called the “study drugs” when referenced together.
How many people will participate?
Up to 14 people from your area will participate in the study.
Up to 24 people from around the country will participate in the study.
COMIRB
APPROVED
For Use
24-Nov-2020
18-Aug-2021


Consent and Authorization Form
COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 10/08/2020
Page 2 of 26
What happens if I join this study?
If you join the study, you will be asked to sign this consent form. You will be given a copy 
to keep and the original form will be kept at the clinic. You can withdraw from the study at 
any time and without giving a reason. This will not affect the standard medical care you 
receive.
There are 3 parts to the study:
1. Screening (before beginning the study drugs)
2. Induction Phase (attempt to eliminate visible lymphoma in your body)
3. Follow-Up
The next section of this form lists what will be expected of you if you join this study.
Study Procedures
While you are taking part in this study, some of the tests and procedures are the same 
type that would be performed as part of your regular cancer care even if you did not join 
the study. Some of the tests and procedures are required only for the study, and are 
identified below as “research” procedures.
The screening tests and procedures will be done to see if you are eligible to join this study. 
You may have had some of these tests and procedures done recently as standard care for 
your cancer, and they may not need to be repeated.

Informed Consent (Research)
This informed consent form will be discussed with you and you will be given a copy 
of this document. If you join the study, you will be asked to sign this consent form 
before you receive any study related tests or procedures.

Medical and Cancer History (Standard of Care)
Before you start the study we will record your date of birth, race, ethnicity, and 
complete medical history. This history will look at the background and progress of 
your cancer and any treatments you have received for your disease.

Physical Examination (Standard of Care)
A physical examination will be completed as part of your standard of care. We will 
also assess if the study drug is affecting your body functions including lungs, heart, 
abdomen, extremities, skin, head (eyes, ears, nose, hair, etc.) and neurologically.

Vital Signs (Standard of Care)
We will take your blood pressure, heart rate, respiratory rate, body temperature and 
weight. Height will be measured only during screening.


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
Performance Status (Standard of Care)
We will assess how well you are performing your daily activities.

Review of Current Medications (Standard of Care)
Your study doctor will let you know which medications you can and cannot take 
while taking part in this study. From the time you first receive the study drugs 
through 30 days after the last dose, we will record medications you may be taking.

Review of Side Effects (Standard of Care)
Some risks have been identified because of the disease process or through use of 
the study drugs themselves and these will be followed very closely by the Principal 
Investigator and study staff. More information will be provided in the Risks section of 
this consent.

Blood and Urine Samples (Standard of Care)
These tests are sometimes called safety labs so the study doctor can be sure it is 
safe for you to take part in this study and to be given the study drugs.
o
Pregnancy test: Women who are able to become pregnant will be given 
either a urine or a blood pregnancy test. A positive pregnancy test prior to 
being given the study drugs will exclude you from starting or continuing to 
take part in the study. This test must be performed 14 days prior to starting 
treatment.
o
Complete blood count (CBC)
o
Comprehensive metabolic panel (CMP)
o
Blood clotting tests (PT/INR, and PTT)
o
Thyroid function tests (TSH)
o
Creatinine Clearance
o
Testing for HIV (human immunodeficiency virus), HBV (hepatitis B virus), 
HCV (hepatitis C virus), and EBV (Epstein-Barr virus)
o
Urinalysis

Blood Samples (Research)
These tests are being done specifically because you are participating in this study.
o
Blood testing: These tests will be done to understand better how the drug is 
working.

Electrocardiogram (ECG or EKG) (Standard of Care)


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This is a simple, noninvasive procedure that records the electrical activity of the 
heart. Electrodes are placed on the skin of the chest and connected in a specific 
order to a machine. Output usually appears on a long scroll of paper that displays a 
printed graph.

Echocardiogram (ECHO) or Multigated Acquisition (MUGA) Scan (Standard of 
Care)
This is a noninvasive scan of the heart using sound waves. This test will be used to 
see how well your heart pumps blood.

Bone Marrow Biopsy/Aspirate (Standard of Care, if necessary)
At various time points during the study, you will have bone marrow examined. This 
involves placing a hollow needle into your hip bone near the small of your back and 
taking a small sample of the bone (bone marrow biopsy) and 2-3 tablespoons of the 
liquid bone marrow inside the bone (bone marrow aspirate).
If a screening bone marrow biopsy is required, it needs to be done within 6 weeks 
prior to study enrollment. A repeat bone marrow biopsy prior to Cycle 3 would only 
be required to assess response if initial biopsy was positive for disease.

