Phase 2 Single-Arm, Open-Label Study of Nivolumab in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)
Phase: PHASE2
Conditions: Blastic Plasmacytoid Dendritic Cell Neoplasm, Hepatosplenic T-Cell Lymphoma, HTLV-1 Infection, NK-Cell Lymphoma, Unclassifiable, Primary Systemic Anaplastic Large Cell Lymphoma, ALK-Negative, Recurrent Adult T-Cell Leukemia/Lymphoma, Recurrent Anaplastic Large Cell Lymphoma, Recurrent Angioimmunoblastic T-cell Lymphoma, Recurrent Enteropathy-Associated T-Cell Lymphoma, Recurrent Mycosis Fungoides, Refractory Adult T-Cell Leukemia/Lymphoma, Refractory Anaplastic Large Cell Lymphoma, Refractory Angioimmunoblastic T-cell Lymphoma, Refractory Enteropathy-Associated T-Cell Lymphoma, Refractory Mycosis Fungoides, Refractory Nasal Type Extranodal NK/T-Cell Lymphoma, Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified
Sponsor: Mayo Clinic



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Table of Contents 
MC1681: Phase 2 Single-Arm, Open-Label Study of Nivolumab in Patients with Relapsed or 
Refractory Peripheral T-cell Lymphoma (PTCL) ............................................................................ 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ......................................................................................................................... 5 
2.0 
Goals ................................................................................................................................. 11 
3.0 
Patient Eligibility .............................................................................................................. 13 
4.0 
Test Schedule .................................................................................................................... 16 
5.0 
Stratification Factors: None .............................................................................................. 18 
6.0 
Registration Procedures .................................................................................................... 18 
7.0 
Protocol Treatment ........................................................................................................... 20 
8.0 
Dose Delay Criteria Based on Adverse Events ................................................................. 21 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 25 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................... 26 
11.0 
Treatment Evaluation ........................................................................................................ 40 
12.0 
Descriptive Factors ........................................................................................................... 43 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 43 
14.0 
Body Fluid Biospecimens ................................................................................................. 45 
15.0 
Drug Information .............................................................................................................. 48 
16.0  
Statistical Considerations and Methodology .................................................................... 51 
17.0  
Pathology Considerations/Tissue Biospecimens .............................................................. 57 
18.0 
Records and Data Collection Procedures .......................................................................... 60 
19.0 
Budget ............................................................................................................................... 61 
20.0 
References ......................................................................................................................... 62 
Appendix I 
ECOG Performance Status ............................................................................................... 63 
Appendix II 
Adverse Event Management Algorithms .......................................................................... 64 
Appendix III 
Specimen Checklist and Shipping Instructions ................................................................. 71 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD, CR2, PR2 
 
 
 
 
 
 
 
 
PD3 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length initial treatment (first 8 cycles): 14 days  
Cycle length continuation treatment (beginning with Cycle 9): 28 days 
2PET-CT based response criteria: Stable Disease (SD), CR – complete response, PR – partial response 
(See Section 11.0) 
3PET-CT based response criteria. Progressive disease (PD) (See Section 11.0). PET confirmation of PD is 
per physician discretion.  
 
 
Generic name: Nivolumab 
Brand name(s): Opdivo® 
Mayo Abbreviation: BMS936558  
Availability: Mayo Cancer Center Pharmacy 
 
Registration 
Nivolumab: initial treatment x 8 cycles1 
Progressive Disease3 
at any time 
Unacceptable adverse  
Event 
Events  
Monitoring 
Patient refusal 
per Section 4.2 
Observation2 
Nivolumab: continue treatment1 
(2 years maximum) 
Event Monitoring 

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1.0 
Background 
1.1 
Disease Background 
Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative 
malignancies with differing patterns of behavior and responses to treatment. Like 
Hodgkin’s lymphoma (HL), NHL usually originates in lymphoid tissues and can spread 
to other organs. NHL, however, is much less predictable than HL and has a far greater 
predilection to disseminate to extranodal sites. The prognosis depends on the histologic 
type, stage, and treatment. The NHLs can be divided into two prognostic groups: the 
indolent lymphomas and the aggressive lymphomas. In Western populations the majority 
of NHL (~85%) are of B-cell origin. 
Approximately 12-15% of the NHL that are not classified as B-cell in origin are T-cell 
and natural killer (NK) cell in origin. Within these malignancies, two broad groups can be 
defined, the precursor or pre-thymic lymphomas (e.g. lymphoblastic lymphoma) and the 
post-thymic lymphomas or peripheral NK/T-cell lymphomas (PTCLs). In the World 
Health Organization (WHO) Classification, the PTCLs can be further subdivided into 
predominantly leukemic, extranodal, and nodal types. Studies in recent years have 
confirmed that lymphomas of the T-cell phenotype have a poorer prognosis than do B-
cell lymphomas (Vose, Armitage et al. 2008). 
To date, CHOP or CHOP-like chemotherapy has constituted the most prevalent approach 
to the treatment of PTCLs. However, except for ALK-positive ALCL, this approach has 
been disappointing both in terms of the response rate and the durability of response. More 
intensive chemotherapy regimens and stem cell transplantation have been studied, 
however patient numbers have been small and the populations heterogeneous; none of 
these approaches have been confirmed to improve outcome in PTCL patients(O'Connor, 
Bhagat et al. 2014). 
In the relapsed and refractory setting, Gemcitabine has been explored both as a single 
agent and in combination. As a single agent in the relapsed setting, it was associated with 
a 51% overall response rate (ORR) with 23% complete responses (CR)(Zinzani, 
Venturini et al. 2010). Bendamustine, as a single agent, was associated with a similar 
ORR (50%) and CR (28%) with short duration of response (DOR) at 3.5 months and 
overall survival (OS) of only 6.2 months(Damaj, Gressin et al. 2013). Despite reasonable 
response rates, the duration of benefit with traditional chemotherapy has been short. 
A number of novel approaches to the treatment of PTCL have recently been reported, 
including treatment with nucleoside analogues, histone deacetylase (HDAC) inhibitors, 
novel anti-folates and immunotherapy. Pralatrexate, a novel anti-folate, has been reported 
to produce durable complete remissions in patients with PTCL. An ORR of 29% was 
observed in patients with relapsed/refractory T-cell lymphomas enrolled in the PROPEL 
Phase II trial(O'Connor, Pro et al. 2011), with 11% CR. Though the median progression 
free survival (PFS) was short (3.5 months), the median DOR was prolonged at 10.1 
months. A similar overall response rate of 25% has been reported with single agent 
treatment with the HDAC inhibitor, romidepsin, in patients with relapsed PTCL. The CR 
rate was 15% with prolonged median DOR of 17 months(Coiffier, Pro et al. 2012). 
Similar results were seen with belinostat, another HDAC inhibitor(O'Connor, Horwitz et 
al. 2015). Pralatrexate, romidepsin and belinostat have received FDA approval for the 
treatment of PTCL in the relapsed/refractory setting. Multiple combination trials are 
ongoing.  

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Immunotherapy with alemtuzumab has shown activity in relapsed/refractory PTCL and 
early results of studies of alemtuzumab reported with ORR of 35% with 14% CR in a 
small study. Immunotoxin therapy with denileukin difitox has also shown promise with a 
reported ORR of 48% with 22% CRs(Lunning, Moskowitz et al. 2013). Despite the initial 
promise of these novel approaches, the duration of clinical benefit has been short and the 
outlook for patients with PTCL remains grim. There is therefore clearly a need for 
additional novel approaches. Emerging data with different checkpoint inhibitors, 
particularly PD-1 blockers, in various hematologic malignancies showed activity, which 
was particularly impressive in HL(Berger, Rotem-Yehudar et al. 2008; Ansell, Lesokhin 
et al. 2015). In a small number of PTCL patients treated with PD-1 blockade, responses 
were seen. 
Hematologic malignancies are unique in that the tumor is itself constituted by cells of the 
immune system. They are attractive targets for immune checkpoint blockade given the 
demonstrated curative potential of other adoptive immune strategies, such as allogeneic 
stem cell transplant. Lymphoid malignancies have previously demonstrated significant 
responsiveness to immunologic manipulations.  
The tumor microenvironment in lymphoid malignancies is characterized by a vast 
inflammatory cell infiltrate consisting of both T helper and regulatory cells. Despite this 
immune cell infiltrate, there is lack of host mediated antitumor effect. Program death 
ligands (PDL) 1 and 2 inhibit T cell activity by interacting with program death receptor 1 
(PD-1) on T cells, which provides lymphoma cells a mechanism to evade immune 
surveillance. Nivolumab, a fully human IgG4 monoclonal antibody which blocks PD-1 
receptor restoring the cancer fighting ability of T cells, was first approved by the FDA in 
metastatic or unresectable melanoma. In a phase I study of 23 heavily pretreated patients 
with relapsed/refractory HL, nivolumab demonstrated promising activity: ORR 87%, CR 
17%, and 24-month PFS of 86%. The most common toxicities included rash (22%), 
thrombocytopenia (17%), stomatitis (13%), increased serum lipase (13%) and 
lymphopenia (13%), which were all manageable without any reports of grade 4 or 5 
events(Ansell, Lesokhin et al. 2015).  
To assess the effect of PD-1 blockade in hematologic malignancies other than cHL, a 
phase 1 dose escalation study of nivolumab in patients with relapsed or refractory 
lymphoid malignancies has been completed and was recently presented. The patients 
included 27 patients with multiple myeloma, 29 with B-cell non-Hodgkin lymphoma (13 
with DLBCL/PMBCL, 10 with FL, 8 other B cell NHL), 23 patients with T-cell 
lymphoma (13 with mycosis fungoides, 5 with peripheral T-cell lymphoma NOS and 5 
with other T cell lymphomas), and 1 patient with chronic myelogenous leukemia (CML). 
Responses were seen in 4 of 10 DLBCL patients (including 1 CR), and 4 of 10 FL 
patients (including the other CR of the study). The only other responses seen were PR in 
2 of 13 (15%) patients with mycosis fungoides and 2 of 5 (40%) patients with PTCL 
NOS(Lesokhin, Ansell et al. 2014). Due to this signal of activity in PTCL, we propose to 
study the efficacy of nivolumab in relapsed and refractory PTCL patients in the current 
study. 
1.2 
Treatment 
1.21 
Nivolumab Background and Associated Known Toxicities 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets 
the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell 
surface membrane receptor. PD-1 is a negative regulatory molecule expressed by 

