Phase II, Multi-Center Trial of Nivolumab and Brentuximab Vedotin in Patients With Untreated Hodgkin Lymphoma Over the Age of 60 Years or Unable to Receive Standard Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) Chemotherapy
Phase: PHASE2
Conditions: Ann Arbor Stage IB Hodgkin Lymphoma, Ann Arbor Stage II Hodgkin Lymphoma, Ann Arbor Stage IIA Hodgkin Lymphoma, Ann Arbor Stage IIB Hodgkin Lymphoma, Ann Arbor Stage III Hodgkin Lymphoma, Ann Arbor Stage IIIA Hodgkin Lymphoma, Ann Arbor Stage IIIB Hodgkin Lymphoma, Ann Arbor Stage IV Hodgkin Lymphoma, Ann Arbor Stage IVA Hodgkin Lymphoma, Ann Arbor Stage IVB Hodgkin Lymphoma, Classic Hodgkin Lymphoma
Sponsor: Academic and Community Cancer Research United

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Academic and Community Cancer Research United (ACCRU) 
 
Phase II, Multi-center Trial of Nivolumab and Brentuximab Vedotin in Patients with Untreated 
Hodgkin Lymphoma Over the Age of 60 Years or Unable to Receive Standard Adriamycin, 
Bleomycin, Vinblastine and Dacarbazine (ABVD) Chemotherapy 
 
For any communications regarding this protocol,  
please contact the person listed on the ProtocolRresource page This is a stand-alone document found 
on the ACCRU website (www.ACCRU.org). 
 
Study Chairs 
                                    ACCRU:           
  
 
 
 
 
 
 
 
 
 FDA IND Sponsor/Investigator:           
 
 
  
 
 
                                  Statistician:  
 
 
  
 
 
                                                          
 
 
Drug Availability                                                                                          
Drug Company Supplied:  Brentuximab Vedotin (Adcetris) 
 
 
 
       Nivolumab (Opdivo) 
 
IND# 128842 (For Combination of both drugs together) 
 
 
 Study contributor(s) not responsible for patient care. 
 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
 
 
Bristol-Myers Squibb #CA209-446 
Seattle Genetics IST # 35-IST-032 
 
Document History 
Effective Date 
Pre-activation ACCRU 
February 26, 2016 
Activation 
May 13, 2016 
Amendment 1 
June 26, 2016  
Amendment 2 
June 2, 2017 
                                      Amendment 3 
 
          December 8, 2017    
Amendment 4              
June 15, 2018                   
Amendment 5 
 
         September 03, 2019 
Ammedment 6  
        January 29, 2020

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Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using Lugano Classification Response Criteria 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
 
 
 
 
  
 
 

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Schema 
 
 
 
 
 
 
 
 
 
 
  
 
 
CMR3, PMR3 
 
 
 
 
 
 
 
 
 
  
 
 
                               NMR3 or PMD3 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length: Cycles 1-7 = 21 days, Cycle 8 = 6-8 weeks  
2 Every 30 days x 90days, then, every 90 days x 2.5 years, then every 6  months until 5 years from 
registration 
3PET-CT based response criteria.  See Section 11.0.   
4Progressive disease by PET-CT or CT based response criteria (see Section 11.0).  PET confirmation of 
progressive disease is per physician discretion.   
Prior to discussing protocol entry with the patient, call the ACCRU Registration Office 
 for dose level and to insure that a place on the protocol is open to the patient.  
 
 
 
Generic name: Brentuximab Vedotin 
Brand name(s): Adcetris 
ACCRU Abbreviation:  SGN35   
Availability:   Almac, Inc. (United States) 
                       Takekda Ireland (Non-U.S.) 
 
Generic name: Nivolumab   
  
 
Brand name(s): Opdivo 
ACCRU Abbreviation: BMS936558 
  
Availability:  
  
 
Registration 
Pre-medicate with  acetaminophen, 
diphenhydramine and  hydrocortisone at least 30 
minutes prior to infusions 
 
BV IV over 30 minutes D1 
Nivolumab over 60 minutes IV D1 
x 2 cycles1 
 
PMD or PD4 at any time, 
Unacceptable adverse                       Event 
    Events, 
 
 
     Monitoring 
Patient refusal  
Subsequent treatment
 
               per Section 18.0 
 
Observation2 
Pre-medicate with acetaminophen, 
diphenhydramine and  hydrocortisone at 
least 30 minutes prior to infusions 
 
BV IV over 30 minutes D1 
Nivolumab over 60 minutes IV D1 x 6 
additional cycles1 (max 8 cycles total) 
Event Monitoring 
per Section 18.0 

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1.0 
Background   
 
1.1 
Disease Background 
 
Hodgkin lymphoma (HL) is predicted to affect over 9,000 patients in the United States in 
2015, approximately 20% of which are greater than 60 years old 1. While current front-
line regimens such as adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) and 
Stanford V produce long-term remissions in younger patients (5-year overall survival 
(OS) 90%) 2, their efficacy is less in the elderly. In E2496, a phase III study of 45 patients 
60 years or greater, ABVD and Stanford V regimens produced an overall response rate 
(ORR) of 68%, a complete response (CR) rate of 64%, and a 5-year OS of only 58% 3.  
Furthermore, treatment related mortality (TRM) was 9% with increased rates of grade 3-4 
neutropenia (82%) and anemia (24%) and grade 3-5 infections (11%) and pulmonary 
toxicity (24%).   The age-related disparity in overall survival with a potentially curable 
lymphoma demonstrates the need for alternative, more tolerable, front line options for the 
elderly.   
 
New biologic molecules have been developed recently to specifically target the malignant 
lymphocyte and its microenvironment with a goal of improving anti-tumor efficacy, 
while limiting toxicity.  Brentuximab vedotin (BV) is an antibody drug conjugate (ADC) 
comprised of a chimeric anti-CD30 monoclonal antibody joined to a microtubule-
disrupting agent, monomethyl auristatin E (MMAE), via a citrulline valine linker.  BV 
gained its approval based on a phase II study demonstrating an ORR of 75% (CR 34%), 
median progression free survival (PFS) of 9.3 months, and a 3-year OS of 40.5 months in 
patients with relapsed and refractory HL following autologous transplant 4,5. In a single-
agent front-line phase II study of HL patients > 60 years-old treated with BV, the interim 
analysis of 27 patients reported an ORR 93%, a CR rate of 70% and PFS of 8.7 months. 
The drug was well tolerated with reports of > grade 3 adverse effects of neutropenia 
(22%), peripheral sensory and motor neuropathy (7% each) and rash (7%) 6.  It is 
currently under study in the ECHELON trial in combination with Adriamycin, 
vinblastine and dacarbazine, being compared with traditional ABVD. 
 
Neoplastic Reed-Sternberg (RS) cells surrounded by a vast inflammatory cell infiltrate 
consisting of both T helper and regulatory cells pathologically characterize HL. 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.  The amplification of chromosome 9p24 leads to over expression of 
PDL-1 and 2 on RS cells, which provides HL a mechanism to evade immune surveillance 
7, Yamamoto, 2008 #2581. Nivolumab (NIV), 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 8. In a phase I study of 23 heavily 
pretreated patients with relapsed/refractory HL, NIV 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 9. Pembroluzimab, a humanized anti-PD-1 antibody, has also been studied in pre-
treated HL revealing an ORR of 57% with CR rate of 20% 10.  
 
Dual inhibition of the malignant lymphocyte and the microenvironment may be 
beneficial to patients with lymphoid malignancies, both in terms of efficacy as well as 
tolerability.  In relapsed follicular lymphoma, the combination of pidiluzumab, a 
humanized anti-PD-1 antibody, and rituximab resulted in an ORR of 66% (CR 52%) and 
median PFS of 18.8 months. The median PFS was not reached in those who achieved a 
response and the regimen was deemed quite tolerable as there were no grade 3 or 4 

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adverse events reported 11.  The cytotoxic component of BV, MMAE, is derived from the 
dolastatin family of microtubule inhibitors.  In immunocompetent mice (C57BL/6) and 
human HL models (L-540 cell line), in addition to triggering apoptosis, dolastatin-10 and 
MMAE were found to be strong inducers of dendritic cell (DC) maturation, resulting in 
T-cell stimulation and adaptive immunity activation 12. In C57BL/6 mice, the 
combination of dolastatin-10 and anti-cytotoxic T-lymphocyte-associated protein 
4(CTLA-4) and PD-1 antibodies was found to be synergistic, leading to an increase ratio 
of interferon gamma producing CD-8 effector T cells in the tumor and improvement in 
complete tumor regression rate from 8% to 58%. Based on these data, we propose that 
the combination of BV and NIV will provide an efficacious but tolerable regimen for 
elderly patients with previously untreated HL.  
 
1.2 
Brentuximab vedotin Background and Associated Known Toxicities 
 
Cancer immunotherapy is based on the premise that tumors can be recognized as foreign 
rather than as self and, can be effectively attacked by an activated immune system. An 
effective immune response in this setting is thought to rely on immune surveillance of 
tumor antigens expressed on cancer cells that ultimately results in an adaptive immune 
response and cancer cell death. This functions by aborting the emergence of tumors as 
they arise and/or causing tumor shrinkage where they are present. Meanwhile, tumor 
progression may depend upon acquisition of traits that allow cancer cells to evade 
immune surveillance and an effective immune response 13. This evasion may occur by 
exploiting any of the checkpoints that control the regulatory immune response, including 
display of antigens and control of costimulatory pathways that affect the proliferation of 
cells involved in immunity. Current immunotherapy efforts attempt to break the apparent 
tolerance of the immune system to tumor cells and antigens by either introducing cancer 
antigens by therapeutic vaccination or by modulating regulatory checkpoints of the 
immune system, either directly by stimulation of immune cells by antibodies directed to 
receptors on T and B cells or indirectly by cytokine manipulation. T-cell stimulation is a 
complex process involving the integration of numerous positive as well as negative 
costimulatory signals in addition to antigen recognition by the T-cell receptor (TCR) 14. 
Collectively, these signals govern the balance between T-cell activation and tolerance to 
antigens. 
 
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a 
member of the CD28 family of T-cell costimulary receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA 14.PD-1 contains an intracellular membrane proximal 
immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal immunoreceptor 
tyrosine-based switch motif (ITSM). Two ligands specific for PD-1 have been identified: 
PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). PD-L1 and PD-L2 have been 
shown to down-regulate T-cell activation upon binding to PD-1 in both murine and 
human systems 15,16.PD-1 delivers a negative signal by the recruitment of SHP-2 to the 
phosphorylated tyrosine residue in the ITSM in its cytoplasmic region 16,17. PD-1 is 
primarily expressed on activated T cells, B cells, and myeloid cells 18. 
Further evidence for a negative regulatory role of PD-1 comes from studies of PD-1-
deficient mice. PD-1-deficient mice develop various autoimmune phenotypes, including 
dilated cardiomyopathy, a lupus-like syndrome with arthritis and nephritis, and 
accelerated diabetes mellitus 19-21. The emergence of these autoimmune phenotypes is 
dependent upon the genetic background of the mouse strain, and many of these 
phenotypes emerge at different times and show variable penetrance. In addition to the 
phenotypes of null mutations, PD-1 inhibition by antibody-mediated blockade in several 
murine models has been found to play a role in the development of autoimmune diseases 
such as encephalomyelitis, graft-versus-host disease, and type I diabetes 22,23.Taken 
together, these results suggest that PD-1 blockade has the potential to activate anti-self T-

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cell responses, but these responses are variable and dependent upon various host genetic 
factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens. 
 
Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor 
rejection. Antitumor activity by PD-1 blockade functions in PD-L1-positive tumors as 
well as in tumors that are negative for the expression of PD-L1 24-26. This suggests that 
host mechanisms (ie, expression of PD-L1 in antigen-presenting cells) limit the antitumor 
response. Consequently, both PD-L1 positive and negative tumors may be targeted using 
this approach. In humans, constitutive PD-L1 expression is normally limited to 
macrophage-lineage cells, although expression of PD-L1 can be induced on other 
hematologic cells as well, including activated T cells. However, aberrant expression of 
PD-L1 by tumor cells has been reported in a number of human malignancies 27,28. PD-L1 
expressed by tumor cells has been shown to enhance apoptosis of activated tumor-
specific T cells in vitro 16 Moreover, the expression of PD- L1 may protect the tumor 
cells from the induction of apoptosis by effector T cells 29. 
Retrospective analyses of several human tumor types suggest that tumor over-expression 
(as measured by IHC) of PD-L1 may permit immune evasion by tumors. In renal cell 
carcinoma, high surface expression levels of PD-L1 on tumor cells are related to tumor 
aggressiveness 28,30. 
 
Subjects with high tumor and/or lymphocyte PD-L1 levels are 4.5 times more likely to 
die from their cancer than subjects exhibiting low levels of PD-L1 expression. In 
addition, in multivariate analysis, high expression of PD-L1 is correlated to have a worse 
overall survival rate compared with low expression levels of PD-L1 31. 
PD-1 blockade by nivolumab is therefore considered a promising immunotherapeutic 
option. 
 
Brentuximab vedotin (ADCETRISTM, the first “A” of the experimental arm acronym) is 
an antibody-drug conjugate (ADC) composed of the anti-CD30 chimeric 
immunoglobulin G1 (IgG1) monoclonal antibody cAC10 and the potent antimicrotubule 
drug monomethyl auristatin E connected by a protease-cleavable linker. cAC10 binds to 
the CD30 antigen, which has a very  low expression on normal cells but is found on the 
HRS cells of HL, on anaplastic large cell lymphoma (ALCL) cells, and on tumor cells of 
other varied lymphoproliferative disorders. 
 
Brentuximab vedotin is approved in the United States as ADCETRISTM for the treatment 
of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure 
of at least 2 prior multi-agent chemotherapy regimens in patients who are not ASCT 
candidates and for the treatment of patients with systemic ALCL after failure of at least 1 
prior multi- agent chemotherapy regimen (1). 
 
 
1.21  
Nonclinical Experience 
 
 Brentuximab vedotin has the potential to target and selectively deliver a potent 
cytotoxic to tumor cells. It induces cell death of both HL and ALCL cell lines in 
vitro with subnanomolar concentrations producing 50% inhibition (IC50) and has 
demonstrated antitumor activity in xenograft models of the same tumors. 
 
 Multiple-dose brentuximab vedotin toxicity studies have been performed in 
monkeys and rats. In both species, hypocellularity of the bone marrow and 
lymphoid depletion of the thymus were observed. In addition, lesions were seen 
in the kidneys, liver, and spleen in monkeys and in the liver and testes in rats. 

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Reversibility of toxicity was demonstrated for all of the findings with the 
exception of the testicular changes in rats. At the recovery sacrifice 4 weeks 
following the last dose of brentuximab vedotin, testicular changes (diffuse 
seminiferous tubule degeneration) were still evident. The no observed adverse 
effect level for brentuximab vedotin was defined at 1.0 mg/kg in monkeys and 
0.5 mg/kg in rats. Human equivalent doses are 0.32 and 0.08 mg/kg, respectively. 
 
1.211 In the L450cy tumor model 32, administration of  doxorubicin 
(Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) plus 
brentuximab vedotin in tumor-bearing mice demonstrated significantly increased 
antitumor activity as compared to the mice treated with ABVD or brentuximab 
vedotin alone, suggesting a synergistic effect 33. ABVD and brentuximab 
vedotin-treated  animals demonstrated 0/8 and 4/9 durable responses, 
respectively, while the combination of brentuximab vedotin and ABVD resulted 
in 9/9 durable tumor regressions in all experimental animals. In addition, 
combination therapy was associated with a statistically significant tumor  growth 
delay (TGD) relative to each treatment arm alone (combination  vs brentuximab 
vedotin: P < 0.0101, combination versus ABVD: P < 0.0001). Improved efficacy 
in high tumor burden models suggests that combining brentuximab vedotin with 
ABVD may be associated with greater efficacy. 
 
Similarly, when treatment was initiated when tumors reached 300 mm3  volume, 
the combination of brentuximab vedotin with ABVD significantly increased the 
TGD, resulting in durable responses in 5 of 10 animals. The delay in tumor 
growth induced by the combination treatment was highly significant relative to 
each individual treatment arm alone (combination versus brentuximab vedotin:  
P < 0.05, combination versus ABVD: P < 0.001). 
 
Doxorubicin, vinblastine, and bleomycin had little if any single-agent antitumor 
activity in L540cy xenograft models and did not significantly improve antitumor 
activity of Brentuximab vedotin (ADCETRISTM) (1).   
 
 
1.22 
Clinical Experience 
 
The safety and efficacy of brentuximab vedotin has been evaluated in more 
than 450 patients with HL, sALCL, and other CD30+ hematologic 
malignancies in 11 clinical  
studies. Clinical data have been collected from 2 
completed phase 1 dose-escalation  
studies (SG035-0001 and SG035-0002), 
a pivotal phase 2 study in relapsed or refractory HL after ASCT (SG035-0003), a 
pivotal phase 2 study in relapsed or refractory systemic ALCL (sALCL) (SG035-
0004), and a phase 1 drug-drug interaction study (SGN35-008A). Preliminary 
and final analyses of safety data indicate that brentuximab vedotin has a 
manageable safety profile in the studied populations. 
 
 
1.221 In Study SG035-0001, a total of 45 patients with CD30+ hematologic 
 
malignancies (42 with HL, 2 with sALCL, 1 with angioimmunoblastic T-
 
cell lymphoma) were treated with brentuximab vedotin at dose levels of 
 
0.1 to 3.6 mg/kg administered intravenously (IV) every 3 weeks. The 
 
primary objectives of the study were to establish a maximum tolerated 
 
dose (MTD) of brentuximab vedotin and to assess the associated toxicity 
 
profile. The most common adverse events (AEs) were fatigue (36%), 
 
pyrexia (33%), diarrhea, nausea, peripheral neuropathy, and neutropenia 
 
(22% each). Notable serious adverse events (SAEs) considered at least 
 
possibly related to treatment included anaphylaxis, myocardial 
 
infarction, and peripheral neuropathy. Numerous responses, including 

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complete remissions (CRs), were observed. The maximum tolerated dose 
 
(MTD) was determined to be 1.8 mg/kg administered IV over 30 minutes 
 
every 3 weeks. 
 
 
1.222 In Study SG035-0002, a total of 44 patients with CD30-positive 
 
hematologic malignancies (including 38 with HL) were treated with 
 
brentuximab vedotin at dose levels of 0.4 to 1.4 mg/kg administered IV 
 
weekly for 3 of 4 weeks. The primary objectives explored in this study 
 
were to establish the safety profile and MTD of weekly brentuximab 
 
vedotin monotherapy in patients with relapsed/refractory CD30+ 
 
hematologic malignancies.   
 
Brentuximab vedotin (ADCETRISTM) Clinical Study Protocol C25003 
 
Amendment 4, EudraCT: 2011-005450-60 
 
 
1.223 Although this weekly regimen was designed to enable combination use 
 
with gemcitabine, efficacy with brentuximab vedotin monotherapy was 
 
deemed sufficient and the planned brentuximab vedotin/gemcitabine 
 
combination was not pursued. The most common AEs were peripheral 
 
sensory neuropathy (66%); fatigue (52%); nausea (50%); diarrhea (32%); 
 
arthralgia (27%); pyrexia (25%); and decreased appetite, myalgia, and 
 
upper respiratory tract infection (23% each). Treatment discontinuations 
 
due to AEs were observed in 30% of patients. The most frequent AE that 
 
led to dose modification or delay was peripheral sensory neuropathy. 
 
Acute infusion reaction AEs occurred in a total of 6 patients. Overall, 
 
these acute infusion reaction AEs were reported as less than Grade 2 in 
 
severity and resolved. Overall, 2 patients (14%) who had an acute 
 
infusion reaction also had antitherapeutic antibodies at any postbaseline 
 
visit. 
 
 
1.224 In SG035-0003, a phase 2 single-arm, open-label study in patients with 
 
relapsed or refractory HL after ASCT, and SG035-0004, a phase 2 trial 
 
conducted in patients with relapsed or refractory sALCL, brentuximab 
 
vedotin was administered at a dose of 1.8 mg/kg every 3 weeks. One 
 
hundred two patients with relapsed and refractory HL and 58 patients 
 
with relapsed and refractory sALCL were exposed for a median duration 
 
of approximately 27weeks (9 cycles) and 20 weeks (6 cycles), 
 
respectively. Most patients (89%) in the 2 phase 2 studies were between 
 
the ages of 18 and 65 years. The primary endpoint of both studies was 
 
overall response rate (ORR) as assessed by an independent review 
 
facility (IRF). Key secondary endpoints included duration of response, 
 
CR rate per IRF, OS, and progression free survival (PFS). The key 
 
efficacy results in HL (SG035-0003) include ORR per IRF (75% [95% 
 
confidence interval (CI): 64.9-82.6%]), CR rate per IRF (34% [95% CI: 
 
25.2 44.6%]), B symptom resolution rate (77%), and duration of 
 
response (DOR; 6.7 months). Of interest, for those patients achieving a 
 
CR, the median DOR was 20.5 months. Key efficacy endpoints in 
 
sALCL (SG035-0004) include ORR per IRF (88% [95% CI: 74.6-
 
93.9%]), CR rate per IRF (53% [95% CI: 39.6-66.7%]), and B symptom 
 
resolution rate (82%). 
 
 
1.225 Treatment-emergent AEs (TEAEs) occurring in ≥ 20% of patients in 
 
phase 2 were peripheral sensory neuropathy (44%), fatigue (42%), 
 
nausea (41%), diarrhea (34%), pyrexia (31%), upper respiratory tract 
 
infection (28%), neutropenia (21%), and vomiting (20%). These events 

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were primarily mild to moderate in severity and reversible. 
 
Approximately half of patients had treatment-emergent peripheral 
 
neuropathy, predominantly sensory neuropathy, with an onset and 
 
severity pattern consistent with a cumulative effect. Dose delay and 
 
subsequent reduction to 1.2 mg/kg was generally effective in managing 
 
peripheral neuropathy. Grade 3 and 4 neutropenia occurred in 13% and 
 
7% of patients, respectively. 
 
Brentuximab vedotin (ADCETRISTM) Clinical Study Protocol 
C25003 Amendment 4, EudraCT: 2011-005450-60 
 
 
1.226 These events were typically of short duration and well managed by brief 
 
dose delays with growth factor support in some cases. Infusion-related 
 
reactions occurred in approximately 10% of patients and were typically 
 
managed by dose interruption. Infusion-related reaction prophylaxis in 
 
subsequent treatment cycles was instituted at the discretion of the 
 
investigator. The clinical laboratory parameters for which the most 
 
patients had new or worsening shifts to ≥ Grade 3 were low neutrophils 
 
(11%), lymphocytes (11%), platelets (6%), leukocytes (5%), and high 
 
glucose (6%). Only 1 patient in the phase 2 studies had Grade 3 ALT and 
 
aspartate aminotransferase (AST). 
 