Imaging (CT or MRI) (Standard of Care)
These tests will be performed to check the status of your disease. These tests must 
be performed 4 weeks prior to study enrollment.
o
CT: A computed tomography scan uses x-rays to make detailed pictures of 
parts of the body and the structures inside the body.
o
MRI: Magnetic resonance imaging is a test that uses a magnetic field and 
pulses of radio wave energy to make pictures of organs and structures inside 
the body.

Positron Emission Tomography (PET/CT) Scan (Standard of Care)
Positron emission tomography (PET) scan is a test that uses radioactive glucose 
(sugar) and a computer to create images of how organs and tissues in the body are 
functioning. Abnormal cells in the body use glucose at a different rate than normal 
cells and this allows the scanner to create a detailed picture of how your body is 
working. A PET/CT scan is mandatory before and after treatment. A CT scan may 
be performed in place of a PET/CT scan at other time points during the study, 
depending on your insurance carrier.

Tumor Tissue Samples (Standard of Care)
o
Archived Tissue: If you had surgery for your cancer in the past, you must 
agree to allow us to contact the institution where you had your surgery and 
ask them to send us a portion of your tumor tissue that they have stored so


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Version Date: 10/08/2020
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we may use it for this to confirm your diagnosis of PTCL and for future 
research.
o
Tumor tissue biopsy during screening: If archived tissue is not available, we 
will ask you to allow us to take a fresh biopsy of your tumor tissue prior to 
treatment to confirm your diagnosis and to store it for optional future 
research. This biopsy may be core needle, excisional, or incisional since fine 
needle aspirations are typically inadequate to make a diagnosis of PTCL.

Lumbar Puncture (Standard of Care, if necessary)
A lumbar puncture (spinal tap) is performed in your lower back, in the lumbar 
region. During a lumbar puncture, a needle is inserted between two lumbar bones 
(vertebrae) to remove a sample of cerebrospinal fluid. This is the fluid that 
surrounds your brain and spinal cord to protect from injury. If this procedure is 
required, it will need to be performed 6 weeks prior to starting treatment.

Receiving the Study Drugs
EPOCH regimen (Standard of Care):
You will receive these drugs through an intravenous infusion, using a central 
venous catheter. This involves the insertion of a catheter, or small tube, into a large 
vein in the arm, or into a vein under your collar bone. This may be done under local 
anesthesia. You will receive these drugs over 5 days including a continuous 96 hour 
infusion.
Nivolumab (Research): You will also receive these drugs through an intravenous 
infusion, using a central venous catheter.
Study Visits
Please refer to Study Calendar for schedule of events. In addition, please note the 
following information.
Screening
If screening tests and procedures are performed within 48 hours of Cycle 1 Day 1, routine 
lab testing and physical exams do not need to be repeated.
Induction Cycles
All assessments must be done prior to treatment and may be performed up to 2 days prior 
to treatment.
If after your treatment during the Induction cycles, the PET/CT scan shows evidence of 
disease, a biopsy of that area may be done at the study doctor’s discretion. The PET/CT 
scan should be within 6 weeks of cycle 6 day 1.


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Version Date: 10/08/2020
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End of Treatment
Any subject that has had a PET/CT scan within 21 days of their end of treatment will not 
have to repeat that procedure.
For subjects that choose to have the stem cell transplant after the Induction phase, you will 
undergo a PET/CT scan or CT scan (PET preferred) approximately 3 months after the 
transplant. This will be considered your end of treatment visit for the study.
Follow-Up
The follow-up period starts after the end of treatment visit. Subjects will be contacted via 
phone every 3 months for 2 years for disease status and survival information.
*For subjects who have completed one cycle of chemotherapy prior to joining this study 
please note the following.

These subjects are essentially starting at Cycle 2 of the induction phase.

PET scan normally performed prior to cycle 3 would be performed prior to cycle 4 of 
all chemotherapy.

Imaging must have been performed within 4 weeks of Cycle 1 Day 1 of 
chemotherapy.