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activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed 
death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands 
promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. Nivolumab was expressed in Chinese hamster 
ovary (CHO) cells and is produced using standard mammalian cell cultivation 
and chromatographic purification technologies. The clinical study product is a 
sterile solution for parenteral administration. Nivolumab is approved for use in 
multiple countries including the United States (US, Dec-2014), the European 
Union (EU, Jun-2015), and Japan (Jul-2014). 
1.22 
Nonclinical Studies  
Nivolumab has been shown to bind specifically to the human PD-1 receptor and 
not to related members of the CD28 family(Wang, Thudium et al. 2014). 
Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, 
resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release 
in vitro(McDermott and Atkins 2013). Nivolumab binds with high affinity to 
activated human T-cells expressing cell surface PD-1 and to cynomolgus monkey 
PD-1(Wang, Thudium et al. 2014). In a mixed lymphocyte reaction (MLR), 
nivolumab promoted a reproducible concentration-dependent enhancement of 
IFN- γ release(Wang, Thudium et al. 2014). In intravenous (IV) repeat-dose 
toxicology studies in cynomolgus monkeys, nivolumab was well tolerated at 
doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 
mg/kg, administered twice weekly for 27 doses. While nivolumab alone was well 
tolerated in cynomolgus monkeys, combination studies have highlighted the 
potential for enhanced toxicity when combined with other immunostimulatory 
agents(Wang, Thudium et al. 2014). 
In addition, an enhanced pre- and postnatal development (ePPND) study, 
nivolumab was administered twice weekly at 10 or 50 mg/kg to pregnant 
cynomolgus monkeys from gestational day (GD) 20 to 22 until parturition. 
Nivolumab was well tolerated at both doses, and there were no nivolumab-related 
effects on viability, clinical signs, food consumption, body weights, 
immunological endpoints, or clinical/anatomic pathology parameters in these 
females throughout the study. However, in the offspring, maternal nivolumab 
administration at both doses was associated with fetal/neonatal mortality 
characterized by: 1) dose-dependent increases in third trimester fetal losses 
(12.5% and 33.3% at 10 and 50 mg/kg, respectively, relative to 7.1% in controls), 
which occurred predominantly after GD 120; and 2) increased neonatal mortality 
at 10 mg/kg, which was noted in 3 infants with extreme prematurity during the 
first 2 postnatal weeks. The cause(s) of these fetal losses and infant prematurity 
could not be determined. There were no premonitory signs of pregnancy 
complications or developmental abnormalities observed in affected dams or their 
offspring. Although infants were exposed to nivolumab at levels similar to their 
mothers, there were no gross or microscopic lesions clearly attributable to 
nivolumab. Although the cause of these pregnancy failures was undetermined, 
nivolumab-related effects on pregnancy maintenance is consistent with the 
established role of PD-L1 in maintaining fetomaternal tolerance in mice(Habicht, 
Dada et al. 2007). In these models, maternal regulatory T cells are thought to be 
the principal mediators of fetal tolerance via suppression of autoimmune 
reactions directed towards the fetus. PD-1 signaling can support placental 
expansion of regulatory T cells and/or suppress effector T cell function. 

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Abrogation of PD-1 signaling (eg, PD-L1 knockout, nivolumab administration, 
etc) may eliminate the suppressive activity of regulatory T cells in the placenta, 
resulting in increased inflammatory reactions towards the fetus and associated 
decreased fetal survival rates(Habicht, Dada et al. 2007).  
1.23  
Effects in Humans  
The PK, clinical activity, and safety of nivolumab have been assessed in subjects 
with non-small cell lung cancer (NSCLC), melanoma, and clear-cell renal cell 
carcinoma (RCC) in addition to other tumor types. Clinical activity and safety 
information was obtained from Phase 2/3 studies (CA209063, CA209017, 
CA209057, ONO-4538-05, and ONO-4538-06) in subjects with advanced or 
metastatic squamous (SQ) and nonsquamous (NSQ) NSCLC, Phase 2/3 studies 
(CA209037, CA209066, CA209067, and CA209069) in subjects with 
unresectable or metastatic melanoma, and a Phase 2 study (CA209010) in 
subjects with advanced or metastatic clear-cell RCC. Data are also provided from 
Phase 1 studies MDX1106-03, CA209012, CA209016, and CA209039 and from 
Phase 1 safety cohort of CA209143. Nivolumab is being investigated both as 
monotherapy and in combination with chemotherapy, targeted therapies, and 
other immunotherapies. 
Nivolumab is approved in multiple countries including the US for treatment of 
previously treated, unresectable or metastatic melanoma and previously treated, 
metastatic squamous NSCLC, the EU for treatment of previously treated, 
unresectable or metastatic melanoma, and Japan for treatment of unresectable 
melanoma.  
1.24 
Clinical Pharmacokinetics  
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose 
range of 0.1 to 10 mg/kg administered as a single dose or as multiple doses of 
nivolumab every 2 or 3 weeks. The geometric mean (% CV%) clearance (CL) 
was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state 
(Vss) was 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) was 
26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 
weeks when administered at 3 mg/kg Q2W, and systemic accumulation was 
approximately 3-fold. The exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The 
clearance of nivolumab increased with increasing body weight. The PPK analysis 
suggested that the following factors had no clinically important effect on the CL 
of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK 
analysis suggested no difference in CL of nivolumab based on age, gender, race, 
tumor type, baseline tumor size, and hepatic impairment.  
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body 
weight, and mild hepatic impairment had an effect on nivolumab CL, the effect 
was not clinically meaningful. When nivolumab is administered in combination 
with ipilimumab, the CL of nivolumab was increased by 24%, whereas there was 
no effect on the clearance of ipilimumab. Additionally, PPK and exposure 
response analyses have been performed to support use of 240 mg Q2W dosing in 
addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of 
nivolumab at 240 mg flat dose was identical to a dose of 3 mg/kg for subjects 
weighing 80 kg, which was the approximate median body weight in nivolumab 
clinical trials.  

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The regimen of nivolumab 480 mg Q4W, either as the starting therapy or as 
maintenance treatment following nivolumab 240 mg Q2W, is currently being 
evaluated in multiple clinical studies. As of Sep 2016, 4 patients in the 
nivolumab clinical development programs have received nivolumab 480 mg 
Q4W for at least 1 dose. There have been no new safety signals identified during 
routine clinical and pharmacovigilance monitoring of these studies. Clinical 
evaluation of this dose regimen is in its early stages, as such PK, immunogenicity 
or summary of safety information are not currently available.  
In study CA209522, nivolumab 480 mg Q4W is to be administered in the 
maintenance phase following nivolumab 240 mg Q2W for 8 dose as a more 
convenient dosing schedule for patients without compromising safety or efficacy. 
Nivolumab 480 mg Q4W has been selected based on clinical data and modeling 
and simulation approaches using population PK (PPK) and exposure-response 
analyses of data from studies in multiple tumor types (melanoma, non-small-cell 
lung cancer, and renal cellcarcinoma). Using an updated PPK model that 
incorporated a time-varying clearance, nivolumab 480 mg Q4W is predicted to 
provide average steady state concentrations (Cavgss) similar to nivolumab 3 
mg/kg Q2W. Nivolumab 480 mg Q4W is predicted to provide greater 
(approximately 40%) maximum steady state concentrations (Cmaxss) and lower 
(approximately 20%) trough steady state concentrations (Cminss). Nivolumab 
has been shown to be safe and well tolerated up to doses of 10 mg/kg Q2W and 
has not demonstrated a clear dose response or exposure-response relationships. 
Based on these safety findings, the predicted Cmaxss at 480 mg Q4W (Figure 1) 
are not considered to put subjects at increased risk for AEs, because they are 
predicted to be lower and within the exposure ranges observed following 
nivolumab 10 mg/kg Q2W. The approved dose of 3 mg/kg Q2W has shown 
survival benefit across multiple tumor types compared to respective standards of 
care. Nivolumab exposure was not a predictor of survival in exposure-response 
analyses conducted for multiple tumor types. The Cminss values following 
nivolumab 480 mg Q4W are predicted to be in the range of those on the flat part 
of the exposure-response curves, and are not expected to impact efficacy.  
Based on these data, administration of nivolumab 480 mg Q4W in the 
maintenance phase of study CA209522 is expected to have similar efficacy and 
safety profiles to nivolumab 3 mg/kg Q2W. 
 