 
1.227 In the phase 2 studies, 31% of patients had an SAE, 28% had an SAE of 
 
Grade 3 or higher, and 15% had an SAE that was determined by the 
 
investigator to be related to brentuximab vedotin. The most common 
 
SAE preferred terms (2%) were abdominal pain, disease progression 
 
(recurrent sALCL), pulmonary embolism, and septic shock. A higher 
 
proportion of sALCL patients experienced SAEs, including deaths within 
 
30 days of last dose, relative to HL patients, likely due to the older age 
 
and more aggressive nature of the malignancy in this patient population. 
 
 
1.228 A total of 9 deaths were reported within the safety evaluation period 
 
(within 30 days of the last dose of brentuximab vedotin) in 357 patients 
 
across the 6 phase 1 and phase 2 studies for which data are available. 
 
Two patient deaths (0.6%) were considered related to study treatment. 
 
One patient in Study SG035-0001 who received 3.6 mg/kg in phase 1 
 
died due to febrile neutropenia and presumed septic shock. A second 
 
treatment-related death in Study SGN35-008A was attributed to 
 
pancytopenia, cytomegalovirus (CMV) infection, and intracranial 
 
hemorrhage. The remaining on-study deaths were primarily related to 
 
disease progression in sALCL patients. 
 
 
1.229a Brentuximab vedotin has been shown to induce durable remissions in 
 
patients with HL both pre- and post-ASCT, and in patients with relapsed 
 
or refractory sALCL. PFS results comparing PFS with brentuximab 
 
vedotin to PFS from prior systemic therapy indicate that PFS is 
 
significantly prolonged with brentuximab vedotin for both HL and 
 
sALCL. A substantial number of HL and sALCL patients with B 
 
symptoms at baseline saw these symptoms resolve during treatment with 
 
brentuximab vedotin. In addition, the large majority of sALCL patients 
 
presenting with cutaneous lesions at baseline experienced resolution of 
 
these symptoms after receiving brentuximab vedotin. 
 
Study SGN35-009 is a phase 1, 2-arm, open label, multicenter study to 
 
evaluate the safety of brentuximab vedotin when administered in 
 
combination with standard therapy (ABVD) or a modified standard 

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(doxorubicin (Adriamycin), vinblastine, dacarbazine [AVD]). To date, 
 
patients have received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab 
 
vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin 
 
with AVD, depending upon cohort assignment. The combination 
 
regimens are administered on Days 1 and 15 of each 28-day cycle for up 
 
to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity 
 
(DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥ 7 
 
days in standard ABVD or AVD therapy. No DLTs were observed. 
 
Enrollment of an expansion cohort further testing 1.2 mg/kg brentuximab 
 
vedotin plus AVD is now complete and treatment of enrolled patients is 
 
ongoing within this cohort. 
 
 
1.229b Of the 51 patients enrolled in Study SGN35-009, the mean age was 34.8 
 
(range 18-59); 47% of patients had Stage IV disease at diagnosis, and 
 
25% had a Hasenclever Hodgkin’s Prognosis Score (IPS) ≥ 4. A recent 
 
review of interim safety data as of 07 February 2012 for all 51 enrolled 
 
patients included data from 25 patients in the brentuximab vedotin plus 
 
ABVD cohorts and 26 patients in the brentuximab vedotin plus AVD 
 
cohorts. The most commonly reported TEAEs were nausea, neutropenia, 
 
peripheral sensory neuropathy, fatigue, vomiting, constipation, alopecia, 
 
pyrexia, bone pain, decreased appetite, diarrhea, and insomnia, each 
 
reported in 25% or more patients. Peripheral neuropathy events have 
 
been reported in 25 patients (49%); 1 patient had Grade 3 peripheral 
 
motor and sensory neuropathy, but no other patient’s peripheral 
 
neuropathy event exceeded Grade 2. In the brentuximab vedotin plus 
 
ABVD cohorts, Grade ≥ 3 events included neutropenia (n = 20, 80%), 
 
febrile neutropenia (n = 5), pulmonary toxicity (n = 5), anemia (n = 4), 
 
dyspnea (n = 3), pulmonary embolism (n = 3), syncope (n = 3), and 
 
anorectal cellulitis, cough, fatigue, hypokalemia, hyponatremia, 
 
leukopenia, pericardial effusion, rash, and respiratory failure (n = 1 
 
each). In the brentuximab vedotin plus AVD cohorts, Grade ≥ 3 events 
 
included neutropenia (n = 17, 65%), anemia (n = 3), febrile neutropenia 
 
(n = 2), and decreased appetite, dyspnea, elevated ALT, fatigue, 
 
leukopenia, peripheral sensory and motor neuropathy, Pneumocystis 
 
jiroveci pneumonia, SIADH, syncope, and tooth abscess (n = 1 each). 
 
 
1.229c Interim efficacy data as of 07 February 2012 demonstrate that all patients 
 
who completed frontline therapy on study for whom response assessment 
 
results are available achieved a CR at the end of treatment, including 18 
 
patients from the ABVD cohorts and 6 patients from the AVD cohorts. 
 
Additionally, an exploratory analysis of interim fluorodeoxyglucose 
 
(FDG) positron emission tomography (PET) results after 2 cycles of 
 
therapy was performed by independent radiology review using the 
 
Deauville criteria.(8) Of 37 patients, 36 (97%) had a negative interim 
 
PET after Cycle 2 by central review, including 22 of 22 (100%) negative  
 
 
in the ABVD cohorts and 14 of 15 (93%) negative in the AVD cohorts. 
 
1.3 
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 activated T and B lymphocytes 34. 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), 

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ACCRU# RU051505I 
 
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 is 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. OPDIVOTM (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).  
 
 
1.31 
Nonclinical Studies  
 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and 
not to related members of the CD28 family.2,3 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.4,5,6 Nivolumab 
binds with high affinity to activated human T-cells expressing cell surface PD-1 
and to cynomolgus monkey PD-1.2 In a mixed lymphocyte reaction (MLR), 
nivolumab promoted a reproducible concentration-dependent enhancement of 
IFN-
35.  
 
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 36.  
 
In addition, an enhanced pre- and postnatal development (ePPND) study in 
pregnant cynomolgus monkeys with nivolumab was conducted 37. Administration 
of nivolumab at up to 50 mg/kg 2QW was well tolerated by pregnant monkeys; 
however, nivolumab was determined to be a selective developmental toxicant 
when administered from the period of organogenesis to parturition at ≥10 mg/kg 
(area under the concentration-time curve [AUC] from time zero to 168 hours 
[AUC(0-168 h)] 117,000 µg•h/mL). Specifically, increased developmental 
mortality (including late gestational fetal losses and extreme prematurity with 
associated neonatal mortality) was noted in the absence of overt maternal 
toxicity. There were no nivolumab-related changes in surviving infants tested 
throughout the 6-month postnatal period. Although the cause of these pregnancy 
failures was undetermined, nivolumab-related effects on pregnancy maintenance 
are consistent with the established role of PD-L1 in maintaining fetomaternal 
tolerance in mice 38. Approved v 15.0 930038243 16.0 18 Investigator 
Brochure BMS-936558/MDX1106 nivolumab.  
 
 
1.32 
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 presented in this Investigator Brochure (IB) focuses primarily on that 
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 

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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.  
 
 
1.33 
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.  
 
 
1.34 
Clinical Efficacy  
 
Nivolumab has demonstrated durable responses exceeding 6 months as 
monotherapy and in combination with ipilimumab or other agents  in several 
tumor types, including NSCLC, melanoma, RCC, and some lymphomas 9,11,39. 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.  
 
 
 

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1.4 
Safey in Subjects with Relapsed or Refractory Hematologic Malignancies 
 
CA209039 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 non Hodgkin’s lymphoma 
[small lymphocytic lymphoma] in 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).  
 
 
1.41 
Clinical Activity of Nivolumab in Lymphoma 
 
In a broad phase II study, Ansell et al treated 23 patients with classical HL who 
had been heavily pretreated 9.  Nivolumab at a dose of 3 mg/kg was administered 
q 2 weeks until CR< 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 Lesokhin et al reported 29 patients with a variety of 
histologies of B-NHL with responses in 36% of diffuse large B-cell NHL (9% 
CR), 40% of follicular NHL (10% CR) 40.   
 
1.5 
Rationale 
 
Given the impressive activity of both Brentuximab Vedotin and nivolumab in patients 
with relapsed and refractory Hodgkin Lymphoma, and their lack of overlapping 
toxicities, the combination is worthy of study. Given the poor results and tolerability of 
traditional chemotherapy in older patients with Hodgkin Lymphoma, as described above, 
this combination can be considered for first-line therapy. 
 
 
 
 
 

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ACCRU# RU051505I 
 
2.0 
Goals    
 
2.1 
Primary 
 
2.11  
The primary objective of the study is to determine the efficacy based on overall 
rmetabolic response rate (PMR + CMR) of Brentuximab Vedotin /Nivolumab in 
previously untreated Hodgkin Lymphoma  patients 60 years of age or older, or 
those considered unsuitable for standard chemotherapy because of a low cardiac 
ejection fraction (<50%) or impaired pulmonary or renal function.   
 
2.2 
Secondary 
 
2.21 
The complete metabolic response (CMR) rate  
 
2.22 
Safety and tolerability of the regimen in this patient population 
 
2.23 
Duration of response (DOR) 
 
2.24 
Progression-free survival (PFS) 
 
2.25 
Overall survival (OS) 
 
 
2.3 
Correlative Research 
 
 
 
2.31 
T-cell/cytokine– 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. 
 
 
 
 
 
2.32 
Biomarkers- intratumoral cell populations, genetic variability, serum cytokines  
 
 
 
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. 
 
3.0 
Patient Eligibility    
 
 
Prior to discussing protocol entry with the patient, call the 
 
 for dose level and to ensure that a place on the protocol is open to the 
patient. 
 
3.1 
Registration – Inclusion Criteria 
 
3.11 
Classical Hodgkin Lymphoma determined by local hematopathology review 
 
 
3.12 
One of the following: 
 
Age ≥ 60 years 
 
Age <60 years but unsuitable for standard chemotherapy because of a cardiac 
ejection fraction of <50%, a pulmonary diffusion capacity <80%, or a 
creatinine clearance ≥30 and <60 mL/min, or refused standard chemotherapy 
despite efforts  to convince them otherwise. 
 
 

Amendment 6 
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ACCRU# RU051505I 
 
 
3.13 
Requirement for systemic chemotherapy: all stages except IA (not bulky 
disease),  if involved field is considered Radiotherapy (RT) curative.    
 
3.14 
Previously untreated with either chemotherapy, radiation therapy or either 
brentuximab vedotin or nivolumab, or another check point inhibitor.  
 
3.15 
ECOG Performance Status (PS) 0, 1, or 2  (Appendix II) 
 
3.16 
The following laboratory values obtained  7 days prior to registration.  
 
 
Absolute neutrophil count (ANC) ≥1500/mm3, unless secondary to bone 
marrow involvement. 
 
Leukocytes  3,000/mm3 
 
Platelet count 100,000/mm3 
 
Hemoglobin >9.0 g/dL – unless determined by treating physician to be 
disease related 
 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
 
Aspartate transaminase (AST)  2.5 x ULN 
 
Alanine Transaminase (ALT)  2.5 x ULN 
 
Creatinine 2.0 mg/dL 
 
Amylase and/or lipase ≤1.5 x ULN 
 
3.17 
Women of childbearing potential must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to registration   
 
 
 
 
Note: Women of child-bearing potential (WOCBP) must use appropriate  
 
 
 
method(s) of contraception. WOCBP should use an adequate method to avoid  
 
 
 
pregnancy for 23 weeks (30 days plus the time required for nivolumab to  
 
 
 
undergo five half-lives) after the last dose of investigational drug. 
  