Subjects that underwent the following procedures prior to Cycle 1 of standard 
chemotherapy do NOT need to have them repeated:
o
Testing for HIV (human immunodeficiency virus), HBV (hepatitis B virus), 
HCV (hepatitis C virus), and EBV (Epstein-Barr virus)
o
CT/MRI
o
PET scan
o
Bone marrow biopsy/aspirate
o
ECHO or MUGA scan
o
Lumbar puncture


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PI: Bradley Haverkos, MD
Version Date: 09/15/2020
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Induction Treatment with 
Nivolumab + Chemotherapy
Post-Induction
Long 
Term 
Follow- 
Up
Tests and procedures
Screening
≤ 28 days 
prior to 
C1D1; 6 
weeks 
prior for 
PET/CT
C1 – C6
Treatment
Hematology 
between 
Induction 
Cycles
End of 
Induction Visit 
(3-6 weeks 
after C6D1)
Autologous 
Transplant & 
Post- 
Transplant
End of 
Treatment
Medical History, Physical 
Exam and Vital Signs
X
X
X
X
Adverse Events
X
X
X
X
X
Medications
X
X
X
X
X
ECOG Performance Status
X
X
X
Pregnancy Test (blood or 
urine)
X
Tumor tissue sample for 
confirmation of diagnosis 
and research purposes or 
fresh tumor biopsy
X
X
Hematology
X
X
2x per week
X
X
Chemistry
X
X
X
X
Urinalysis
X
X
X
Thyroid Function Tests
X
X
X
X
PT/INR, PTT
X
HIV, HBV, HCV, HTLV
testing
X
EBV PCR (in EBV+ subset)
X
X
X
X
Tumor 
Measurement/Evaluation (CT 
and/or MRI when indicated)
X
Before C3
X
X
X
PET/CT scan
X
Before C3, C4, 
& C6
X
X
Bone marrow aspirate and 
biopsy (unilateral or 
bilateral)
X
Before C3
X
X
Electrocardiogram
X
ECHO or MUGA scan
X


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PI: Bradley Haverkos, MD
Version Date: 09/15/2020
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COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 1/10/2020
Lumbar Puncture
X
X
X
X
Research blood samples
X
Before C2 and
C3
X
X
X
Drug Administration
X
Survival status
X
X
X


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Version Date: 09/15/2020
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How long will I be in the study?
You may continue receiving study drugs for up to 6 cycles (approximately 6 months) and 
be followed every 3 months for the next 2 years.
What are the possible discomforts or risks?
You may have side effects while you are in this study, but you will be carefully checked by 
the study doctor for any problems. There may be risks or side effects of the study 
treatment that are unknown at this time. You should tell the study doctor about anything 
that is bothering you or any side effects you have, even if you do not think they are related 
to the study treatment. Many side effects go away shortly after the medications are 
stopped, but in some cases side effects can be serious, long lasting, or permanent.
Because this treatment is experimental, it is possible that the addition of a new drug, 
nivolumab, to standard of care may make the therapy either more or less effective.
Risks of the Study Drugs
What are the possible discomforts or risks?
You may have side effects while you are in this study, but you will be carefully checked by 
the study doctor for any problems. There may be risks or side effects of the study 
treatment that are unknown at this time. You should tell the study doctor about anything 
that is bothering you or any side effects you have, even if you do not think they are related 
to the study treatment. Many side effects go away shortly after the medications are 
stopped, but in some cases side effects can be serious, long lasting, permanent, or lead to 
death.
Risks of Nivolumab
Most Common:

Fatigue

Pain in Muscles, bones, and joints

Diarrhea

Cough

Constipation

Back pain

Fever

Rash

Itchy Skin

Nausea

Shortness of breath


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Version Date: 10/08/2020
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
Decreased appetite

Upper respiratory tract infection

Weakness 
Less Common:
Lung problems (pneumonitis) Symptoms may include:
• new or worsening cough
• chest pain
• shortness of breath
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and 
symptoms of colitis may include:
• diarrhea or more bowel movements than usual
• blood in your stools or dark, tarry, sticky stools
• severe stomach-area pain or tenderness
Liver problems (hepatitis) Signs and symptoms may include:
• yellowing of your skin or the whites of your eyes
• severe nausea or vomiting
• pain on the right side of your stomach area (abdomen)
• drowsiness
• dark urine (tea colored)
• bleeding or bruising more easily than normal
• feeling less hungry than usual
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas) 
Signs and symptoms may include:
• headaches that will not go away or unusual headaches
• extreme tiredness
• weight gain or weight loss
• dizziness or fainting
• hair loss
• feeling cold
• constipation
• voice gets deeper
• excessive thirst or lots of urine
• changes in mood or behavior, such as decreased sex drive, irritability, or 
forgetfulness
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may 
include:


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• decrease in the amount of urine
• blood in your urine
• swelling in your ankles
• loss of appetite
Skin Problems. Signs of these problems may include:
• rash
• itching
• skin blistering
• ulcers in mouth or other mucous membranes
Inflammation of the brain (encephalitis) Signs and symptoms may include:
• headache
• fever
• tiredness or weakness
• confusion
• memory problems
• sleepiness
• seeing or hearing things that are not really there (hallucinations)
• seizures
• stiff neck
Rare but Serious:
Severe infusion reactions. Tell your doctor or nurse right away if you get these symptoms 
during an infusion of Nivolumab:
o chills or shaking
o itching or rash
o flushing
o difficulty breathing
o dizziness
o fever
o feeling like passing out
Risks of Etoposide
More common

bad, unusual, or unpleasant (after) taste

change in taste

constipation

cracked lips


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PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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
hair loss or thinning of the hair

lack or loss of strength

swelling or inflammation of the mouth

weight loss

black, tarry stools

bleeding gums

blood in the urine or stools

chest pain

chills

cough

fever

painful or difficult urination

pale skin

pinpoint red spots on the skin

shortness of breath

sore throat

sores, ulcers, or white spots on the lips or in the mouth

swollen glands

troubled breathing with exertion

unusual bleeding or bruising

unusual tiredness or weakness 
Less common

blurred vision

confusion

cough or hoarseness, accompanied by fever or chills

difficulty with swallowing

dizziness

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or 
sitting position

face is warm or hot to touch

fast heartbeat

headache

hives, itching, or skin rash

lower back or side pain, accompanied by fever or chills

nervousness

numbness or tingling in the fingers or toes

pain or redness at the site of injection

pale skin at the site of injection


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PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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
pounding in the ears

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

redness to face

slow or fast heartbeat

sweating

tightness in the chest 
Rare

back pain

difficulty with walking

loss of consciousness

swelling of the face or tongue

tightness in the throat
Risks of Doxorubicin
More common

hair loss, thinning of hair

nausea and vomiting

sores in the mouth and on the lips
Less common

cough or hoarseness accompanied by fever or chills

darkening or redness of the skin (if you recently had radiation treatment)

fast or irregular heartbeat

fever or chills

joint pain

lower back or side pain accompanied by fever or chills

pain at the injection site

painful or difficult urination accompanied by fever or chills

red streaks along the injected vein

shortness of breath

stomach pain

swelling of the feet and lower legs

darkening of the soles, palms, or nails

diarrhea


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PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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Rare

black, tarry stools

blood in the urine

pinpoint red spots on the skin

unusual bleeding or bruising
Risks of Vincristine
More common

abdominal or stomach pain

black, tarry stools

bleeding gums

blood in the urine or stools

blurred vision

burning, tingling, numbness or pain in the hands, arms, feet, or legs

change in consciousness

change in muscle reflexes

chest pain

chills

confusion

cough

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or 
sitting position

fever

increased sensitivity to pain or touch

low blood pressure or pulse

lower back or side pain

nerve pain

painful or difficult urination

pale skin

pinpoint red spots on the skin

sensation of pins and needles

severe constipation

severe vomiting

shortness of breath

sneezing

sore throat

stabbing pain


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PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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
sweating

tightness in the chest

troubled breathing

ulcers, sores, or white spots in the mouth

unsteadiness or awkwardness

unusual bleeding or bruising

unusual tiredness or weakness 
Less common

blue lips, fingernails, or skin

irregular, fast or slow, or shallow breathing

Lack or loss of strength

mental depression or anxiety

muscle weakness

nightmares or unusually vivid dreams
Risks of Prednisone
More common

aggression

agitation

blurred vision

decrease in the amount of urine

dizziness

fast, slow, pounding, or irregular heartbeat or pulse

headache

irritability

mood changes

noisy, rattling breathing

numbness or tingling in the arms or legs

pounding in the ears

shortness of breath

swelling of the fingers, hands, feet, or lower legs

trouble thinking, speaking, or walking

troubled breathing at rest

weight gain
Risks of Cyclophosphamide


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Version Date: 10/08/2020
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More common