 

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Figure 1: 
Predicted Nivolumab Cmax vs Time, by Dosing Regimen 
 
 
Source:/global/pkms/data/CA/209/dose-optimization/prd/ppk-simulation-tvcl/final/R/plots 
1.25 
Clinical Efficacy  
Nivolumab has demonstrated durable responses exceeding 6 months as 
monotherapy and in combination with ipilimumab in several tumor types, 
including NSCLC, melanoma, RCC, and some lymphomas. In confirmatory 
trials, nivolumab as monotherapy demonstrated a statistically significant 
improvement in OS as compared with the current standard of care in subjects 
with advanced or metastatic NSCLC and in subjects with unresectable or 
metastatic melanoma. Nivolumab in combination with ipilimumab improved PFS 
and ORR over ipilimumab alone in subjects with unresectable or metastatic 
melanoma.  
1.26 
Safety in Subjects with Relapsed or Refractory Hematologic Malignancies 
Nivolumab, at 1 or 3 mg/kg, has an acceptable safety profile in subjects with 
relapsed or refractory hematologic malignancy, as demonstrated by the 
frequency, severity, and types of AEs, drug-related deaths, SAEs, and AEs 
leading to discontinuation. The following were the key safety findings for 105 
subjects treated with nivolumab monotherapy in CA209039 as of 15-Apr-2015:  
• 
The most frequently reported drug-related AEs (>10% of subjects) were 
fatigue (16.2%) and rash (10.5%). The majority were Grade 1-2 in severity. 
• 
The most frequently reported drug-related SAE was pneumonitis (4.8%). 
• 
Drug-related AEs leading to discontinuation were reported for 14.3% of 
subjects. The most frequently reported AE leading to discontinuation were 
pneumonitis (2.9%).  
• 
The most frequently reported drug-related select AE categories were skin 
(19.0%), GI (9.5%), and pulmonary (9.5%). The most frequently reported 
(>5% of total treated subjects) drug-related select AEs were rash (10.5%), 
pneumonitis (9.5%), pruritus (9.5%), and diarrhea (8.6%). Drug-related 
select AEs were mostly Grade 1-2 in all categories.  
• 
Most deaths were due to disease progression. One death was reported due to 
study drug toxicity (The subject with NHL [small lymphocytic lymphoma] in 

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the 3 mg/kg treatment group died due to Grade 5 pneumonitis with onset 10 
days after the subject received the only dose of nivolumab).  
1.27 
Clinical Activity of Nivolumab in Lymphoma 
In a broad phase I study, Ansell et al treated 23 patients with classical HL who 
had been heavily pretreated(Ansell, Lesokhin et al. 2015). Nivolumab at a dose 
of 3 mg/kg was administered q 2 weeks until tumor progression, or toxicity. Of 
these, 78% had progressed following a prior autologous stem cell transplant, and 
78% following brentuximab vedotin. An objective response was achieved in 
87%, including 17% with a CR. The rate of progression-free survival at 24 weeks 
was 86%. Therapy was discontinued in 6 patients to go to stem cell 
transplantation, with disease progression in 4, and toxicity in 2. 
From the same study Lesokin et al(Lesokhin, Ansell et al. 2014) reported 29 
patients with a variety of histologies of NHL with responses in 36% of diffuse 
large B-cell NHL (9% CR), 40% of follicular NHL (10% CR). In patients with T-
NHL, ORR was 17% (no CR). When mycosis fungoides was excluded from the 
analysis, an ORR of 40% in the 5 patients with PTCL was seen.  
 
1.3 
Rationale 
Given the observed activity of nivolumab in patients with relapsed and refractory PTCL 
in a small cohort of patients, the lack of significant toxicities, and since there is a need for 
newer non-cytotoxic therapies for the relapsed/refractory PTCL subgroup, we will 
explore the efficacy of nivolumab in the relapsed/refractory setting. Correlative studies 
will help further help us understand predictors of response or non-response to nivolumab. 
 
2.0 
Goals  
2.1 
Primary 
To assess the clinical benefit of nivolumab in T-cell lymphomas, as measured by 
objective response rate (ORR) within 12 cycles according to the Lugano Classification 
Response Criteria (2014) (Section 11.0) 
 
2.2 
Secondary 
2.21 
To assess safety and tolerability of the regimen in this patient population 
 
2.22 
To assess progression-free survival (PFS) 
 
2.23 
To assess duration of response (DOR) 
 
2.24 
To assess overall survival (OS) 
 
2.3 
Correlative Research 
2.31 
To evaluate T-cell/cytokine profile in the peripheral blood – peripheral blood 
specimens will be used to assess T-cell activation and cytokine up regulation as 
measures of treatment effect. This goal will be exploratory in nature and reported 
descriptively 
 

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2.32 
To evaluate intratumoral Biomarkers- intratumoral cell populations and 
distribution, genetic variability, mutational burden and T-cell activation will be 
evaluated to identify potential biomarkers that correlate with response to therapy. 
This goal will also be exploratory in nature 
 
2.33 
To assess the potential association between PD-L1/PD-1/PD-L2 expression 
ontumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy 
of PD-1 blockade. 
 
 

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3.0 
Patient Eligibility 
3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
 
3.12 
Relapsed or refractory T-cell lymphoma (TCL) biopsy-proven ≤6 months prior to 
registration, including the following subtypes: 
• Peripheral T-cell lymphoma, not otherwise specified 
• Anaplastic large cell lymphoma, ALK negative, primary systemic type 
• Angioimmunoblastic T-cell lymphoma 
• Extranodal NK/T-cell lymphoma, nasal type 
•  
• Blastic NK-cell lymphoma 
• Enteropathy-associated T-cell lymphoma 
• Hepatosplenic gamma delta T-cell lymphoma 
• Transformed mycosis fungoides 
• T/NK-cell lymphoma, unclassifiable 
 
3.13 
Measurable disease: Subjects must have at least one lesion that is >15mm 
(1.5 cm) in the longest diameter on cross-sectional imaging and measureable in 
two perpendicular dimensions per computed tomography (spiral CT) or MRI. 
 
3.14 
After failure of ASCT or after failure of frontline therapy in subjects who 
declined or are not ASCT candidates 
 
3.15 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix I) 
 
3.16 
The following laboratory values obtained ≤7 days prior to registration.  
• 
White blood cell (WBC) ≥3000/mm3 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin >9.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless elevation due to 
Gilbert’s Syndrome 
• 
Aspartate transaminase (AST) ≤2.5 x ULN 
• 
Creatinine ≤2.0 mg/dL 
• 
Calculated creatinine clearance must be ≥45 ml/min using the Cockcroft-
Gault formula below: 
 
 
3.17 
Negative serum or urine pregnancy test done ≤7 days prior to registration, 
for persons of childbearing potential only. 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =  
(140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 

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Note: Persons of child-bearing potential (POCBP) must use appropriate 
method(s) of contraception. POCBP should use an adequate method to avoid 
pregnancy for 23 weeks (30 days plus the time required for nivolumab to 
undergo five half-lives) after the last dose of investigational drug. 
Men who are sexually active with POCBP must use any contraceptive method 
with a failure rate of less than 1% per year. Men receiving nivolumab and who 
are sexually active with POCBP will be instructed to adhere to contraception for 
a period of 31 weeks after the last dose of investigational product. Persons who 
are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile) as well as azoospermic men do not require contraception. Should a person 
become pregnant or suspect being pregnant while participating in this study, the 
person should inform the treating physician immediately. 
 
3.18 
Provide written informed consent. 
 
3.19a 
Willing to return to enrolling institution for follow-up during the Active 
Monitoring Phase of the study. 
Note: The Active Monitoring Phase of a study includes active treatment and 
observation. 
3.19b Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6.2, 14.0 and 17.0). 
3.2 
Exclusion Criteria  
3.21 
All primary cutaneous T-cell lymphomas and Adult T-cell lymphoma/leukemia 
(HTLV1+) 
 
3.22 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.24 
Active, known or suspected autoimmune disease.  
Note: Subjects are permitted to enroll if they have vitiligo, type I diabetes 
mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment 
 
3.25 
Use of systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications <14 days of registration. 
Note: Inhaled or topical steroids are permitted. >10 mg daily prednisone 
equivalents are permitted only in adrenal insufficiency in the absence of active 
autoimmune disease. 

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3.26 
Prohibited Treatments and or Therapies 
a) Autologous Stem Cell Transplant (ASCT) ≤12 weeks prior to first dose of the 
study drug. 
b) Prior treatments (window prior to registration):  
chemotherapy ≤2 weeks  
nitrosureas ≤6 weeks 
therapeutic anticancer antibodies ≤4 weeks 
radio- or toxin immunoconjugates ≤10 weeks 
radiation therapy ≤3 weeks 
or major surgery ≤2 weeks 
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell 
costimulation or immune checkpoint pathways 
d) Prior treatment with PD1 and PD-L1 inhibiting therapy 
e) Prior allogeneic SCT 
f) Chest radiation ≤24 weeks prior to registration 
 
3.27 
Immunocompromised patients, patients with known history of testing positive for 
human immunodeficiency virus (HIV) or known acquired immunodeficiency 
syndrome (AIDS) and currently receiving antiretroviral therapy, active Hepatitis 
B virus surface antigen (HBV sAg+), active Hepatitis C (if Ab+ then PCR+) 
indicating acute or chronic infection  
 
3.28 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.29a 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.29b Other active malignancy ≤3 years prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. 
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer.  
 
3.29c 
Active CNS involvement or leptomeningeal involvement 
 
3.29d History of pancreatitis. 
 