 
 
Men who are sexually active with WOCBP must use any contraceptive method  
 
 
 
with a failure rate of less than 1% per year.  Men receiving nivolumab and who  
 
 
 
are sexually active with WOCBP will be instructed to adhere to contraception for 
 
 
 
a period of 31 weeks after the last dose of investigational product.  Women who  
 
 
 
are not of childbearing potential (ie, who are postmenopausal or surgically  
 
 
 
sterile) as well as azoospermic men do not require contraception. Should a  
 
 
 
woman become pregnant or suspect she is pregnant while participating in this  
 
 
 
study, she should inform her treating physician immediately. 
 
3.18 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note:  During the Active Monitoring Phase of a study (i.e., 
active treatment and observation), participants must be willing to return to the 
consenting institution for follow-up. 
 
3.19a 
Ability to understand and willingness to sign an informed written consent.  
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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ACCRU# RU051505I 
 
 
3.19b Provide blood and tissue samples for mandatory correlative research purposes 
(see sections 4.0, 14.0 and 17.0). 
 
3.2.1 
Registration – Exclusion Criteria  
 
3.21 
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    
 
3.22 
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. 
 
3.23 
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, or conditions not expected to recur in the absence 
of an external trigger 
 
3.24 
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 and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
 
3.25 
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, patients with a 
prior history of known or suspected autoimmune disease, active Hepatitis B virus 
surface antigen (HBV sAg+), active Hepatitis C (if Ab+ then PCR+) indicating 
acute or chronic infection, and/or  history of interstitial lung disease. 
 
3.26 
Allergy to Brentuximab Vedotin and/or Nivolumab 
 
3.27 
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. 
 
3.28 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.29a 
Have had prior chemotherapy or radiotherapy for Hodgkin lymphoma 
 
3.29b Have received either of the study drugs 
 
3.29c 
<60 years who are considered candidates for standard chemotherapy 
 

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ACCRU# RU051505I 
 
3.29d > Grade 2 peripheral neuropathy 
 
3.29e 
Other active malignancy ≤2 years prior to registration, unless treated with 
curative intent.  EXCEPTIONS:  Non-melanotic skin cancer or carcinoma-in-situ 
of the cervix.  NOTE:  If there is a history or prior malignancy, they must not be 
receiving other specific treatment for their cancer.  
 
3.29f 
Active CNS involvement or leptomeningeal metastases involvement.  
 
3.29g Known history of pancreatitis. 

Amendment 6 
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ACCRU # RU051505I 
 
 
 
 
 
 
4.0 
Test Schedule 
 
 
 
Active Monitoring Phase 
 
 
 
Tests and procedures 
 
 
Baseline 
<14 days of 
Registration 
 
 
Prior to 
each new 
cycle10 
</= 3 days 
(starting at 
cycle 2) 
 
 
Restaging 
End of 
Cycle 8 (6-8 
Weeks after 
Day 1 of 
Cycle 8)  
 
 
 
 
End of 
Treatment if 
discontinued 
early (at PD 
or PMD, 
withdrawal, 
or removal) 
 
 
Observation  
(Every 30 days x 90 
days, , then every 90 
days x 2.5 years, 
then every 6 months 
until 5 years from 
registration) 
+/-14Days 
 
History and exam 
X 
X1 
X 
X 
X 
B Symptoms9 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
Height (baseline only), Weight 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
Cardiac ejection fraction 
   X14 
 
 
 
 
ECG 
X 
 
 
 
 
Pulmonary function studies (including oxygen 
saturation)12 
X 
 
 
 
 
HBV sAg and HCV Ab or HCV RNA 
X 
 
 
 
 
Comprehensive metabolic panel: (ALT, AST, 
total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, 
Cl, LDH, Glucose, amylase, lipase, Albumin, 
bicarbonate 
X4 
X 
X 
X 
 
INRR, 13 
 
X 
X 
X 
X 
TSH (with Free T4 and Free T3) 
X4 
X11 
X 
X 
 
Hematology: 
CBC/differential 
 X4 
X 
X 
X 
X 
Erythrocyte sedimentation rate 
X 
 
 
 
 
Uric Acid 
X 
 
 
 
 
Pregnancy Test3 
X 
X 
X 
X 
X 
PET-CT  
   X14 
X2 
X 
X 
 
CT scan Chest/Abd/Pelvis 
 
 
 
 
X5 
Mandatory Research blood samples (See 
section 14.0)R, 6 
 
X15 
X 
X 
X8 
Mandatory Tissue sample7, R 
X 
 
 
 
 
 
(Footnotes on next page) 
 
 

Amendment 6 
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ACCRU # RU051505I 
 
 
 
 
 
 
1 
If on physical exam there are any palpable lymph nodes present: Tumor (bidiminsional) measurements by physical exam to be done at end of every cycle, prior 
to next cycle. 
2 
End of cycle 2, prior to Cycle 3 (≤ 5 days) 
3 
For women of childbearing potential only.  A serum or urine pregnancy testing is required  ≤ 24 hours before registration, then every other cycle. (more 
frequently if required by local standard). After discontinuation from nivolumab, these should be repeated at approximately 30 days and approximately 70 days 
[or more frequently if required by local standard]. 
4 
Must be obtained <7 days prior to registration. 
5 
CT scan is every 3 months during the first year of observation, then as clinically indicated. 
6 
Must be drawn on Day 1 of each cycle before treatment Cycles 1-8, at restaging 6-8 weeks post Cycle 8 Day 1, end of treatment if discontinued early (PD or 
PMD, withdrawal or removal), and at time of PD or PMD.  
7 
To be submitted within <14 days following Registration; see 17.0 Pathology Considerations/Tissue Biospecimens 
8 
Only at time of PD or PMD 
9 
Unexplained persistent fever > 38o C( or >100.4o 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 
10 If tests have been done ≤ 14 days prior to registration they need not be repeated for the first cycle. 
11 Thyroid function testing should be done every third cycle day 1 (≤ 3 days) for subjects receiving nivolumab. 
12 Oxygen saturation by pulse oximetry at rest (also specify supplemental oxygen level, if applicable) should be assessed at baseline 
13 ONLY if clinically indicated 
14 Must be obtained ≤28 days prior to registration. 
15   Research blood draw to be done prior to every cycle, including Cycle 1. 
R Research funded (see Section 19.1) 
 
 

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ACCRU RU051505I  
 
 
 
5.0 
Stratification Factors:  None 
 
6.0  
Registration Procedures 
 
6.1 
Safety Analysis Phase 
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office 
 for dose level and to ensure that a place on the protocol is 
open for the patient.  
 
6.11 
Registration Procedures 
 
To register a patient, fax 
a completed eligibility checklist to the 
Academic and Community Cancer Research United (ACCRU) Registration 
Office between 8 a.m. and 4:30 p.m. central time Monday through Friday.   
 
6.2 
Phase II Cohort 
 
6.21 
To register a patient, access the ACCRU web page at
 go to the 
Application section and click on “Registration” 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 Academic and Community Cancer Research United 
(ACCRU) Registration Office at 
 
 
 
The instructions for the registration/randomization application are available on the 
above web page under the Study Resources section, “Application Training.”  
 
Prior to initiation of protocol study intervention, this process must be completed in its 
entirety and a ACCRU subject ID number must be available as noted in the 
instructions.  It is the responsibility of the individual and institution 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 ACCRU Registration Office 
.  If the 
patient was fully registered, the ACCRU Registration Office staff 
can access the information from the centralized database and 
confirm the registration. 
 
Refer to “Application Training” at 
 click on 
“Registration, Installation & Entry Instructions”.  
 
6.3 
Safety Analysis Cohort and Phase II Cohort 
 
 
6.31 
Correlative Research 
 
A mandatory correlative research component is part of this study. The patient 
will be automatically registered onto this component (see Sections 3.0, 14.0 and 
17.0). 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 

Amendment 6               Page 21  
 
ACCRU RU051505I  
 
 
 
 
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  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. Approvals should be uploaded using 
the online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals 
should be uploaded using online ACCRU Regulatory Management Systems 
(ARMS).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. 
 
Submission of annual IRB approvals is required until the study has been closed 
through your IRB. 
 
6.34 
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 to learn about, prevent, or treat cancer. 
 
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 (for example:  
diabetes, Alzheimer’s disease, or heart disease). 
 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.35 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist or hematologist.  
 
 
6.36 
Treatment cannot begin prior to registration and must begin 14 days after 
registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.54) must be documented and 
graded. 
 
6.39a 
Study drug is available on site.  
 
6.39b Blood draw kit is available on site. Kits must be used for this study. 
 
7.0 
Protocol Treatment 
 
7.1 
Safety Analysis Phase:   Since this combination has not been studied to date, the first 6 
patients treated at dose level 1 will be used as an early safety analysis per Section 16.4.  If 
2 or more patients experience a dose-limiting toxcitity (DLT) as defined below, then the 
starting dose level will be adjusted and additional cohorts may be evaluated at dose levels 
-1 and -2 in the safety analysis phase as described in section 16.4.   A conference call will 

Amendment 6               Page 22  
 
ACCRU RU051505I  
 
 
 
be held weekly amongst the investigators to discuss patients on study or proposed for 
accrual.  Investigators are to contact the ACCRU Operations Office (507-266-0800 as 
soon as any DLT occurs. 
 
7.11 
Safety Analysis Dose Levels 
 
Dose level 
Brentuximab Vedotin 
Nivolumab 
-2 
1.2 mg/kg IV Day 1  
Omit 
-1 
1.8 mg/kg IV Day 1  
Omit 
*1 
1.8 mg/kg IV Day 1 
3 mg/kg IV Day 1 
 
 
*starting dose level  
 
7.12 
Definition of Dose Limiting Toxicity (DLT) 
 
For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse 
event occurring during the first cycle of treatment that is possibly, probably, or 
definitely related to study treatment and that meets one of the following: 
•  Any ≥Grade 4 non-hematological organ toxicity (except for  Grade 4 
nivolumab related diarrhea, pneumonitis, LFT elevations, that improve within 7 
days) 
•  Any ≥Grade 4 hematological toxicity (excluding asymptomatic Grade 4 
elevations in amylase or lipase) 
 
 
7.2 
Treatment Schedule - Use actual weight  
 
7.21 
Pretreatment medication  
  
Agent 
 
Dose Level 
Route 
Day 
Cycle Length 
Acetaminophen1 
650 mg 
PO 
Day 1 
Cycles 1-7 
(21 days) 
Cycle 8  
(6-8 weeks) 
Diphenhydramine1 
25-50 mg 
IV infused or 
PO at least 30 
minutes prior 
to  
brentuximab 
Vedotin and  
Nivolumab 
infusions 
 
Day 1 
 
 
Cycles 1-7 
(21 days) 
Cycle 8  
(6-8 weeks) 
Hydrocortisone1 
(or other steroid 
equivalent) 
  
100 mg       
 
 
IV infused at 
least 30 
minutes prior 
to  
brentuximab 
Vedotin and  
Nivolumab 
infusions 
 
Day 1 
 
 
Cycles 1-7 
(21 days) 
Cycle 8  
(6-8 weeks)  
1. If Brentuximab Vedotin is omitted there are no premedications to be given with just 
Nivolumab. 