cough or hoarseness

fever or chills

lower back or side pain

missing menstrual periods

painful or difficult urination

darkening of the skin and fingernails

loss of appetite

nausea or vomiting 
Less common

black, tarry stools

pinpoint red spots on the skin

unusual bleeding or bruising

diarrhea

flushing or redness of the face

headache

increased sweating

skin rash, hives, or itching

stomach pain

swollen lips 
Rare

frequent urination

redness, swelling, or pain at the injection site

sores in the mouth and on the lips

sudden shortness of breath

unusual thirst

yellow eyes or skin
Risks of the Study Procedures
Blood collection
Blood sampling and needle punctures carry some risk. Possible side effects include, but 
are not limited to, fainting, bleeding, bruising, discomfort, dizziness, infection and/ or pain 
at the puncture site.


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Version Date: 10/08/2020
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Having an IV inserted in your vein
In this study we will insert a needle, connected to a plastic tube, into a vein in your arm. 
We will use the tube to take blood samples or give you fluids. You will feel some pain when 
we first insert the tube into your vein. You may have some redness, swelling, or bruising 
where the tube goes under your skin. In some cases, this type of tube can cause an 
infection where it goes under the skin. In rare cases, it can cause a blood clot in the vein.
You will have this tube inserted for about four or five hours.
Bone marrow biopsy
In this study we will take four samples of bone marrow from your pelvic bone. Before we 
take each sample, we will give you some numbing medication on the skin outside your 
pelvic bone (on your hip). After your skin is numb, we will push a special needle into the 
center of your pelvic bone. Then, we will draw the bone marrow up into the syringe. When 
we do this, you will have a pulling feeling as the marrow leaves the bone and goes into the 
syringe. The area around the bone will be sore for a few days. There is a very small 
chance that you will be allergic to the numbing medicine. There is also a very small chance 
that you could bleed or develop an infection.
Tumor biopsy
In this study, an additional biopsy may be required from you. There are some risks to 
taking a biopsy. There is a small chance that you could get an infection where the needle 
goes in. You may also experience redness, swelling, minor bleeding or bruising at the site 
where the cut was made or the needle inserted. You may experience mild to moderate 
pain at the site of the needle puncture. There is also a small chance that you could have 
an allergic reaction to the numbing medicine. After your skin heals up, you may have a 
small scar where we take the samples. If an X-ray is used to help place the needle, you 
will be exposed to additional radiation. The amount of radiation you receive during each 
biopsy procedure is approximately equal to the radiation you would receive in about 4 
years in your normal environment.
There may be some additional risks, depending on where your tumor is located. If you 
have a biopsy of a solid organ, like your liver or a kidney, or of a lymph node, there is a risk 
of pain, bleeding, and infection. There is a risk of damage to nearby structures or organs. 
There is a risk of injury due to positioning of the needle and a small risk of heart or lung 
problems. If you have a lung biopsy, there is a risk of air getting into the space around your 
lung that would require a tube to be placed in between your ribs to draw the air out. If this 
tube is placed, some additional risks include damage to other nearby structures, including 
the lung, a prolonged air leak, and a possible need for additional tubes or procedures. 
There is a small risk of death from complications of a biopsy.


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Electrocardiogram (EKG)
An electrocardiogram (EKG) is a test that records the electrical activity of the heart. Skin 
irritation is rare but could occur during an EKG from the electrodes or the gel that is used.
Imaging (PET, CT scans)
Procedures such as CT scans, X-rays and/or radioactive drugs will be used during this 
research study to see how you are doing. The cumulative radiation exposure from these 
tests is considered small and is not likely to adversely affect you or your disease. However, 
the effects of radiation add up over a lifetime. It is possible that having several of these 
tests may add to your risk of injury or disease. When deciding to enter this study, think 
about your past and future contact with radiation. Examples of contact with radiation 
include x-rays taken for any reason or radiation therapy for cancer treatment.
MRI
Some people cannot have an MRI because they have some type of metal in their body. 
For instance, if you have a heart pacemaker, artificial heart valves, metal implants such as 
metal ear implants, bullet pieces, chemotherapy or insulin pumps or any other metal such 
as metal clips or rings, they cannot have an MRI. During this test, you will lie in a small 
closed area inside a large magnetic tube. Some people are scared or anxious in small 
places (claustrophobic). The MRI scanner makes loud banging noises while taking a 
measurement, so either ear plugs or specially designed headphones will be used to 
reduce the noise.
Lumbar Puncture