 
 
 

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4.0 
Test Schedule 
4.1 
Study Calendar 
 
Baseline 
Active Monitoring Phase 
Tests and procedures 
≤14 days 
prior to 
Registration 
≤7 days 
prior to 
Registration 
Cycle 1 
Day 1 
prior to 
treatment 
End of 
each cycle 
Restaging 
End of 
Cycles 4, 
8, and 12 
End of 
Treatment1 
Observation 
Post-
treatment 
followup2 
window 
 
 
 
±3 days 
±7 days 
±7 days 
±14 days 
History and exam, ECOG PS, Weight 
X 
 
 
X3 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Adverse event assessment 
X 
 
 
X 
X 
X 
X 
Pregnancy Test4 
 
X 
X 
X 
X 
X 
X 
B Symptoms5 
X 
 
 
 
 
 
 
Hematology: CBC with 5 part differential 
 
X 
 
X 
X 
X 
X 
Comprehensive metabolic panel: ALT, AST, total bilirubin, alkaline 
phosphatase, BUN or serum urea, creatinine, Ca, Mg, Na, K, Cl, LDH, 
glucose, amylase, lipase, albumin, bicarbonate 
 
X 
 
X 
X 
X 
X 
Uric Acid 
 
X 
 
 
 
 
 
Erythrocyte sedimentation rate 
X 
 
 
 
 
 
 
HBV sAg and HCV Ab or HCV RNA 
X 
 
 
 
 
 
 
TSH (with Free T4 and Free T3) 
 
X 
 
X6 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
                                                     
1 At PD or PMD, withdrawal, removal, or completion of protocol therapy 
2 Four visits: 1) 35±7 days after last treatment 2) 100-120 days post treatment 3) 230-250 days post treatment 4) 330-390 days post treatment 
3 If on physical exam there are any palpable lymph nodes present: Tumor (bidimensional) measurements by physical exam to be done at end of every cycle, prior 
to next cycle. 
4 For persons of childbearing potential only: Serum pregnancy testing is required ≤7 days prior to registration and again ≤24 hrs prior to the first infusion, and 
then every 28 days (±7 days) during the study therapy period regardless of dosing schedule. After discontinuation from nivolumab, these tests should be 
repeated at approximately 30 days and approximately 70 days [or more frequently if required by local standard]. 
5 Unexplained persistent fever >38° C( or >100.4° F) in previous month, recurring drenching night sweats during the previous month, and/or unexplained weight 
loss >10% of body weight in the previous six months. 
6 Thyroid function testing should be done every third month (±3 days). 

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Baseline 
Active Monitoring Phase 
Tests and procedures 
≤14 days 
prior to 
Registration 
≤7 days 
prior to 
Registration 
Cycle 1 
Day 1 
prior to 
treatment 
End of 
each cycle 
Restaging 
End of 
Cycles 4, 
8, and 12 
End of 
Treatment1 
Observation 
Post-
treatment 
followup2 
window 
 
 
 
±3 days 
±7 days 
±7 days 
±14 days 
PET-CT7 
X 
 
 
 
X 
X 
 
CT scan Chest/Abd/Pelvis 
 
 
 
 
X8 
 
X 
Mandatory research blood/bone marrow samples (See Section 14.0)R,9 
 
 
XR 
XR 
XR 
XR 
XR,10 
Mandatory tissue sample (See Section 17.0)R,11 
XR 
 
 
 
 
 
XR 
Cycle = 14 days during initial therapy (Cycles 1-8) 
Cycle = 28 days during continuation therapy (beginning with Cycle 9) 
R Research funded (see Section 19.0) 
 
 
                                                     
7 Baseline ≤28 days prior to registration, then End of Cycle 4 (≤5 days prior to Cycle 5), end of Cycle 8, and end of Cycle 12 
8 CT scans after the 12th cycle will be done every 16 weeks as long as treatment continues. Then every 3 months during the first year of observation, then as 
clinically indicated. 
9 Must be drawn on Day 1 of each cycle before treatment Cycles 1-4, at restaging post Cycle 12, end of treatment for any reason, and at time of PD or PMD. 
10 Only at time of PD or PMD. 
11 Baseline sample to be submitted ≤14 days prior to Registration; see Section 17.0 

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4.2 
Event Monitoring 
CRF 
Event Monitoring Phase1 
q. 3 
months 
until PD 
At PD2 
After 
PD q. 6 
mos. 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression by uploading it into the 
Supporting Documentation form in the Rave system. 
5.0 
Stratification Factors: None 
 
6.0 
Registration Procedures 
6.1 
Registering a patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application. The registration/randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the Web site. If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page 
 and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
. If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Correlative Research  
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19b, 14.0 and 17.0). 
6.3 
Documentation required 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 

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When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Verification 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.5 
Correlative research options 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of lymphoma at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤7 days after registration. 
6.7 
Pretreatment tests/procedures  
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9a 
Treatment location 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo Clinic 
Arizona, or Mayo Clinic Florida institutions under the supervision of a hematologist. 
6.9b 
Study drug availability 
Study drug is available on site for this patient 
6.9c 
Blood draw kits 
Blood draw kit is available on site for this patient (not applicable to MCR). 
 
 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Treatment Schedule 
Agent 
Dose Level 
Route 
Day 
Cycle Length 
Nivolumab 
240mg 
IV 
Cycles 1-8 
Day 1 
Every 14 days for 8 cycles 
480 mg 
IV 
Beginning 
Cycle 9, 
Day 1 
Every 28 days for a maximum of 24 
cycles  
(Total of 32 cycles) 
No routine premedications are needed with nivolumab administration. 
 
7.2 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 14 days during intial treatment and every 28 days during continuation therapy.  
After therapy discontinuation, the patient must return to the institution for four visits: 1) 
35±7 days after last treatment; 2) 100-120 days post treatment; 3) 230-250 days post 
treatment; and 4) 330-390 days post treatment, during observation (Active Monitoring 
Phase) until the patient goes to event monitoring per Section 13.0. 
 
 
 

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8.0 
Dose Delay Criteria Based on Adverse Events 
For events with an attribution of possibly, probably or definitely related to study medication, 
strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines. If 
multiple adverse events are seen, administer dose based on greatest reduction required for any 
single adverse event observed. Reductions or increases apply to treatment given in the preceding 
cycle and are based on adverse events observed since the prior dose. 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
No dose reductions or escalations are allowed for nivolumab. 
8.2 
Dose Delay Criteria for Nivolumab 
See Management Algorithms (Appendix II) 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0*  
unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
Event 
Agent 
Action 
Investigations 
Alanine 
aminotransferase 
increased,  
Aspartate 
aminotransferase 
increased, 
 and/or  
Blood bilirubin 
increased 
Nivolumab 
If a patient has a baseline AST/ALT that 
is within the normal limits, delay dosing 
for nivolumab-related ≥Grade 2 (>3-5 x 
ULN) elevations and start corticosteroids  
at 0.5 to 1 mg/kg/day prednisone 
equivalents. Nivolumab may be resumed 
if the value improves to Grade 1 (≤3 x 
ULN) or better. 
If a patient has a baseline AST/ALT in the 
Grade 1 range (ULN to ≤3 x ULN), delay 
dosing for nivolumab-related ≥Grade 3 
(>5 to 8 x ULN) elevations and start 
corticosteroids at 1 to 2 mg/kg/day 
prednisone equivalents. Nivolumab may 
be resumed if the value improves to Grade 
2 (>3 to 5 x ULN) or better.  
If a patient has a baseline total bilirubin 
that is within normal limits, delay dosing 
for nivolumab-related Grade 2 elevations 
(>1.5-3 x ULN) and start corticosteroids  
at 0.5 to 1 mg/kg/day prednisone 
equivalents. Nivolumab may be resumed 
if the bilirubin improves to Grade 1 (≤1.5 
x ULN) or better.  
If a patient has a baseline total bilirubin 
that is in the Grade 1 range (ULN to ≤1.5 
x ULN), delay dosing for nivolumab-
related Grade 3 elevations (>3-5 x ULN) 
and start corticosteroids at 1 to 2 
mg/kg/day prednisone equivalents. 

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CTCAE 
System/Organ/Class 
(SOC) 
Event 
Agent 
Action 
Nivolumab may be resumed if the total 
bilirubin improves to Grade 2 (≤3 x ULN) 
or better. 
Doses of nivolumab should be 
discontinued permanently for the 
following LFT abnormalities: AST or 
ALT >8 x ULN (Grade 3) or drug-induced 
liver injury (DILI); Total bilirubin >5 x 
ULN (Grade 3) or DIL; concurrent AST 
or ALT >3 x ULN and total bilirubin >2 x 
ULN. Administer corticosteroids 1 to 2 
mg/kg/day prednisone equivalents.  
Subjects with combined Grade 2 
AST/ALT meeting discontinuation 
parameters: go to event monitoring per 
Section 4.2. 
Gastrointestinal 
disorders 
Pancreatitis 
Nivolumab 
Grade 2: Hold nivolumab until resolution, 
maximum 3 weeks.  
If >3 weeks, discontinue nivolumab and 
patient goes to event monitoring. 
 
 
 
Grade 3 or Grade 4, hold nivolumab until 
Grade 2 or better then reintroduce 
If it recurs, the drug is discontinued and 
patient goes to event monitoring 
 
 
 
Any ≥Grade 3 drug-related amylase or 
lipase abnormality that is not associated 
with symptoms or clinical manifestations 
of pancreatitis does not require dose delay 
The PI should be consulted for ≥Grade 3 
amylase or lipase abnormalities 
Gastrointestinal 
disorders 
Diarrhea 
Nivolumab 
Grade ≥2 despite maximal supportive 
care: Hold drug until resolution to 
baseline grade. If suspicious and clinically 
indicated, initiate work up to rule out 
infectious causes and colitis 
 
 
 
Grade 3 or 4 despite maximal supportive 
care: Discontinue drug and start 
corticosteroids until resolution to baseline 
and patient goes to event monitoring. If 
suspicious and clinically indicated, initiate 
work up to rule out infectious causes and 
colitis 
 
Colitis 
Nivolumab 
Grade ≥2: Hold drug until resolution to 
baseline grade 
Grade ≥3: Discontinue drug and start 

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CTCAE 
System/Organ/Class 
(SOC) 
Event 
Agent 
Action 
corticosteroids until resolution to baseline 
grade and patient goes to event monitoring 
General disorders and 
administration site 
conditions 
Fatigue 
Nivolumab 
Grade 3: Hold drug until Grade 2 or better 
Metabolism and 
nutrition disorders 
Hyperglycemia 
Nivolumab 
Grade 4: Permanently discontinue 
nivolumab 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
Nivolumab 
Grade ≥2: Hold drug and start 
corticosteroids until resolution to baseline 
grade 
Grade ≥3: Discontinue nivolumab and 
initiate treatment with high doses of 
corticosteroids and patient goes to event 
monitoring 
 