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ACCRU RU051505I  
 
 
 
7.22 
Treatment Schedule 
 
Agent 
Dose Level 
Route 
Day 
Cycle Length 
Brentuximab 
vedotin 
1.8 mg/kg (cap 
at 180 mg) in 
100 to 250 mL 
NS to final 
concentration 
0.4 mg/mL to 
1.8 mg/mL 
IV infused  
over 30 
minutes,  
  before 
nivolumab  
Day 1 
 
 
 
 
 
Cycles 1-7 
(21 days) 
Cycle 8  
(6-8 weeks)  
Nivolumab 
3 mg/kg in 100 
cc NS 
IV infused 
over 60 
minutes.  
1 hour   
after 
completion of 
Brentuximab 
vedotin 
Day 1 
 
 
 
7.222 The dosing calculations should be based on the actual body  
 
 
weight at baseline. If the subject’s weight on the day of dosing  
 
 
differs by > 10% from the weight used to calculate the original  
 
 
dose, the dose must be recalculated. All doses should be rounded 
 
 
to the nearest milligram. Subjects should be carefully monitored  
 
 
for infusion reactions during nivolumab administration. If an  
 
 
acute infusion reaction is noted, subjects should be managed  
 
 
according to Protocol Section 9.Doses of nivolumab may be  
 
 
interrupted, delayed, or discontinued depending on how well the  
 
 
subject tolerates the treatment. Nivolumab Injection, 100 mg/10  
 
 
mL (10 mg/mL) and 40 mg/mL (10 mg/mL)   Nivolumab 
 
 
 
injection is to be administered as an IV infusion through a 0.2- 
 
 
micron to 1.2-micron pore size, low-protein binding  
 
 
 
polyethersulfone membrane in-line filter at the protocol-  
 
 
specified doses. It is not to be administered as an IV push or  
 
 
bolus injection. Nivolumab injection can be infused undiluted  
 
 
(10 mg/mL) or diluted with 0.9% Sodium Chloride Injection,  
 
 
USP or 5% Dextrose Injection, USP to protein concentrations as  
 
 
low as 1 mg/mL. Care must be taken to assure sterility of the  
 
 
prepared solution as the product does not contain any  
 
 
 
antimicrobial preservative or bacteriostatic agent. 
 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 21 days during treatment (with the exception of  Cycle 8). After 
therapy completion, the patient must return to the institution, every 30 days x 90 days, 
then every 60 days x 180 days, then every 90 days x 2 years, then every 6 months until 5 
years post registration, during observation (Active Monitoring Phase) until the patient 
goes to event monitoring per Section 13.0. 
 
7.4 
Patients will be treated for a planned maximum of 8 cycles.  
 
7.5 
A PET-CT scan will be performed within 5 days prior to starting cycle 3. Patients who 

Amendment 6               Page 24  
 
ACCRU RU051505I  
 
 
 
are in CMR or PMR continue treatment for a total of 8 cycles as tolerated. Those with 
NMR or PMD at the first interim PET-CT (within 5 days prior to starting cycle 3), or 
who experience PD or PMD any time thereafter go off treatment to event monitoring and 
are treated as per their primary hematologist/oncologist.   
 
7.6 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days (+/- 3 days) during protocol treatment. Protocol treatment may not be 
administered by a local medical doctor (LMD).   
 
8.0 
Dosage Modification Based on Adverse Events  
 
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 to 
produce mild-to-moderate, but not debilitating, side effects.  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  
Dose Levels (Based on Adverse Events in Tables 8.2) 
 
Brentuximab Vedotin 
 
Starting Dose 
1.8 mg/kg IV Day 1 
1st dose 
reduction 
1.2 mg/kg IV Day 1 
2nd dose 
reduction 
Discontinue 
 
 
Nivolumab 
 
Starting Dose 
3.0 mg/kg IV Day 1 
1st dose 
reduction 
Discontinue 
 
Note: If either drug is discontinued, the patient may continue treatment with the 
other drug.  If both drugs are discontinued, the patient will go to event monitoring 
per Section 18.0. 
 
 

Amendment 6               Page 25  
 
ACCRU RU051505I  
 
 
 
8.2 
Recommended Brentuximab Vedotin  (BV) and Nivolumab Dose Modifications 
for Treatment-Associated Toxicity 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
 
 
 
 
Investigations 
Platelet count 
decreased 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade 3: Hold both BV and 
nivolumab until grade 2 or better, 
then reinstitute  BV at 1.2 mg/kg 
and resume nivolumab at same 
dose. 

Amendment 6               Page 26  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Investigations 
Alanine 
aminotransferase 
Increased, Aspartate 
aminotransferase 
Increased, and/or Blood 
bilirubin increased 
 
NOTE: increased 
bilirubin does not factor 
into dose modifications 
if secondary to 
Gilbert’s syndrome. 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade 2 (>3 to 5 x ULN) AST 
or ALT elevations: Omit dosing 
for nivolumab;continue BV at 
the same dose level. Nivolumab 
may be resumed if the value 
improves to Grade 1 (≤3 x ULN) 
or better.  
 
Grade 2 Bilirubin elevations 
(>1.5 to 3 x ULN): Omit dosing 
for nivolumab; continue BV at 
the same dose level. Nivolumab 
may be resumed if the bilirubin 
improves to Grade 1 (>ULN to 
1.5 x ULN) or better.  
 
Grade 2 (>3 to 5 x ULN) AST 
or ALT elevations WITH 
Grade 2 Bilirubin elevations 
(>1.5 to 3 x ULN): Hold both 
nivolumab and BV until 
ALT/AST value improves to 
Grade 1 (≤3 x ULN) or better 
and bilirubin value improves to 
Grade 1 (>ULN to 1.5 x ULN) 
or better.  
 
 
Grade 3 (AST or ALT, OR 
Bilirubin elevations): 
Discontinue nivolumab; hold 
dosing for BV until toxicity is < 
Grade 2 or has returned to 
baseline, then resume at the 
same dose level. 
 
Grade 4 (AST or ALT, OR 
Bilirubin elevations): 
Discontinue both nivolumab 
and BV. Patient should go to 
event monitoring, per Section 
18.  

Amendment 6               Page 27  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Investigations 
Creatinine Increased 
Nivolumab  
Patients will be monitored for 
elevated serum creatinine prior 
to and periodically during 
treatment. Administer 
corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone 
equivalents followed by 
corticosteroid taper for life-
threatening (Grade 4) serum 
creatinine elevation and 
permanently Discontinue 
nivolumab; continue BV at the 
same dose level.  
For severe (Grade 3) or 
moderate (Grade 2) serum 
creatinine elevation, withhold 
nivolumab and administer 
corticosteroids at a dose of 0.5 to 
1 mg/kg/day prednisone 
equivalents followed by 
corticosteroid taper; if worsening 
or no improvement occurs, 
increase dose of corticosteroids 
to 1 to 2 mg/kg/day prednisone 
equivalents and permanently 
Discontinue nivolumab; 
continue BV at the same dose 
level. 
Investigations  
Neutrophil (ANC) 
count decreased 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
≥Grade 3; hold both BV and 
nivolumab until resolved to 
grade 1 (or baseline). At this 
point myeloid growth factors can 
be used at investigator’s 
discretion. 
If not resolved to ≤Grade 1 or 
better within 28 days, 
discontinue nivolumab and BV. 
Patient should go to event 
monitoring per Section 18. 

Amendment 6               Page 28  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
 
Amylase and/or lipase 
increase 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥ 3: Hold BV and 
nivolumab until resolved to 
≤Grade 2, then resume at same 
dose, per protocol. If  there is 
clinical or radiographic evidence 
of pancreatitis, refer to 
pancreatitis AE actions (below).   
Immune System 
Disorders 
Immune system 
disorders-other 
Nivolumab 
If patient experiences immune-
mediated rash Grade 3: Omit 
nivolumab dose until symptoms 
resolve and management with 
coritcosteroids is complete, and 
then restart at the same dose 
level. If reoccurance, discontinue 
nivolumab (continue 
brentuximab vedotin per 
protocol). 
Grade 4: Permanently 
discontinue nivolumab (continue 
BV per protocol). 
For any suspected immune-
mediated adverse reactions, 
exclude other causes. Based on 
the severity of the adverse 
reaction, omit nivolumab, 
administer high-dose 
corticosteroids, and if 
appropriate, initiate hormone-
replacement therapy. Upon 
improvement to Grade 1 or less, 
initiate corticosteroid taper and 
continue to taper over at least 1 
month. Consider restarting 
nivolumab after completion of 
corticosteroid taper based on the 
severity of the event (continue 
BV per protocol). 
 
Infections and 
Infestations 
Encephalitis infection 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Discontinue Nivolumab if 
patient experiences immune-
mediated encephalitis. Continue 
BV at same dose per protocol.   

Amendment 6               Page 29  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Nervous system 
disorders 
Peripheral sensory 
neuropathy or 
peripheral motor 
neuropathy 
Brentuximab 
Vedotin (BV) 
Grade 2 
Reduce BV by 1 dose level and 
resume treatment; if already at 
1.2 mg/kg, continue dosing at 
that level. 
 
Grade 3 
Omit BV until toxicity is ≤ 
Grade 2, then consult with PI  
 
Grade 4 
Discontinue BV.  Continue 
Nivolumab at same dose per 
protocol.  
Gastrointestinal 
disorders 
Pancreatitis 
Brentuximmab 
Vedotin and 
Nivolumab  
Grade 2 
Omit nivolumab until resolution, 
maximum 3 weeks. If > 3 weeks, 
discontinue nivolumab ONLY 
(continue BV per protocol). 
 
Grade 3 or Grade 4, 
Discontinue BV . Hold 
nivolumab until grade 1 or 
better, then reintroduce.  If it 
recurs, then discontinue 
nivolumab and patient should go 
to event monitoring, per Section 
18. 
Gastrointestinal 
disorders 
Diarrhea 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥2:  Hold both BV and 
nivolumab until resolution to 
baseline grade 
 
Grade 3: Hold both BV and 
nivolumab and start 
corticosteroids until resolution to 
baseline grade. 
 
Grade >4: Discontinue BV and 
Nivolumab. Patient should go to 
event monitoring, per Section 
18. 

Amendment 6               Page 30  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Gastrointestinal 
disorders 
Colitis 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥2:  Hold both BV and 
nivolumab until resolution to 
baseline grade 
 
Grade 3: Hold both BV and 
nivolumab and start 
corticosteroids until resolution to 
baseline grade. 
 
Grade >4: Discontinue BV and 
Nivolumab. Patient should go to 
event monitoring, per Section 
18. 
General disorders and 
administration site 
conditions 
Fatigue 
 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade 3: Hold both BV and 
nivolumab until grade 2 or better 
Endocrine Disorders 
Adrenal insufficiency 
Hypothyroidism, 
Hyperthyroidism, 
Endocrine Disorders-
Other (i.e. 
Hypophysitis, diabetes) 
 
Nivolumab 
Grade >3:  Omit nivolumab 
until symptoms resolve and 
management with corticosteroids 
(if needed for symptoms of acute 
inflammation) is complete, and 
then restart at the same dose 
level. If reoccurence, 
discontinue. (continue BV per 
protocol). Nivolumab should be 
continued in the presence of 
hormone replacement therapy, as 
long as no symptoms are present. 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥2:  Hold both BV and 
nivolumab and start 
corticosteroids until resolution to 
baseline grade. 
 
Grade >3: Discontinue BV and 
nivolumab and initiate treatment 
with high doses of 
corticosteroids. Patient should go 
to event monitoring, per Section 
18. 