Post-lumbar puncture headache. Up to 25 percent of people who have 
undergone a lumbar puncture develop a headache afterward due to a leak of fluid 
into nearby tissues.
The headache typically starts several hours up to two days after the procedure and 
may be accompanied by nausea, vomiting and dizziness. The headaches are 
usually present when sitting or standing and resolve after lying down. Post-lumbar 
puncture headaches can last from a few hours to a week or more.

Back discomfort or pain. You may feel pain or tenderness in your lower back after 
the procedure. The pain might radiate down the back of your legs.

Bleeding. Bleeding may occur near the puncture site or, rarely, into the epidural 
space.

Brainstem herniation. Increased pressure within the skull (intracranial), due to a 
brain tumor or other space-occupying lesion, can lead to compression of the 
brainstem after a sample of cerebrospinal fluid is removed.


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PI: Bradley Haverkos, MD
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A computerized tomography (CT) scan or MRI prior to a lumbar puncture can be 
obtained to determine if there is evidence of a space-occupying lesion that results in 
increased intracranial pressure. This complication is rare.
Reproductive Risks
While participating in this research study, you should not become pregnant, nurse a baby, 
or father a baby. Both men and women who are able to have children must use a highly 
effective means of birth control approved by your study doctor.
If you are a female who has stopped having menstrual periods for at least 1 year 
(menopause), please discuss with your study doctor the need for birth control. If you 
become pregnant, you must stop taking the study drugs at once and notify your doctor 
immediately. You will not be allowed to continue in the study. You may be asked 
questions about the outcome of your pregnancy and the baby.
You must continue the use of birth control during the entire time of your study participation 
and to at least 5 months after the last dose of nivolumab.
Risk of Loss of Confidentiality
There is a risk that people outside the research team will see your research information. 
We will do all that we can to protect your information, but it cannot be guaranteed.
There may be other risks that could arise which are not reasonably foreseeable. If new 
information becomes available which could influence your willingness to continue, this new 
information will be discussed with you.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about a combination of the standard 
chemotherapy regimen with an additional drug (Nivolumab). However, there is no guarantee that your 
health will improve if you join this study. Also, there could be risks to being in this study. If there are 
risks, these are described in the section describing the discomforts or risks.
Are there alternative treatments?
There may be other ways of treating your cancer. Instead of taking part in this study:

You may choose to receive treatment with an approved therapy.

You may choose to participate in a different study with another experimental drug.

You may choose to receive comfort/ palliative care.

You may choose to get no treatment at all.
You should talk to your doctor about your choices. Make sure you understand all of your 


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COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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choices before you decide to take part in this study. You may leave this study and still 
have these other choices available to you.
Who is paying for this study?
Bristol Meyers Squibb (BMS) is providing a grant of funding support for this study. BMS 
manufactures the study drug, Nivolumab, and will provide this drug for the study. This 
research is being conducted by Dr. Bradley Haverkos. The research study will only pay for 
procedures not considered standard of care.
Three of the investigators in this study, Dr. Tomer, Dr. Forsberg, and Dr. Pollyea, have a 
financial interest with Celgene Corporation (affiliated with Bristol Myers Squibb 
Pharmaceutical). Bristol Myers Squibb Pharmaceutical is the manufacturer of Nivolumab. Dr. 
Tomer and Dr. Forsberg are speakers for the company, and Dr. Pollyea is an advisory board 
member. Please feel free to ask any questions you may have about this matter.
Will I be paid for being in the study?
You will not be paid to be in the study.
Will I have to pay for anything?
The drug manufacturer, BMS, will pay for the cost of the study drug, Nivolumab. The 
funding for this study will also pay for any tests or procedures that are related to the 
research study.
The study drug regimen DA-EPOCH is considered standard treatment for your type of 
cancer. This drug will be obtained through your insurance, and you will be responsible for 
any applicable copays required by your insurance policy.
There are some medical procedures that you would get for your condition whether you were 
in this study or not, such as routine blood draws, imaging, drugs for the EPOCH regimen, 
and administration of nivolumab. These are considered standard of care. You and/or your 
health insurance may be billed for the costs of medical care during this study if these 
expenses are related to standard of care procedures. If you have health insurance, the cost 
of these services will be billed to your insurance company. If your insurance does not cover 
these costs, or you do not have insurance, these costs will be your responsibility.
Ask your study doctor to discuss the costs that will or will not be covered by this research 
study. This discussion should include the costs of treating possible side effect. Otherwise, 
you might have unexpected expenses from being in this study.
Is my participation voluntary?
Taking part in this study is voluntary. You have the right to choose not to take part in this 
study. If you choose to take part, you have the right to stop at any time. If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled.