Cough 
Nivolumab 
Grade ≥2: Hold drug and start 
corticosteroids until resolution to baseline 
grade 
Grade ≥3: Discontinue nivolumab and 
initiate treatment with high doses of 
corticosteroids and patient goes to event 
monitoring 
 
Dyspnea 
Nivolumab 
Grade ≥2: Hold drug until resolution to 
baseline grade 
All other hematologic 
and non-hematologic 
All other hematologic 
and non-hematologic 
Nivolumab 
Grade ≥2: Hold nivolumab until resolution 
to Grade 1 or baseline, except for 
lymphopenia and leukopenia 
NOTE: Grade 3 lymphopenia or 
leukopenia do not require dose delay 
 
8.3 
Discontinuation Criteria for Nivolumab 
Treatment should be permanently discontinued for the following: 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment  
• 
Any Grade 3 non-skin, drug-related adverse event lasting >7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, and infusion reactions, and 
endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
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• 
Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding requires 
discontinuation 
• 
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:  
• 
AST or ALT >8 x ULN 
• 
Total bilirubin >5 x ULN 
• 
Concurrent AST or ALT >3 x ULN and total bilirubin >2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
o Grade 4 lymphopenia or leucopenia 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Investigator [as allowed by protocol] 
• 
Any dosing interruption lasting >6 weeks with the following exceptions: 
o Dosing delays or interruptions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting >6 weeks, the 
Investigator must be consulted. Tumor assessments should continue as per 
protocol even if dosing is interrupted or delayed 
o Dosing interruptions or delays lasting >6 weeks that occur for non-drug-
related reasons may be allowed if approved by the Investigator. Prior to re-
initiating treatment in a subject with a dosing interruption lasting >6 weeks, 
the Investigator must be consulted. Tumor assessments should continue as 
per protocol even if dosing is interrupted 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
 
 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
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 antidiarrheals, 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. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
 
9.4 
Diarrhea 
Diarrhea can be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
If suspicious and clinically indicated, initiate work up to rule out infectious causes and 
colitis at treating physician’s discretion. 
 
9.5 
Hepatotoxicity 
As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to 
hepatoxicity should be used with caution in patients treated with nivolumab-containing 
regimen. 
 
9.6 
Additional adverse events 
Please refer to Appendix II for additional Adverse Event Management Algorithms 
excerpted from the investigator’s brochure for nivolumab (version 15). 
 
 
 

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Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 

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10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting  
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. If patient is 
hospitalized, please follow normal reporting criteria. These events must still be 
reported via Routine Reporting (see Section 10.6). * 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the 
event will not require 
expedited reporting1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Investigations 
Neutrophil count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
White blood count  
≤Grade 4 
Lymphocyte count decreased 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment 
on this trial 
● Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the 
cancer.] 

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Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
 
 

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10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC. 
 
 

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10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
CTCAE 
System/Organ/Class 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Gastrointestinal disorders 
Number of stools at baseline 
X 
 
 
Diarrhea 
 
X 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
X 
X 
Dyspnea 
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash acneiform 
X 
X 
 
Rash maculo-papular 
X 
X 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
BMS Additional Event Reporting Instructions 
10.81 Adverse event reporting is required as per the Study Agreement.  
• 
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. 
• 
For subjects randomized and never treated with study drug, SAEs should be 
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• 
If the BMS safety address is not included in the protocol document (e.g. 
multicenter studies where events are reported centrally), the procedure for 
safety reporting must be reviewed/approved by the BMS Protocol Manager.  
Procedures for such reporting must be reviewed and approved by BMS prior 
to study activation. 
• 
The BMS SAE form should be used to report SAEs.  If the BMS form cannot 
be used, another acceptable form (i.e CIOMS or Medwatch) must be 
reviewed and approved by BMS.  The BMS protocol ID number must be 
included on whatever form is submitted by the Sponsor/Investigator. 
• 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those 
thought to be associated with protocol-specified procedures. The investigator 
should report any SAE occurring after these time periods that is believed to 
be related to study drug or protocol-specified procedure. For drugs with 
potential for delayed SAEs (e.g., delayed excretion of the parent or active 
metabolites), a longer follow-up period may be warranted to allow collection 
of these SAEs, laboratory tests, and other assessments. 
• 
For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection  
• 
In accordance with local regulations, BMS will notify investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (i.e., not previously described in the IB). In the European Union 
(EU), an event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Investigator notification of these events 
will be in the form of an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR 
include: increased frequency of a clinically significant expected 
SAE, an SAE considered associated with study procedures that could 
modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or 
sponsor decision to end or temporarily halt a clinical study for safety 
reasons. 
o Upon receiving an ESR from BMS, the investigator must review and 
retain the ESR with the IB. Where required by local regulations or 
when there is a central IRB/IEC for the study, the sponsor will 
submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. 
The investigator should also comply with the IRB/IEC procedures 
for reporting any other safety information.  
o In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent 
health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
10.82 Serious Adverse Event Collection and Reporting 

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Email: 
 
• 
An SAE report should be completed for any event where doubt exists 
regarding its seriousness.  
• 
For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection in the protocol. 
• 
If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of 
previous therapy or a complication of a study procedure), the relationship 
should be specified in the narrative section of the SAE Report Form. 
• 
If only limited information is initially available, follow-up reports are 
required. (Note: Follow-up SAE reports should include the same investigator 
term(s) initially reported.) 
• 
If an ongoing SAE changes in its intensity or relationship to study drug or if 
new information becomes available, a follow-up SAE report should be sent 
within 24 hours to BMS using the same procedure used for transmitting the 
initial SAE report. All SAEs should be followed to resolution or stabilization.  
All SAEs should be followed to resolution or stabilization. 
10.84 DEFINITIONS 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any 
dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing 
hospitalization (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.)  
• 
Potential drug induced liver injury (DILI) is also considered an important 
medical event.  
• 
Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE.  
• 
Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
NOTE: (PI- determines if this information should be included. This 
is provided as supplemental information that is included in BMS-

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sponsored trials) 
The following hospitalizations are not considered SAEs in BMS 
clinical studies:  
− 
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 
− 
Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention 
(eg, lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason). 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational 
product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). The casual relationship can be one of the 
following: 
Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a 
causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
• 
Nonserious Adverse Events 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.  
• 
Nonserious AE information should also be collected from the start of a 
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baseline status for the subjects.  
A nonserious adverse event is an AE not classified as serious.  
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study 
drug. All nonserious 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.  
Nonserious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for nonserious AEs that 
cause interruption or discontinuation of study drug and for those present at the 
end of study treatment as appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded 
following institutional procedures. Test results that constitute SAEs should be 
documented and reported 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 subject to have study drug 
discontinued or interrupted 
• 
any laboratory abnormality that required the subject to receive specific 
corrective therapy.  
10.85 Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event.  All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEsPotential drug induced liver injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT 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. 
10.86 Pregnancy 
If, following initiation of the investigational product, it is subsequently 
discovered that a study subject is pregnant or may have been pregnant at the time 
of investigational product exposure, including during at least 6 half lives after 
product administration, the investigational product will be permanently 

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discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety).  
The investigator must immediately notify Worldwide Safety @BMS of this event 
via the Pregnancy Surveillance Form in accordance with SAE reporting 
procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome and, where applicable, offspring information must be 
reported on the Pregnancy Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should 
be reported to BMS. Information on this pregnancy will be collected on the 
Pregnancy Surveillance Form. 
10.87 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. 
10.88 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether 
or not these procedures are required by the protocol, should also be recorded as a 
nonserious or serious AE, as appropriate, and reported accordingly. 
 
 

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11.0 
Treatment Evaluation  
Lugano Classification Response Criteria 
11.1 
Response Considerations  
Schedule of Evaluations: PET/CT scans are required at baseline for all patients. In 
addition to a baseline PET/CT scan, confirmatory scans should also be obtained post 
Cycle 4, 8, and 12 of chemotherapy, then a CT scan every 16 weeks thereafter. During 
observation, CT scan should be obtained every 3 months during the first year to evaluate 
for disease progression. 
Definitions for clinical response for patients with lymphoma are from the recently revised 
Cheson’s et al criteria published in 2014, derived from the original criteria published in 
2007. (Cheson et al, 2014)(Cheson et al, 2007). Lymph node measurements should be 
taken from the CT portion of the PET/CT, or other dedicated CT scans where applicable. 
Measurement of lymphadenopathy for purposes of assessing for PR will be determined 
by adding the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD). The PPD of a single node is sufficient to evaluate for PD (see Table 11.2). 
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 (eg, 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 and pathologically negative. 
Response is based on PET/CT based on the revised 2014 Lugano Classification. (Cheson 
et al, 2014). 
Progressive disease is based on either PET-CT based (PMD) or CT based (PD) response 
criteria. PET confirmation of progressive disease is per physician discretion. 
11.2 
Pseudoprogression  
Some therapeutic agents, particularly immunotherapeutics, display different patterns 
of anti-tumor response, which may include a period of increasing tumor burden 
followed by a response, stable disease followed by slow decline in tumor burden, or 
even a response in the presence of new lesions (Chow, 2013; Wolchok et al., 2009). 
Immune-mediated responses may take longer to manifest than those from cytotoxic 
agents. In other cancer settings, a phenomenon called “tumor flare” or 
pseudoprogression has also been described, in which increased metabolic activity in 
FDG-PET is observed on posttreatment PET-CT which represents a biologic effect 
on the tumor and its microenvironment. (REF) 
In order to avoid falsely assigning disease progression during the the study, a subject 
whose radiologic disease assessment is indicative of progression may, at the 
discretion of the Investigator, continue on treatment pending a repeat scan, if all of 
the following criteria are met:  
• 
absence of symptomatic or clinical progression  
• 
stable performance status  
• 
adequate tolerance to nivolumab 
• 
treating beyond progression does not delay an intervention felt to be 
in the patient’s best interest  
If the second confirmatory scan indicates unequivocal disease progression, the 