Amendment 6               Page 31  
 
ACCRU RU051505I  
 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Respitory, thoracic 
and mediastinal 
disorders 
Cough 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥2:  Hold both BV and 
nivolumab and start 
corticosteroids until resolution to 
baseline grade. 
 
Grade >3: Discontinue BV and 
nivolumab and initiate treatment 
with high doses of 
corticosteroids. Patient should go 
to event monitoring, per Section 
18. 
Respiratory, thoracic 
and mediastinal 
disorders 
Dsypnea 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥3:  Hold both BV and 
nivolumab up to four weeksuntil 
resolution to baseline grade. If 
no resolution patient should go 
to event monitoring, per Section 
18. 
All other hematologic 
and non-hematologic 
All other hematologic 
and non-hematologic 
Brentuximab 
Vedotin (BV) and 
Nivolumab 
Grade ≥ 2:    Hold both BV and 
Nivolumab up to four weeks 
until resolution to Grade 1 or 
baseline. If no resolution patient 
should go to event monitoring, 
per Section 18. 
* 
Located at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
** Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors is 
discouraged but if necessary should follow published guidelines of the American Society 
of Clinical Oncology (ASCO) Update of Recommendation for the Use of White Blood 
Cell Growth Factors:  An Evidence-Based Clinical Practice Guideline.  J Clin Oncol 
2006; 24:3187-3205, 2006.  
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as anti-diarrheal, 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. 

Amendment 6               Page 32  
 
ACCRU RU051505I  
 
 
 
9.4 
Diarrhea:  This could 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. 
 
9.5 
As there is potential for hepatic toxicity with nivolumab or nivolumab combinations, 
drugs with a predisposition to hepatoxicity should be used with caution in patients treated 
with nivolumab-containing regimen. 
 
9.6 
Please refer to Appendix V for additional Adverse Event Management Algorithms  
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. The sponsor/sponsor-investigator is responsible for notifying FDA and all 
participating investigators in a written safety report of any of the following:  
 
 
Any suspected adverse reaction that is both serious and unexpected.  
 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 

Amendment 6               Page 33  
 
ACCRU RU051505I  
 
 
 
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: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
 
b. Identify the grade and severity of the event using the CTCAE version 4.0.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52and 
18.0). 
 
10.11 
Each CTCAE term in the current version is a unique representation of a  
 
 
specific event used for medical documentation and scientific analysis and 
 
 
is a single MedDRA Lowest Level Term (LLT). 
 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the 
 
same as serious AE which is defined in the table 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 

Amendment 6               Page 34  
 
ACCRU RU051505I  
 
 
 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug/device and the adverse event.  
. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination)Arm 
 
 When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, 
biologic, cellular product, or other investigational therapy under an 
IND), the entire combination (arm) is then considered an 
investigational intervention for reporting.  
 
10.32 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 10.52). * 
 
 

Amendment 6               Page 35  
 
ACCRU RU051505I  
 
 
 
 
 
*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  
 
*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.   
 
A list of known/expected AEs is reported in the investigator brochure, package insert or 
the literature, including AEs resulting from a drug overdose. 
 
10.331 Death 
 
 
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. 
 
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the event 
will not require expedited reporting. 
Investigations 
Neutrophil count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
White blood count  
≤Grade 4 
Lymphocyte count decreased 
≤Grade 4 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 

Amendment 6               Page 36  
 
ACCRU RU051505I  
 
 
 
 
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. 
 
10.332 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 to 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. 
 
10.333 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. 
 
10.334 Pregnancy  
 
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.  
 
NOTE: When submitting ACCRU 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.  
 

Amendment 6               Page 37  
 
ACCRU RU051505I  
 
 
 
10.3341 BMS Reporting: If, following initiation of the investigational 
product, it is subsequently discovered that a study subject is pregnant or 
may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the 
investigational product will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for subject safety).  
 
The investigator must immediately notify
 
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 and Seattle Genetics. Information on this 
pregnancy will be collected on the Pregnancy Surveillance [provided 
upon request from BMS]. 
 
 
10.3342 Seattle Genetics Reporting: Based on the estimated date of 
conception, all pregnancies that occur from time of informed consent to 
within 6 months of last study drug dose, including any pregnancies that 
occur in the partner of a male study patient, are required to be reported to 
Seattle Genetics within 48 hours of becoming aware of such pregnancy. 
Email or fax the Seattle Genetics Pregnancy Report Form to 
 (USA 
only toll free). The Seattle Genetics Preganancy Report Form can be 
found posted with the protocol on the ACCRU website. 
 
All pregnancies that occur during this time period will be monitored for 
the full duration; all perinatal and neonatal outcomes should be reported. 
Infants should be followed for a minimum of 8 weeks.  
 
Abortion, whether accidental, therapeutic, or spontaneous, should be 
reported as a SAE. Congenital anomalies or birth defects, as defined by 
the ‘serious’ criterion above should be reported as SAEs. 
 
 

Amendment 6               Page 38  
 
ACCRU RU051505I  
 
 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41  Expedited Reporting via the ACCRU Adverse Event Expedited Report Form 
for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational  Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization     
≥ 24 hrs. 
7 Calendar Days 
24-Hours; 1 Calendar 
Day 
Not resulting in 
Hospitalization     
≥ 24 hrs. 
Not required 
Note: Protocol specific exceptions to expedited reporting of serious adverse events are found in 
section 10.32 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 1 Calendar Day” - The AE must initially be reported within 24 hours of learning of 
the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 

Amendment 6               Page 39  
 
ACCRU RU051505I  
 
 
 
 
Follow site-specific reporting guidelines. 
 
Submit the ACCRU Adverse Event Expedited Report Form to the ACCRU 
SAE Coordinator via fax 
  The ACCRU SAE Coordinator 
will forward to Bristol-Myers-Squibb and Seattle Genetics. 
 
ACCRU SAE Coordinator will forward to 
 
as appropriate. The ACCRU SAE Coordinator will also fax or e-mail to 
Seattle Genetics at: Facsimile 
 or Email: 
   
 
The ACCRU IND Coordinator will assist the sponsor-investigator in 
notifying the FDA if required.  
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events.  In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies.   
 
10.52 ACCRU will provide a study-specific cumulative SAE line listing of all SAEs  
 
 
including an assessment of causality to the Product. This will be e-mailed  
 
 
monthly to Seattle Genetics at: 
 
 
10.53 Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs,  
 
 
related or not related to study drug, must be collected, including those thought to 

Amendment 6               Page 40  
 
ACCRU RU051505I  
 
 
 
be associated with protocol-specified procedures. All SAEs must be collected 
that occur after discontinuation of dosing (please refer to test schedule). All 
SAEs must be collected that occur during the screening period. If applicable, 
SAEs must be collected that relate to any protocol-specified procedure (eg, a 
follow-up skin biopsy).  The investigator should report any SAE that occurs after 
these time periods that is believed to be related to study drug or protocol-
specified procedure. SAEs, whether related or not related to study drug, and 
pregnancies must be reported to ACCRU within 24 hours and the ACCRU SAE 
coordinator will report to BMS within 1 business day. SAEs must be recorded on 
BMS or an approved form; pregnancies on a Pregnancy Surveillance Form. 
 
10.54 Baseline and Adverse Events Evaluations 
 
Pre-treatment symptoms/conditions to be graded at baseline and adverse events 
to be graded at each evaluation per the CTCAE v4.0 grading unless otherwise 
stated in the table below: 
 
 
System Organ 
Class  
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Nervous System 
Disorders 
Peripheral motor neuropathy 
X 
X 
Investigations 
Creatinine increased 
X 
X 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumonitis 
X 
X 
Dyspnea 
X 
X 
 
 
 
10.55  Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable)  
 
10.551 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.552 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.553   Grade 5 AEs (Deaths) 
 
10.5531 Any death within 100 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.5532 Any death more than 100 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. 

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ACCRU RU051505I  
 
 
 
 
 
10.56 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). 
 
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 2 of chemotherapy and 6-8 weeks post cycle 8 of chemotherapy.   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). Up to six of the largest target nodes, 
nodal masses, or other lymphomatous lesions that are measurable in two diameters 
(longest diameter [LDi] and shortest diameter) should be identified from different body 
regions representative of the patient’s overall disease burden and include mediastinal and 
retroperitoneal disease, if involved. A measurable node must have an LDi greater than 1.5 
cm. Measurable extranodal disease (eg, hepatic nodules) may be included in the six 
representative, measured lesions. A measurable extranodal lesion should have an LDi 
greater than 1.0 cm. 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. 

Amendment 6               Page 42  
 
ACCRU RU051505I  
 
 
 
11.2  Lugano Classification Response criteria (Cheson et al, 2014)  
 
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
Complete metabolic response (CMR) 
 
Complete radiologic response (CR) 
(all of the following) 
 Lymph nodes 
and 
extralymphatic 
sites   
Score 1, 2, or 3*  with or without a residual mass 
on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
Individual target nodes/nodal masses 
must regress to ≤ 1.5 cm in LDi 
No extralymphatic sites of disease 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Response 
Partial metabolic response (PMR) 
Partial remission (PR) 
(all of the following) 
 Lymph nodes 
and 
extralymphatic 
sites   
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding 
disease 
At end of treatment, these findings indicate 
residual disease 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm X 5 mm as the 
default value 
When no longer visible, 0 X 0 mm 
For a node > 5 mm X 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 
New lesions 
None 
None 
Bone marrow  
Residual uptake higher than uptake in normal 
marrow but but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration should 
be given to further evaluation with MRI or biopsy 
or an interval scan 
Not Applicable  
No Response or 
Stable Disease 
No metabolic response (NMR) 
Stable disease (SD) 

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ACCRU RU051505I  
 
 
 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable 
nodes and extranodal sites; no criteria 
for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression  
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression  
New lesions 
None 
None 
Bone marrow  
No change from baseline 
Not Applicable 
Progressive 
disease 
Progressive metabolic disease (PMD) 
Progressive disease (PD) 
requires at least 1 of the following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
PPD progression: 
 
An individual node/lesion must be 
abnormal with:  
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen 
must increase to 
> 16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Extranodal 
lesions 
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 

Amendment 6               Page 44  
 
ACCRU RU051505I  
 
 
 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six 
of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. A measurable node must have an LDi greater than 1.5 cm. Measurable extranodal disease (eg, 
hepatic nodules) may be included in the six representative, measured lesions. A measurable extranodal lesion 
should have an LDi greater than 1.0 cm. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in 
solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for measurability but are still 
considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be 
difficult  to follow  quantitatively with  measurement, including pleural effusions,  ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed  and followed  by 
imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with  complete metabolic response, but  should be no higher than surrounding 
normal physiologic uptake (eg, with  marrow  activation as a result  of  chemotherapy or myeloid growth 
factors). 
†PET Deauville 5PS: 1, no uptake above background; 2, uptake≤mediastinum; 3, uptake > mediastinum but ≤ 
liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of 
uptake unlikely to be related to lymphoma. 
 
12.0 
Descriptive Factors   
 
12.1 
Group:    Age ≥60 years old vs. Age < 60 years old and unable to receive standard ABVD 
 
chemotherapy  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients will be evaluated for response after 2 cycles of treatment.  Patients who are NMR 
or PMD after 2 cycles of treatment will discontinue treatment and go to the event-
monitoring phase per Section 18.0.  Patients who are CMR or PMR will continue 
treatment per protocol.    
 
13.2 
Patients who develop progressive disease by either PET-CT based (PMD) or CT based 
(PD) response criteria (see Section 11.0) at any time while receiving therapy or during 
observation will go to the event-monitoring phase per Section 18.0. 
 