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COMIRB #18-0708
PI: Bradley Haverkos, MD
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If you leave this study, you will still receive your normal medical care. The only medical 
care that you will lose is the medical care you are getting as part of this study. You might 
be able to get that same kind of medical care outside of the study. Ask your study doctor.
Can I be removed from this study?
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason.
What happens if I am injured or hurt during the study?
If you have an injury while you are in this study, you should call Dr. Haverkos immediately. 
His phone number is720-848-8698 (office hours) or 720-848-0000 (24-hour contact number, 
and ask for HEME BMT Attending on-call).
We will arrange to get you medical care if you have an injury that is caused by this 
research. However, you or your insurance company will have to pay for that care.
Who do I call if I have questions?
The researcher carrying out this study is Bradley Haverkos, MD. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may call 
Dr. Haverkos at 720-848-8698 (office hours) or 720-848-0000 (24-hour contact number, and 
ask for HEME BMT Attending on-call). You will be given a copy of this form to keep.
You may have questions about your rights as someone in this study. You can call Dr. 
Haverkos with questions. You can also call the responsible Institutional Review Board 
(COMIRB). You can call them at 303-724-1055.
A description of this clinical trial will be available on http://www.Clinical Trials.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.
Optional Consent for Specimen Banking for Future Research
Dr. Haverkos would like to keep some blood, tissue from biopsies, and/or archived tissue 
that was taken during previous biopsy procedures. If you agree, the samples will be kept 
and may be used in future research to learn more about cancer. The research that is done 
with your samples is not designed to specifically help you. It might help people who have 
cancer and other diseases in the future. Reports about research done with your samples 
will not be given to you or your doctor. These reports will not be put in your health records. 
The research using your samples will not affect your care.


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PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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The choice to let Dr. Haverkos keep the tissue samples for future research is up to you. No 
matter what you decide to do, it will not affect the care that you will receive as part of the 
study. If you decide now that your samples can be kept for research, you can change your 
mind at any time and contact your study doctor to let him know that you do not want Dr.
Haverkos to use your samples any longer, and they will no longer be used for research. 
Otherwise, they may be kept until they are used up, or until Dr. Haverkos decides to 
destroy them.
When your samples are given to other researchers in the future, Dr. Haverkos will not give 
them your name, address, phone number or any other information that will let the 
researchers know who you are.
Sometimes samples are used for genetic research (about diseases that are passed on in 
families). If your samples are used for this kind of research, the results will not be told to 
you and will not be put in your health records. Your samples will only be used for research 
and will not be sold. The research done with your samples may help to develop new 
products in the future, but there is no plan for you to be paid.
We may share data from our research with other researchers or data banks. One such 
data bank is called dbGAP, which collects genetic and other data and is sponsored by the 
National Institutes of Health. By broadly sharing data in data banks like this, we can make 
our discoveries more accessible to other researchers. Information which directly identifies 
you will not be sent to these data banks.
Because your genetic information is unique to you, there is a small risk that someone 
could connect the information back to you. Also, genetic research and broadly sharing data 
may involve risks to you or people like yourself that are unknown at this time.
The possible benefits of research from your samples include learning more about what 
causes cancer and other diseases, how to prevent them and how to treat them. The 
greatest risk to you is the release of your private information. Dr. Haverkos will protect your 
records so that your name, address and phone number will be kept private. The chance 
that this information will be given to someone else is very small. There will be no cost to 
you for any data or sample collection and storage by Dr. Haverkos.
Please read each sentence below and think about your choice. After reading each 
sentence, circle “yes” or “no.” If you have questions, please talk to your doctor or nurse. 
Remember, no matter what you decide to do about the storage and future use of your 
samples, you may still take part in the study.