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four visits: 1) 35±7 days after last treatment; 2) 100-120 days post treatment; 3) 230-250 
days post treatment; and 4) 330-390 days post treatment, during observation (Active 
Monitoring Phase) until the patient goes to event monitoring for up to 5 years from time 
of registration (see Section 4.2).  
13.5 
Maximum cycles for patients who achieve CR/CMR 
Patients who achieve a CR/CMR will receive a maximum total of 32 cycles (i.e 2 years 
of therapy). After 2 years, they should be observed (see Section 13.4 above). 
13.6 
Continuation of therapy after PR/PMR or SD 
Patients who are in PR/PMR or SD will continue on therapy for a total of 2 years. After 2 
years, they should be observed (see Section 13.4 above) until PD and then they will go to 
event monitoring (see Section 13.5 above). Subsequent treatment is at the discretion of 
their attending physician. 
13.7 
Definition of Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.8 
Definition of Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.9 
Definition of Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 

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14.0 
Body Fluid Biospecimens  
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol (see Appendix III for handling) 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per tube 
(# of tubes to 
be collected) 
Baseline 
Cycles 1-4  
Day 1  
Pre-
treatment 
End of 
Cycle 12 
End of 
treatment2 
At time 
of PMD 
or PD2 
 
Tumor biopsy or bone 
marrow aspirate1 
Mandatory 
Tumor or 
bone marrow 
ACD 
(yellow top) 
6 mL 
(1 tube) 
X 
 
 
 
 
 
Peripheral blood  
Mandatory Whole Blood 
EDTA 
(purple top) 
10 mL 
(4 tubes) 
 
X 
X 
X 
X 
 
Peripheral blood 
Mandatory Whole Blood 
No 
anticoagulant 
(red top) 
10 mL 
(1 tube) 
 
X 
X 
X 
X 
 
1 Only obtained when a clinical biopsy/bone marrow is needed. Biopsies and bone marrow samples can be collected ≤90 days prior to 
registration provided there is no intervening treatment. If a biopsy or bone marrow was performed prior to consenting the patient for this 
study, a repeat biopsy or bone marrow is not required to obtain the research aspirate sample at baseline. 
2 Samples are required, however there is no protocol violation if sample is not obtained. 
NOTE: All samples will be sent to Predolin Biobank Stabile 613 (See Section 14.33) 
 

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14.41 Blood/blood product samples will be collected for the following research  
14.411 DNA extraction and storage of DNA for future pharmacogenetic assays 
(e.g., for genetic polymorphisms, neoantigens and mutational burden that 
may correlate with treatment efficacy). Dr. Stephen Ansell’s laboratory 
Stabile 6-28 will initially analyze a portion of the DNA using standard 
laboratory protocols. Remaining DNA will be stored frozen at -70ºC by 
Dr. Stephen Ansell’s Lab, according to patient consent information) until 
specific analyses are identified. As protocols are developed, they will be 
presented for IRB review and approval. 
14.412 A portion of the serum/plasma/PBMCs will initially be analyzed for the 
presence of Cytokines and T-cell activation in Dr. Stephen Ansell’s 
laboratory using standard laboratory protocols. According to patient 
consent information remaining serum/plasma will be stored frozen at -
70ºC by Dr. Stephen Ansell’s Lab, until specific analyses are identified. 
As protocols are developed, they will be presented for IRB review and 
approval. 
Serum cytokine analysis: Samples will be subjected to multiplex ELISA 
(Invitrogen, Camarillo, CA) to measure 30 serum cytokines in pre-
treatment and subsequent blood samples. Luminex-200 system version 
1.7 will be used for reading plates and MasterPlex QT1.0 system 
(MiraiBio) will be used to analyze data. Cytokines will include 
epidermal growth factor (EGF), eotaxin, basic fibroblast growth factor 
(FGF-b), granulocyte macrophage colony stimulating factor (GM-CSF), 
hepatocyte growth factor (HGF), IFN-α, IFN-ϒ, interleukin 1 receptor 
antagonist (IL-1RA), IL-1β,IL-2, IL-2R , IL-4, 5, 6, 7, 8, 10,12,13,15,17, 
Inducible protein-10 (IP10/CXCL10), monocyte chemotactic protein 
1(MCP-1), monokine induced by interferon γ, (MIG/CXCL9), MIP-1α 
(CCL3), MIP1β (CCL4), regulated on activation normal T-cell expressed 
and secreted (RANTES),TNF-α and vascular endothelial growth factor 
(VEGF). Internal control serum will be included in all assays to control 
for interassay variation. 
Flow cytometry: To define changes in peripheral blood cell populations 
(Activated vs, exhausted T-cells, Treg cells, monocytes and MDSCs) 
after treatment with nivolumab, peripheral blood mononuclear cells will 
be stained with fluorochrome-conjugated antibodies to human CD69 
(R&D Systems), CD3 (clone HIT3a), CD19 (clone 4G7), PD1 (clone 
EH12.1), CD14 (clone M5E2), CD163 (clone GH1/61), CD21 (clone B-
ly4), CD273 (clone M1H18), CD274 (clone M1H1), TIM3 (clone 
344823), and CD23 (clone EBVCS-5; all obtained from BD Biosciences) 
and the data will be analyzed using CellQuest software (Becton 
Dickinson). 
14.413 We will collect serum/plasma for future research studies, according to 
patient consent information on molecular determinants of efficacy and 
tolerability. Samples will be stored frozen at -70ºC by Dr. Stephen 
Ansell’s Lab until specific analyses are identified. As protocols are 
developed, they will be presented for IRB review and approval. 
 
 

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15.0 
Drug Information 
15.1 
Nivolumab (Opdivo®, BMS-936558) 
15.11 Background: Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal 
antibody that selectively inhibits programmed cell death-1 (PD-1) activity by 
binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from 
binding. The negative PD-1 receptor signaling that regulates T-cell activation and 
proliferation is therefore disrupted. This releases PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. 
15.12 Formulation: Available for injection 10mg/ml (4mL, 10mL) in a single-use vial 
[contains in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80] 
15.13 Preparation and storage: Appropriate dose/required volume should be added to 
an IV container of either 0.9% Sodium Chloride or 5% Dextrose in Water with a 
final concentration of 0.35 mg/ml to 10 mg/ml. Mix diluted solution by gentle 
inversion. Do not shake. Discard partially used vials or empty vials. Store at 
room temperature for no more than 8 hours (includes time of administration) or 
under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the 
time of infusion preparation.  Protect from light and freezing. 
15.14 Administration: Administer over 60 minutes through a line with a sterile, 
nonpyrogenic, low protein binding 0.2 to 1.2 micrometer in-line filter. 
Establishing that nivolumab can be safely administered using a shorter infusion 
time (30 minutes) is under investigation. It cannot be administered as an IV push 
or bolus injection. Do not administer other medications through the same IV line. 
Flush IV line at the end of the infusion. 
15.15 Pharmacokinetic information: 
Distribution:  Vd: 8 L 
Half-life elimination:  ~27days 
Renal Impairment: No clinically important differences in the  
clearance of nivolumab were found between subjects with mild or moderate renal 
impairment and subjects with normal renal function. Data from subjects with 
severe renal impairment are too limited to draw conclusions on this population. 
Hepatic Impairment: No clinically important differences in the clearance of 
nivolumab were found between subjects with mild hepatic impairment and 
normal hepatic function. Nivolumab has not been studied in subjects with 
moderate (total bilirubin >1.5 to 3 times ULN and any AST) or severe hepatic 
impairment (total bilirubin >3 times ULN and any AST). 
15.16 Potential Drug Interactions:  No formal pharmacokinetic drug-drug interaction 
studies have been conducted. 
15.17 Known potential toxicities:  Consult the package insert for the most current and 
complete information. 
Very common known potential toxicities, ≥10%: 
Gastrointestinal: Diarrhea 
General:  Fatigue 
Less common known potential toxicities, 1% - 10%: 
Endocrine: Hypothyroidism, hyperthyroidism, hyperglycemia 
Gastrointestinal: Nausea, vomiting, constipation, abdominal pain, stomatitis, dry 

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mouth, colitis,  
General: Pyrexia, asthenia, peripheral edema, chills,  
Immune system: infusion related reaction 
Investigations: Increased AST/ALT, increased lipase, increased alkaline 
phosphatase, increased creatinine, increased amylase, increased thyroid 
stimulating hormone 
Metabolism and nutrition disorders: Decreased appetite, hyponatremia 
Musculoskeletal: Arthralgia, myalgia, back pain, pain in extremities  
Nervous system: Headache, dizziness 
Respiratory: Pneumonitis, dyspnea, cough 
Skin and subcutaneous tissue disorders: Pruritis, rash, dry skin, maculopapular 
rash, vitiligo, erythema, generalized pruritus 
Uncommon known potential toxicities, 0.1%-<1%: 
Cardiac: Tachycardia, atrial fibrillation 
Ear: Vertigo 
Endocrine and metabolic: Adrenal insufficiency, thyroiditis, hypophysitis, 
diabetes mellitus, hypopituitarism,   autoimmune thyroiditis 
Eye: Dry eye, blurred vision, uveitis 
Gastrointestinal: Pancreatitis, gastritis 
General: Mucosal inflammation, edema, face edema, localized edema, peripheral 
swelling, swelling face 
Hepatic: Hepatitis,autoimmune hepatitis,  
Immune system: Hypersensitivity,  
Infections: Upper respiratory tract infection, bronchitis 
Investigations: increased bilirubin 
Musculoskeletal: Musculoskeletal pain, arthritis, musculoskeletal chest 
pain, neck pain, polyarthritis, bones pain 
Nervous system: Peripheral neuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
Renal and urinary: Acute kidney injury; renal failure,  tubulointerstitial 
nephritis 
Respiratory: Respiratory failure, interstitial lung disease, lung infiltration 
Skin and subcutaneous tissue disorders: Alopecia, dermatitis acneiform, 
urticaria, psoriasis, dermatitis, rash (pruritic, macular, erythematous, 
generalized, popular, pustular), drug eruption   
Vascular: Hypotension, hypertension 
 