13.3 
Patients who go off protocol treatment for unacceptable adverse events, subsequent 
treatment or refusal will go to the event-monitoring phase per Section 18.0. 
 
13.4 
Observation: The patient will be observed every 30 days x90 days then every 90 days x 
2.5 years, then every 6 months until 5 years from registration. If the patient develops 
disease progression (see section 13.2) or receives subsequent treatment before disease 
progression while in observation, they will go directly to the event monitoring phase per 
section 18.0.  
 
13.5 
Patients who achieve a PMR or CMR will receive a maximum total of 8 cycles of 
treatment.  After 8 cycles, they go to observation per Section 13.4 above.    
 
 
13.6 
Early Safety Analysis Phase Only:  If a patient fails to complete the first cycle (21 days) 
of treatment for reasons other than toxicity, the patient will be regarded as in evaluable 
and will be replaced.    

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ACCRU RU051505I  
 
 
 
 
13.7 
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 
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 
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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ACCRU RU051505I  
 
 
 
 
 
14.0 
Body Fluid Biospecimens   
 
14.1 Summary Table of Research Blood/Blood Products to Be Collected for This Protocol  
Indicate if 
specimen 
is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume 
to collect 
per tube 
(number 
of tubes 
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted 
by 
participating 
site 
Cycles 1-8 
Day 1 
Pre-
treatment 
 
 
 
 
 
6-8 
weeks 
after 
Day 1 of 
Cycle 8 
End of 
Treatment, 
If 
discontinued 
early(At 
PMD or PD, 
withdrawal 
or removal) 
 
 
 
 
 
 
 
 
At time 
of PMD 
or PD 
Additional 
processing 
required at 
site after 
blood 
draw? 
Storage 
/shipping 
conditions1 
Mandatory 
SST (Marble 
top) 
8.5 ml (1) 
Whole blood 
X 
X 
X 
X 
No 
Refrigerated
/ Do not 
Freeze 
Mandatory 
EDTA 
(purple top) 
10 mL (2) 
Whole blood 
X 
X 
X 
X 
No 
Refrigerated
/ Do not 
Freeze 

Amendment 6 
Page 47                                                             ACCRU RU051505I  
 
 
                                   
 
  
After all samples have been processed according to kit instructions, ship all specimens according to shipping 
instructions (see below for detailed shipping instructions.) 
 
14.2  
Kits will be used for this study and will be contain supplies for collecting, processing and 
shipping specimens. 
 
 
14.21 Participating institutions may obtain kits by e-mailing 
  
 
 E-mail requests should include the site   
 
address, contact information and number of kits being requested. 
 
14.22 Kits will be sent via FedEx® Ground at no additional cost to the   
 
 
participating institutions. Please allow 3 to 4 business days to receive the  
 
kits. 
 
14.23 Any questions concerning sample collection and
  
 
 
 
 
14.24   Peripheral Blood 
 
Draw 8.5 mL of peripheral blood into one SST (marbled) collection tube   
 
and 20 mL of peripheral blood into two lavender top EDTA tubes. It is   
 
important to thoroughly mix the samples with the anticoagulant agent by  
 
gently inverting the tubes not less than five times.  
 
14.3 
Shipping and Handling 
 
 14.31 Samples are to be collected Monday through Thursday ONLY.  
 
 
Samples are to be shipped the same day they are collected. NOTE:   
 
 
Friday and Pre-Holiday shipments should be avoided. 
 
 
  
   
  
Samples are to be shipped to: 
   
  
 
   
  
 
   
  
 
   
  
 
 
 
   
  
 
   
  
 
 
Please e-mail 
 to notify the 
laboratory when specimens are being shipped. The message should include the study name, sample 
type(s), FedEx airbill tracking number, contact name and telephone number. 
 
14.4 
Study Methodology and Storage Information 
 
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 such as PD-L1/2, EZH2, MEF2B, ARID1A, CARD11, 
FOXO1, CREBBP and EP300 that may correlate with efficacy and tolerability.  
Dr. Stephen Ansell’s laboratory Stabile 6-28 will initially analyze a portion of the 
DNA for the presence of 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 ACCRU and IRB review and approval.  
(This collection is part of a general strategy of investigation for the majority of 
ACCRU studies.) 

Amendment 6 
Page 48                                                             ACCRU RU051505I  
 
 
                                   
 
  
 
14.412 A portion of the serum/plasma will initially be analyzed for the presence of 
Cytokines and T-Cells 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 ACCRU and IRB review and approval.  (This collection is part of a general 
strategy of investigation for the  majority of ACCRU studies.) 
 
14.414 As part of ongoing ACCRU research, 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 ACCRU and IRB review and approval.   
 
14.5 
Return of Genetic Testing Research Results 
 
 
For this study, DNA specimens are only being banked and no specific genetic testing is being 
performed.  If, at any time, genetic results are obtained that may have clinical relevance, IRB 
review and approval will be sough regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of research data 
with individual patients should only occur when data have been validated by multiple studies and 
testing has been done in CLIA-approved laboratories. 
 
 
14.51 Peripheral blood assays  
 
14.511 Serum cytokine analysis: Serum cytokine levels have been shown to be prognostic 
in Hodgkin lymphoma [Marri]. Samples will be subjected to multiplex ELISA 
(Invitrogen, Camarillo, CA) to measure 30 serum cytokines in pre-treatment 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. 
 
14.512 Flow cytometry: To define changes in peripheral blood cell populations after 
treatment with brentuximab vedoton and nivolumab, peripheral blood ononuclear 
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). 
 
 
 
 
 
 

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15.0 
Drug Information 
 
 
IND number128842 (for combination of both drugs)  
 
Investigator brochures will be available on the ACCRU website. 
 
 
15.1 
Brentuximab vedotin (SGN-35, Adcetris®) 
 
15.11 Background: Brentuximab vedotin (SGN-35) is a CD30-directed antibody-drug conjugate 
(ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for 
human CD30, 2) the microtubule-disrupting agent monomethyl auristatin E (MMAE), and 
3) a protease-cleavable linker that covalently attaches MMAE to cAC10. The anticancer 
activity of brentuximab vedotin is due the binding of the ADC to CD30- expressing cells, 
followed by internalization of the ADC-CD30 complex, and the release of MMAE via 
proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network 
within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cell.  
 
15.12 Formulation: Brentuximab vedotin is a sterile, preservative-free, white to off-white 
lyophilized cake or powder, supplied in single-use vials. Each vial of brentuximab vedotin 
contains brentuximab vedotin, trehalose, sodium citrate, and polysorbate 80. 
 
 
Brentuximab vedotin is an ADC composed of a CD30 targeted chimeric monoclonal 
antibody (cAC10) covalently linked, via an enzyme-cleavable linker, to the anti-tubulin 
agent MMAE. cAC10 has a typical structure of the human IgG1 subclass. Brentuximab 
vedotin is produced by the chemical conjugation of MMAE to cAC10. Each antibody 
molecule has, on average, two of its interchain disulfides reduced and the resulting cysteine 
residues alkylated with SGD-1006 Intermediate (enzyme-cleavable inker + MMAE), 
leading to a molar ratio of four drugs per antibody. 
 
15.13 Preparation and storage: 
Vials containing brentuximab vedotin must be stored under refrigeration at 2-8°C.  
 
If an excursion occurs, refer to the study-specific Stability Data document which has 
stability data for each product supplied by Seattle Genetics that used in the study. If the 
excursion is between the Acceptable Low Temperature and the Acceptable High 
Temperatures (the green range) and does not exceed the Maximum out of Range Time, the 
excursion does not need to be reported. If the excursion is outside of either the acceptable 
temperature range (the red range) or time range, the product should be quarantined and the 
excursion should be reported to Seattle Genetics. 
 
Report excursions using FM-244 Investigational Product Quality Complaints and 
Temperature Excursions Form. Found as a free standing document on the ACCRU 
Website. 
 
Reconstitution 
1. Reconstitute lyophilized brentuximab vedotin by adding 10.5 mL Sterile Water 
for Injection, USP to the 50 mg vial, directing the stream to the side of the vial. 
The concentration of reconstituted brentuximab vedotin is 5 mg/mL with a total 
volume of 11mL. 
 
2. Gently swirl the vial until contents are completely dissolved. The vial must not be 
shaken. Slight “bubbling” of the solution upon reconstitution may be observed. 
3. Allow the reconstituted vial to settle for a minute to allow bubbles to dissipate. 
The reconstituted product should be a colorless, clear to slightly opalescent 
solution with no visible particulates. 
 

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4. Reconstituted vials must be stored under refrigeration (2-8°C) and must be 
administered within 24 hours of vial reconstitution. Protect infusion bag from 
direct sunlight until time of use. 
 
Dose Calculation 
Actual weight will be used except for patients weighing greater than 100 kg; the 
dose for patients with weight greater than 100 kg will be calculated based on 100 kg. 
Brentuximab vedotin dose should be rounded to the nearest whole number of 
milligrams.  
 
Dose Preparation 
1. Transfer the required volume of reconstituted product to an infusion bag. The 
following bag types are compatible with brentuximab vedotin: polyvinylchloride 
(PVC), ethylene vinyl acetate (EVA), polyolefin, or polyethylene. Closed System 
Transfer Devices (CSTDs) can be used in the preparation of brentuximab 
vedotin. 
 
2. Dilute reconstituted product in either 0.9% Sodium Chloride Injection, USP, 
Lactated Ringer’s solution, USP, or dextrose 5% in water (D5W), USP. The final 
concentration of brentuximab vedotin in infusion bag should be in the range of 
0.4–1.8 mg/mL. 
 
3. Gently invert the infusion bag. DO NOT SHAKE. 
 
4. Prior to administration, inspect the prepared dosing solution (in infusion bag) for 
any particulate matter or discoloration. 
 
5. Do not prepare a single dose of brentuximab vedotin using vials from different 
lots. Use vials from the same lot number for a given dose. 
 
6. The prepared dosing solution must be stored in an infusion bag under refrigeration 
(2-8°C) and must be used within 24 hours of vial reconstitution. Protect infusion 
bag from direct sunlight until time of use. 
 
15.14 Administration:  BRENTUXIMAB VEDOTIN MUST NOT BE ADMINISTERED AS 
AN IV PUSH OR BOLUS. Brentuximab vedotin should be administered over 
approximately 30 minutes and cannot be mixed with other medications. In-line filters 
should not be used during the IV administration.  
 
15.15 Pharmacokinetic information: 
 
a)  Blood levels – The maximum concentrations for serum PK of brentuximab 
vedotin ADC following an IV dose of 1.8 mg/kg were typically observed at the end 
of infusion.  The half-life is 4 to 6 days. Minimal to no accumulation was observed 
with multiple doses with the q3wk regimen. The PK brentuximab vedotin when 
dosed by body-weight (mg/kg) is associated with body-size. The exposure (AUC) of 
ADC increases with increasing body size, although the magnitude of this increases is 
small in relation to the overall variability in ADC exposure. Additionally, this 
population PK meta-analysis indicated that gender, age, and race do not have a 
meaningful effect on the PK of brentuximab vedotin and that no dosing adjustment 
based on these intrinsic factors is recommended in adult patients 
 
b)  Distribution – Following an IV dose of brentuximab vedotin (1.2 to 2.7 mg/kg), 
the steady-state volume of distribution was approximately 6 – 10 L, indicating that 
brentuximab vedotin was primarily limited to the vascular space. 
 
c)  Metabolism and Excretion – The primary route of excretion of MMAE was via 
feces, whereas urinary excretion was moderate. Intact MMAE was the primary 

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species excreted and MMAE was excreted in both feces (72%) and urine (27%), 
suggesting a low propensity for metabolism-based biotransformations.  The terminal 
half-life (t1/2) is approximately 4 to 6 days. 
 