Consent and Authorization Form
COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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I give my permission for my blood and tissue to be stored in a central tissue bank for future 
use by the study investigators:
1. I give my permissions for my blood and tissue samples to be kept by Dr. 
Haverkos for use in future research to learn more about how to prevent, 
detect, or treat lymphoma.
Yes
No
 
Initials
2. I give my permissions for my blood and tissue samples to be used for 
research about other health problems (for example: causes of heart 
disease, osteoporosis, diabetes).
Yes
No
 
Initials
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you. Federal and state laws including the Health Insurance Portability 
and Accountability Act (HIPAA) also protect your privacy. This part of the consent form 
tells you what information about you may be collected in this study and who might see or 
use it.
The institutions involved in this study include:

University of Colorado Denver

University of Colorado Hospital

Thomas Jefferson University

City of Hope Hospital
We cannot do this study without your permission to see, use and give out your information. 
You do not have to give us this permission. If you do not, then you may not join this study.
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the UCD and its affiliate hospitals 
may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information 
but confidentiality cannot be guaranteed.
The use and disclosure of your information has no time limit. You can cancel your 


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COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below. If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected. Your cancellation would not affect 
information already collected in this study.
Bradley Haverkos, MD 
Anschutz Medical Campus 
1665 N. Aurora Court
Mail Stop F754 
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information, such as:

Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB).

The study doctor and the rest of the study team.

Bristol Meyers Squibb, Inc., manufacturer of Nivolumab who is also providing a 
grant of funding support.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all 
of the rules for research.
We might talk about this research study at meetings. We might also print the results of this 
research study in relevant journals. But we will always keep the names of the research 
subjects, like you, private.
You have the right to request access to your personal health information from the 
Investigator.
Information about you that will be seen, collected, used and disclosed in this study:

Name and demographic information (age, sex, ethnicity, address, phone number, 
etc.

Portions of your previous and current medical records that are relevant to this study, 
including but not limited to diagnosis(es), history and physical, laboratory or tissue 
studies, radiology studies, procedure results.

Research visit and research test records.

Tissue samples and the data with the samples.

Billing or financial information.


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COMIRB #18-0708
PI: Bradley Haverkos, MD
Version Date: 10/08/2020
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What happens to Data, Tissue, Blood and Specimens that are collected in this 
study?
Scientists at the University of Colorado Denver and the hospitals involved in this study 
work to find the causes and cures of disease. The data, tissue, blood and specimens 
collected from you during this study are important to this study and to future research. If 
you join this study:

The data, tissue, blood, or other specimens given by you to the investigators for 
this research no longer belong to you.

Both the investigators and any sponsor of this research may study your data, 
tissue, blood, or other specimens collected from you.

If data, tissue, blood, or other specimens are in a form that identifies you, UCD 
or the hospitals involved in this study may use them for future research only with 
your consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not 
belong to you.

There is no plan for you to receive any financial benefit from the creation, use or 
sale of such a product or idea.
HIPAA Authorization for Optional Additional Study Procedures –In this form, you 
were given the option to agree to additional, optional research procedures. You must 
also give us your permission, under HIPAA rules, to use and disclose the information 
collected from these optional procedures, as described above.
Some of these optional procedures may involve genetic testing or the use of your 
genetic information. Your genetic information will not be released to others. If you 
decline to give us permission to use and disclose your information, you cannot take 
part in these optional procedures, but you can still participate in the main study. Please 
initial next to your choice:
 
I give permission for my information, from the optional procedures I have agreed 
to above, to be used and disclosed as described in this section.
 
I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.
Agreement to be in this study and use my data
The research project and the procedures associated with it have been explained to me. 


C o nse nt a n d A ut h oriz ati o n F or m
C O MI R B # 1 8- 0 7 0 8
PI: Br a dl e y H a v er k o s, M D
V er si o n D at e: 1 0/ 0 8/ 2 0 2 0
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