Rare known potential toxicities, < 0.1% (Limited to life-threatening): 
Cardiac: Arrhythmia, ventricular arrhythmia 
Endocrine: Diabetic ketoacidosis, autoimmune hypothyroidism 
Eye disorders: iridocyclitis 
Gastrointestinal: Autoimmune colitis, acute pancreatitis 
Hepatic: Acute hepatitis 
Immune system: Anaphylactic reaction, sarcoidosis  
Musculoskeletal: Myositis, myocarditis, polymyalgia rheumatic, 
polymyositis, rhabdomyolysis 
Nervous system: Polyneuropathy, encephalitis, Myasthenia gravis, 
Guillain-Barre syndrome, demyelinating polyneuropathy, demyelination, 
myasthenic syndrome 
Renal: Nephritis, autoimmune nephritis 

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Respiratory: Pneumonia, acute respiratory distress syndrome 
Skin and subcutaneous tissue disorders: Erythema multiforme, Stevens 
Johnson syndrome, toxic epidermal necrolysis  
Other: Solid organ and tissue transplant rejection, graft versus host disease, 
increased risk of transplant-related complications 
15.18 Drug procurement: Investigational nivolumab is provided free of charge to 
patients by Bristol-Myers Squibb Research and Development. 
15.19 Nursing Guidelines 
15.191 
Nivolumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids.  Additionally combination 
therapy (with ipilimumab) tends to have a higher rate of immune 
mediated side effects. 
15.192 
Diarrhea can be common and can be very severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 8.0 and monitor for effectiveness.  
15.194 
Monitor LFTs closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, new onset diabetes, and adrenal insufficiency) are seen 
with this agent. Patients may present only with the vague sense of 
fatigue and “not feeling well.” Additional symptoms may be that of 
nausea, sweating, headache and decreased activity tolerance. Instruct 
patients to report these signs or symptoms immediately and obtain 
appropriate labs as ordered by MD.  
15.197 
Pancreatitis is possible with nivolumab. Instruct patients to report 
abdominal pain, nausea and vomiting to the study team. 
15.198 
Patients who are started on steroid therapy for any side effects of 
nivolumab toxicity should be instructed to take the steroids as ordered, 
and not to discontinue abruptly as symptoms may return and be severe. 
Patients may be on steroid therapy for weeks. Instruct patients to report 
any increase or change in side effects with any dosage decrease as 
patients may need a slower taper.  

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15.199a Monitor renal functions as patients may experience acute interstitial 
nephritis. Report any increase of levels to the study team. 
15.199b Patients who have previously undergone a solid organ or tissue 
transplant and subsequently undergo therapy with nivolumab are at 
increased risk of organ/tissue rejection.  Instruct patients that it is 
crucial that they stay in touch with their transplant team during 
treatment. 
15.199c Patients who have undergone allogeneic BMT are at higher risk of 
GVHD and death when receiving nivolumab.  Monitor patients closely 
for GVHD symptoms and instruct patients to report these symptoms to 
the study team immediately. 
 
16.0  
Statistical Considerations and Methodology  
16.1 
Overview: 
This is a phase II study of Nivolumab in patients with relapsed or refractory peripheral T-
cell lymphoma (PTCL). It will use a one-stage design with an interim analysis based on a 
Simon optimal design to assess efficacy. 
16.11 
Endpoint: The primary endpoint in this trial is the proportion of objective 
responses (either a CR or PR according to the revised Lugano Classification 
Response criteria (Cheson et al, 2014)). For the primary endpoint, CR or PR will 
be considered synonymous with “success”, unless specified otherwise. All 
patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be evaluable for response.  
16.2  
Statistical Design 
16.21 Decision Rule 
In a previous phase II single arm trial of 130 confirmed PTCL patients receiving 
Romidepsin (14 mg/m2 as a 4 hour transfusion on Days 1, 8 and 15 of 28 day 
cycles), 25% achieved a response (CR/CRu + PR). The CR/CRu rate was 15%. A 
second phase II single arm study of 111 treated PTCL patients receiving 
Pralatrexate (30 mg/m2/wk intravenously for 6 weeks in 7-week cycles) showed a 
29% response rate (CR + PR) with 11% having CR. This study will include 
patients with histologically proven TCL who will be receiving nivolumab 
(240mg every 2 weeks for 4 months, then 480mg every 4 weeks). It is expected 
that this dose will have a complete response rate similar to those presented above. 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 10%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 30%. This design uses 35 evaluable patients to test the 
null hypothesis that the true complete response rate is at most 10%. 
16.211 
Interim Analysis: Enter 12 evaluable patients into the study. If there 
are one or no successes observed in the first 12 evaluable patients, we 
will consider this regimen ineffective in this patient population and 
terminate this study. Otherwise, if the number of successes is at least 2, 
we will continue accrual. 
16.212 
Final Decision Rule: If 5 or fewer successes are observed in the first 35 
evaluable patients, we will consider this regimen ineffective in this 

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patient population. If 6 or more successes are observed in the first 35 
evaluable patients, we may recommend further testing of this regimen 
in subsequent studies in this population. 
16.213 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process. Analyses involving over accrued 
patients are discussed in Section 16.34. 
16.214 
NOTE: We will not suspend accrual at the interim analysis to allow the 
first 12 patients to become evaluable, unless undue toxicity is 
observed. Given the limited overall sample size and the inclusion of an 
adverse events stopping rule, we feel it is ethical to not halt accrual for 
the interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
16.22 
Sample Size: This study is expected to require a minimum of 12 and a maximum 
of 35 evaluable patients. We anticipate accruing 4 additional patients to account 
for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, the study is expected to accrue a maximum of 39 patients overall. 
16.23 
Accrual Rate and Study Duration: The anticipated accrual rate is 10 evaluable 
patients per year. Therefore, the accrual period is expected to be 3 years. The 
primary endpoint will be evaluated approximately 3.5 years after the trial opens, 
or after the last patient accrued has been observed for at least 6 months and data 
collection for the induction phase is complete. The total study duration is 
expected to be approximately 5.5 years, or until all patients have completed all 
cycles of treatment. 
16.24 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .10, i.e. there is a 10% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions and the probability of stopping accrual after the interim 
analysis can be tabulated as a function of the true success proportion as shown in 
the following table. 
 
If the true success proportion is... 
0.10 
0.15 
0.20 
0.25 
0.30 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.098 
0.337 
0.604 
0.795 
0.901 
and the probability of stopping after 
the interim analysis is … 
0.659 
0.444 
0.275 
0.158 
0.085 
 
16.25 Other considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
16.3 
Analysis Plan 
16.31 Primary Outcome Analyses: 

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16.311 Definition: The primary endpoint of this trial is the proportion of 
complete or partial responses to therapy. A success is defined as a CR or 
PR as the objective status during therapy. All patients meeting the 
eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response. 
16.312 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated. 
16.32 Secondary Outcome Analyses: These analyses will include all patients meeting 
the eligibility criteria who have signed a consent form and have begun treatment, 
including patients who fail to achieve a complete response. 
16.321 
Response: Response rates will be estimated using complete and partial 
metabolic responses (CMR or PMR) divided by the total number of 
evaluable patients. All evaluable patients will be used for this analysis. 
These rates will be compared to the primary endpoint to explore any 
differences in the measurement method. 
16.322 
Adverse Events: All eligible patients that have initiated treatment will 
be considered evaluable for assessing adverse event rate(s). The 
maximum grade for each type of adverse event will be recorded for 
each patient, and frequency tables will be reviewed to determine 
patterns. Additionally, the relationship of the adverse event(s) to the 
study treatment will be taken into consideration. 
16.323 
Progression free survival time is defined for all evaluable patients who 
have achieved a CR/CMR or PR/PMR as the time from registration to 
relapse or death due to any cause. The distribution of progression-free 
survival will be estimated using the method of Kaplan-Meier. In 
addition, the progression-free survival rate at 5 years after registration 
will be reported. 
16.324  
Duration of response is defined for all evaluable patients who have 
achieved a CR/CMR or PR/PMR as the date at which the patient’s 
objective status is first noted to be a CR/CMR or PR/PMR to the 
earliest date relapse is documented. The distribution of duration of 
complete response will be estimated using the method of Kaplan-Meier 
16.325 
Overall survival time is defined as the time from registration to death 
due to any cause. The distribution of survival time will be estimated 
using the method of Kaplan-Meier(Kaplan and Meier 1958). In 
addition, the overall survival rate at 2 years after registration will be 
reported. 
16.33  Correlative Analyses 
16.331 
Correlative analyses will be exploratory in nature and will include 
evaluation of T-cell activation, cytokine up regulation, biomarker 
activity with respect to response to therapy (intratumoral cell 
populations, genetic variability, serum cytokines, T-cell activation), 
and PD-L1/PD-1/PD-L2 expression. These factors will be summarized 
and used to help characterize the types of patients accrued to this trial. 
In addition, we will explore differences in the distributions of these 

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risk factors by clinical outcome (progression-free survival status at 
5 years and whether the patient remains in sustained 
CR/CMR/PR/PMR). Nonparametric quantitative comparisons by 
group will be made as appropriate (Fisher’s exact or Wilcoxon rank 
sum). Kaplan-Meier methods and log-rank statistics will be used to 
compare between groups for time-to-event measures. Given the limited 
number of patients, the difference in risk factor distribution by 
outcome will be largely exploratory. 
16.34 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
 
16.4 
Data & Safety Monitoring: 
16.41 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.42 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy 
one of the following: 
• 
if 4 or more patients in the first 10 treated patients (40%) experience a grade 
4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
• 
if after the first 10 patients have been treated, 40% of all patients experience 
a grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment.  
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.5 
Results Reporting on ClinicalTrials.gov:  
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on ClinicalTrials.gov. For purposes of timing of the Results 
Reporting, the initial estimated completion date for the Primary Endpoint of this study is 

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5.5 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 2 months. 
16.6 
Inclusion of Women and Minorities 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, or ethnicity, and there is no reason to expect 
such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial, the sample size is 
not increased in order to provide additional power for subset analyses. 
The diagnosis is more common in men, as the male:female ratio is approximately 
2:1 (Weisenburger, Savage et al. 2011) 
16.63 The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 30% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
13 
25 
0 
38 
Ethnic Category: Total of all subjects 
13 
26 
0 
39 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
12 
25 
0 
37 
Racial Category: Total of all subjects 
13 
26 
0 
39 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
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Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 

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17.0  
Pathology Considerations/Tissue Biospecimens  
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Baseline 
At 
Progression 
Specific 
Details for 
submission 
Pathology review – 
confirm diagnosis 
Mandatory for 
diagnoses 
made at non-
Mayo sites 
H & E, 
stained slides 
All H&E stained 
diagnostic slides 
X 
 
17.2 
Correlative studies 
Mandatory 
Paraffin 
sections 
Tissue block 
(preferred) or 
unstained slides (10 
slides), 4-5 microns 
each 
X 
X1 
17.3 
1. Samples are required, however there is no protocol violation if sample is not obtained. 
 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
17.21 Central pathology review is not required as long as the tissue diagnosis of lymphoma was confirmed by a Mayo 
pathologist. If the tissue diagnosis is not confirmed by a Mayo pathologist, the slides will need to be reviewed to confirm 
the diagnosis. Completion of central pathology review is not required prior to registration; however materials for central 
review must be reviewed within 42 days after registration. 
17.22 Central pathology review will be conducted as needed for confirmation of diagnosis by Dr. Andrew Feldman and 
colleagues at Mayo Clinic Rochester if the initial tissue biopsy was not performed and evaluated at Mayo Clinic. 
17.23 Required materials: 
• 
Lymphoma Pathology Reporting Form (Complete Section I only) 
• 
Tissue Submission Form 
• 
Tumor tissue pathology report 
 

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17.4 
Background and Methodology 
Background: Accumulating evidence has shown that clinical responses to checkpoint 
inhibitor is likely associated with tumor PD-L1 overexpression as well as tumor exomic 
mutation burden. Therefore, we plan to test the spectrum of tumor mutations using 
WES/targeted sequencing as well as measure tumor PD-L1 and other marker staining 
with immunohistochemistry analysis 
17.41  Sequencing: Genomic DNA will be extracted from formalin-fixed, paraffin- 
embedded tissue blocks. H&E-stained sections from each case will be reviewed 
by an expert hematopathologist and representative blocks with at least 30% 
tumor cells will be selected. 10 x 5-micron sections will be cut from blocks in the 
Mayo Clinic Pathology Research Core (based on tissue area of 25 mm2). DNA 
will be extracted in the Mayo Clinic Biospecimens Accessioning and Processing 
Core using the Qiagen FFPE DNA extraction kit. DNA quantitation will be 
performed using a Qubit fluorometer prior to sequencing. 
17.42  Immunohistochemistry (IHC): Expression of PD-L1 has been demonstrated to 
associate with clinical response of cancer patients treated with nivolumab. It is 
also established that CD8+ cytotoxic T cell response is critical to mediate anti-
tumor immunity. Therefore, multiple markers including T cell, tumor cells, as 
well as related co-stimulatory and inhibitory markers will be stained to identify if 
there is any association of expression of these markers with clinical response. 
Serial 5-μm paraffin-embedded sections will be used for IHC. The tissue will be 
deparaffinized with three changes of xylene and cleared through graded series of 
ethanol. Endogenous peroxidase will be quenched by incubation in 50% 
methanol/H2O2 and after rinsing with tap water; all sections will be pretreated 
for 30 minutes with 50 mmol/L EDTA using a steamer and cooled for additional 
5 minutes. All staining will be done automatically on DAKO Autostainer using 
the following antibodies to CD11c (Leica Microsystems 5D11), CD14 (Cell 
Marque EPR 3653), CD163 (DAKO 1F8), CD68 (DAKO PG-M1), CXCL13 
(R&D Systems 53610), FOXP3 (Abcam 236AE/7), CD3 (R&D Systems), PD-L1 
(405.9A11), PD-L2 (366C.9E5) and PD-1 (Abcam NAT). The sections will be 
viewed with an Olympus BXFA51 microscope and pictures taken with an 
Olympus DP71 camera. 
17.43  Fluorescence in situ hybridization (FISH): PD-L1 overexpression is commonly 
due to genetic mutations of the PD-L1 locus. FISH will therefore be performed to 
assess copy number at chromosome 9p24.1. The bacterial artificial chromosome 
probes (CHORI; www.chori.org) RP11-599H2O, which maps to 9p24.1 and 
includes CD274 (encoding PD-L1, labeled with Spectrum Orange), and RP11-
635N21, which also maps to 9p24.1 and includes PDCD1LG2 (encoding PD-L2, 
labeled with Spectrum Green), will be cohybridized. A control centromeric 
probe, Spectrum Aqua–labeled CEP9 (Abbott Molecular) that maps to 9p11-q11, 
will be hybridized according to the manufacturer's recommendations. Nuclei with 
a target:control probe ratio of at least 3:1 will be classified as amplified, those 
with a probe ratio of more than 1:1 but less than 3:1 will be classified as relative 
copy gain, and those with a probe ratio of 1:1 but with more than two copies of 
each probe will be classified as polysomic for chromosome 9p. 
 
 
 

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18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and Data Submission Schedule for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy.  
Supporting documentation for diagnosis will include a pathology report from the most 
recent tumor tissue biopsy, most recent bone marrow biopsy report, and baseline imaging 
report. These reports should be uploaded into the Supporting Documentation: Baseline 
form in the Medidata Rave system ≤14 days after registration. 
For response to treatment, supporting documentation includes an imaging report and, if 
applicable, a Bone Marrow Biopsy report.. 
For patients who progress after study therapy, supporting documentation may include an 
imaging report, bone marrow biopsy report, or pathology report. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
 
 
 

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19.0 
Budget 
19.1 
Costs charged to patient 
All routine clinical care. The participant will be billed for pharmacy and administration 
charges and other ancillary expenses such as any oral medications prescribed at the time 
of discharge. 
19.2 
Tests to be research funded 
Correlative studies described in Sections 14.0 and 17.0. 
19.3 
Other budget concerns 
Nivolumab will be supplied by Bristol-Myers Squibb.  
Protocol administration, study coordinator time, data management, and statistical analysis 
efforts will be funded by a grant from Bristol-Myers Squibb. 
T-Cell Leukemia Lymphoma Foundation will provide funding for investigator effort.  
 
 
 

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20.0 
References 
Ansell, S. M., A. M. Lesokhin, et al. (2015). "PD-1 blockade with nivolumab in relapsed or refractory 
Hodgkin's lymphoma." The New England journal of medicine 372(4): 311-319. 
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humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies." 
Clinical Cancer Research 14(10): 3044-3051. 
Coiffier, B., B. Pro, et al. (2012). "Results from a pivotal, open-label, phase II study of romidepsin in 
relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy." J Clin Oncol 
30(6): 631-636. 
Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors 
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Damaj, G., R. Gressin, et al. (2013). "Results from a prospective, open-label, phase II trial of 
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Duffy D, S. T. (1987). "Confidence intervals for a binomial parameter based on multiusage tests." 
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Habicht, A., S. Dada, et al. (2007). "A link between PDL1 and T regulatory cells in fetomaternal 
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Kaplan, E. L. and P. Meier (1958). "Nonparametric Estimation from Incomplete Observations." Journal 
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Lesokhin, A. M., S. M. Ansell, et al. (2014). "Preliminary Results of a Phase I Study of Nivolumab 
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Lunning, M. A., A. J. Moskowitz, et al. (2013). "Strategies for relapsed peripheral T-cell lymphoma: the 
tail that wags the curve." J Clin Oncol 31(16): 1922-1927. 
McDermott, D. F. and M. B. Atkins (2013). "PD-1 as a potential target in cancer therapy." Cancer Med 
2(5): 662-673. 
O'Connor, O. A., G. Bhagat, et al. (2014). "Changing the paradigms of treatment in peripheral T-cell 
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Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol 
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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat html 
 
 

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Appendix II 
Adverse Event Management Algorithms 
(excerpted from Nivolumab Investigator Brochure version 15, June 2016) 
Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for obstruction. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN and T.bili ≤ 5 x ULN.**The recommended starting dose for grade 4 hepatitis is 2 
mg/kg/day methylprednisolone IV. 
 
 

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Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific grading criteria. 
 
 

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Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once 
sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the 
equivalent dose of oral corticosteroids. 
 
 
 

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Pulmonary Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging and pulmonary 
consultation. 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 

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GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics may 
mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
 
 

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Endocrinopathy Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy.Consider visual field 
testing, endocrinology consulation, and imaging. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
 
 

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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.