Hepatic/Renal Impairment: Patients with hepatic impairment (Child-Pugh class A to C) 
and patients with severe renal impairment (CrCl<30 mL/min) exhibited a trend toward 
moderate decreases in  ADC exposure and increases in MMAE exposure.  Unless 
otherwise specified in the clinical study protocol, the recommended starting dose in 
patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as 
an intravenous infusion over 30 minutes every 3 weeks. Clinical studies evaluating the 
effect of renal or hepatic impairment on the PK of brentuximab vedotin have not yet been 
done in patients with diseases other than cancer; therefore, it is unknown if these findings 
are applicable to treating non-cancer patients (e.g., patients with autoimmune liver disease 
or lupus nephritis) with brentuximab vedotin who have hepatic or renal impairment. 
 
 
15.16 Potential Drug Interactions:  In vitro data indicate that monomethyl auristatin E 
(MMAE) is a substrate and an inhibitor of CYP3A4/5. Co-administration of 
brentuximab vedotin with ketoconazole, a potent CYP3A4 inhibitor, increased 
exposure to MMAE by approximately 34%. Patients who are receiving strong 
CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely 
monitored for adverse reactions. Co-administration of brentuximab vedotin with 
rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 
46%. 
 
 
Brentuximab vedotin is not expected to alter the exposure to drugs that are 
metabolized by CYP3A4 enzymes. 
 
Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to 
pulmonary toxicity that occurred in some patients receiving this combination of treatments. 
 
15.17 Known potential toxicities:   
 
Very common known potential toxicities, ≥ 10%: 
Cardiovascular: Peripheral edema  
Central nervous system: Neuropathy, peripheral sensory neuropathy, fatigue, peripheral 
motor neuropathy, headache  
Dermatologic: Pruritus, alopecia, maculopapular rash 
Endocrine & metabolic: Weight loss 
Gastrointestinal: Nausea, diarrhea, vomiting, decreased appetite, abdominal pain, 
constipation  
Hematologic & oncologic: Neutropenia, anemia, thrombocytopenia 
Immunologic: Antibody development  
Neuromuscular & skeletal: Arthralgia, myalgia, asthenia, muscle spasm 
Respiratory: Upper respiratory tract infection, cough, dyspnea 
Miscellaneous: Fever  
 
 
Common known potential toxicities, 1% - <10%: 
Central nervous system: Chills  
Dermatologic: Cellulitis  
Hepatic: Hepatotoxicity  
Respiratory: Pulmonary toxicity, pneumonia  
 
 
Uncommon and rare known potential toxicities, <1%, post marketing and/or case reports:  
Acute pancreatitis, acute respiratory distress syndrome, anaphylaxis, bacteremia, 
enterocolitis, febrile neutropenia, gastrointestinal erosion, gastrointestinal hemorrhage, 

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gastrointestinal perforation, gastrointestinal ulcer, hyperglycemia, increased serum 
bilirubin, increased serum transaminases, interstitial pulmonary disease, intestinal 
obstruction, JC virus infection, neutropenic enterocolitis, opportunistic infection, 
pancreatitis, pneumonitis, progressive multifocal leukoencephalopathy, sepsis, septic 
shock, serious infection, severe hepatotoxicity, Stevens-Johnson syndrome, toxic 
epidermal necrolysis 
 
 
Hyperglycemia has been reported with BV, notably in patients with high Body Mass Index 
or preexisting hyperglycemia. Any patient, with or without diabetes, who experiences an 
event of hyperglycemia should have their serum glucose closely monitored. Antidiabetic 
treatment should be administered, as appropriate. 
 
 
 
See the current version of the Investigator’s Brochure for more comprehensive 
toxicity data.  
 
 
 
 
15.18 Drug procurement:   
15.181 Brentuximab vedotin will be provided in 50mg vials free of charge from Seattle 
Genetics for investigational use to Almac, Inc. Each participating ACCRU treating 
location will order the drug from Seattle Genetics/Almac, Inc. E-mail or Fax the 
Drug Order Request Form (found on the ACCRU website) to: 
 
Note: Allow 7 business days to process drug order requests. 
 
 
  
 
  
 
 
 
 
 
 
Each participating ACCRU treating location will be responsible for monitoring the 
supply of Brentuximab Vedotin  and Nivolumab and will use the appropriate Drug 
Order Request Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 
15.19 Nursing Guidelines 
15.191 Dosing should be based on actual weight for patients weighing ≤100kg. Patients 
weighing greater than 100 kg, will be dosed based on 100 kg. Round doses to the 
nearest whole milligram. 
 
15.192 DO NOT administer by IV push or bolus. Brentuximab vedotin must be given 
over approximately 30 minutes. Do not mix with other medications. In-line filters 
should not be used during infusion. 
 
15.193 Cytopenias are common. Monitor CBC w/differential closely. Instruct patient to 
report any signs or symptoms of infection, and/or bleeding. 
 
15.194  Rash is common. Rarely patients can devlope Steven’s Johnson Syndrome or 
TENS. Instruct patient to report any rash. Rash/pruritis/dermatitis is seen. Patients 
should report any rash to the study team. Treat per section 8.0 and monitor for 
effectiveness.  

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15.195 Instruct patient that sensory neuropathy is common. Assess for symptoms of 
neuropathy prior to each infusion and discuss with treating MD any ≥grade 2 
neuropathic symptoms. 
 
15.196 Fatigue is common. Discuss with patient energy conserving lifestyle and 
interventions. 
 
15.197 GI side effects can be seen, including diarrhea, nausea, vomiting and abdominal 
pain. Treat symptomatically and monitor for effectiveness. 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. 
 
15.198 Anaphylaxis and septic shock can be seen but are rare. Monitor for sign and 
symptoms of these during infusion. Administer emergency medications as 
ordered. 
 
15.199a Monitor for respiratory symptoms (cough, URI). Treat symptomatically and 
monitor for effectiveness. 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. 
 
15.199b Assess patients medications. Patients who are taking medications that are 
CYP3A4 inhibitors (i.e ketoconazole) should be closely monitored for adverse 
reactions. 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. 
 
15.199e  Monitor LFT’s 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. 
 
15.199g  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 and decreased activity tolerance. Instruct patients to  
 
  report these signs or symptoms immediately and obtain appropriate labs  
 
  as ordered by MD.  
 
15.199h  Pancreatitis is possible with nivolumab. Instruct patients to report  
 
  abdominal pain, nausea and vomiting to the study team. 
 
15.199i   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  

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  any increase or change in side effects with any dosage decrease as  
 
  patients may need a slower taper.  
 
15.199j   Monitor renal function as patients may experience acute interstitial  
 
  nephritis. Report any increase of levels to the study team. 
 
15.2 
Nivolumab (Opdivo®, BMS-936558) 
 
15.21 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. 
 
15.22 Formulation: Available for injection 10mg/ml (4mL, 10mL, 24mL) in a single-use vial 
[contains in sodium citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid 
(pentetic acid), polysorbate 80, and water for injection] 
 
15.23 Preparation and storage: When the dose is based on patient weight (ie, mg/kg), 
nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to concentrations as 
low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat 
dose), nivolumab injection can be infused undiluted or diluted so as not to exceed a 
total infusion volume of 160 mL. For patients weighing less than 40 kilograms (kg), 
the total volume of infusion must not exceed 4 mL per kg of patient weight.  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. If 
stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include 
laboratory coats and gloves. For additional details on prepared drug storage and use 
time of nivolumab under room temperature/light and refrigeration, please refer to the 
BMS-936558 (nivolumab) Investigator Brochure section for “Recommended 
Storage and Use Conditions” 
 
15.24 Administration:  Administer over 30 minutes through a line with a sterile, nonpyrogenic, 
low protein binding 0.2 to 1.2 micrometer in-line filter. 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. 
 
 
15.25 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). 
 

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15.26 Potential Drug Interactions:  Nivolumab is an IgG4 monoclonal antibody, which is 
eliminated by mechanisms similar to that of other antibodies, namely by non-
specific catabolism (mainly by enzymes in the reticuloendothelial system).  These 
enzymes are not known to be inhibited or induced by drugs, and therefore it is 
unlikely that other drugs will have an impact on the PK of nivolumab. 
 
 
15.27 Known potential toxicities: (from package insert): Consult the package insert for 
the most current and complete information.  
 
Very common known potential toxicities (>10%): 
Cardiovascular: Edema (≤13%), peripheral edema (≤13%), hypertension (11%) 
Central nervous system: Fatigue (≤59%), malaise (≤46%), headache (16% to 23%), 
dizziness (≤14%), peripheral neuropathy (≤14%; grade 3: <1%) 
Dermatologic: Skin rash (1% to 40%; immune-mediated: 9% to 16%), pruritus (10% to 
28%), vitiligo (≤11%) 
Endocrine & metabolic: Hyperglycemia (19% to 46%), hyponatremia (19% to 41%), 
increased serum triglycerides (32%), hyperkalemia (11% to 30%), increased thyroid 
stimulating hormone level (≥10% to 26%), hypocalcemia (10% to 26%), increased serum 
cholesterol (21%), hypercalcemia (2% to 19%), thyroiditis (≤12% to 18%; including 
immune-mediated events), hypomagnesemia (14% to 17%), hypokalemia (14% to 16%), 
thyroid dysfunction (15%), hypothyroidism (≤12%; including immune-mediated events) 
Gastrointestinal: Diarrhea (1% to 43%), nausea (20% to 34%), abdominal pain (13% to 
34%), increased serum lipase (20% to 33%), decreased appetite (14% to 28%), vomiting 
(12% to 28%), constipation (10% to 23%), increased serum amylase (13% to 19%) 
Genitourinary: Urinary tract infection (2% to 17%) 
Hematologic & oncologic: Anemia (26% to 50%; grades 3/4: 3% to 8%), lymphocytopenia 
(27% to 42%; grades 3/4: ≤11%), leukopenia (11% to 38%; grades 3/4: ≤5%), 
thrombocytopenia (15% to 37%; grades 3/4: 1% to 3%), neutropenia (13% to 37%; grades 
3/4: 4% to 5%) 
Hepatic: Increased serum alkaline phosphatase (10% to 37%), increased serum aspartate 
aminotransferase (22% to 33%), increased serum alanine aminotransferase (23% to 32%), 
increased serum bilirubin (11% to 14%) 
Immunologic: Graft versus host disease (20%; within 14 days of stem cell infusion), 
antibody development (11%; neutralizing: <1%) 
Neuromuscular & skeletal: Asthenia (≤57%), musculoskeletal pain (20% to 42%), back 
pain (21%), arthralgia (10% to 21%) 
Renal: Increased serum creatinine (12% to 42%) 
Respiratory: Upper respiratory tract infection (2% to 44%), cough (≤36%), productive 
cough (≤36%), dyspnea (≤27%), dyspnea on exertion (≤27%), bronchopneumonia (≤13%), 
pneumonia (≤13%), nasal congestion (11%) 
Miscellaneous: Febrile reaction (35%; events without an infectious cause that required 
steroids), fever (≤29%; may include tumor-associated fever), infusion-related reaction 
(≤14%) 
 
 
 
Cardiovascular: Pulmonary embolism (2% to 3%) 
Central nervous system: Neuritis (<10%), peripheral nerve palsy (peroneal: <10%), 
insomnia (9%) 
Dermatologic: Erythema of skin (10%), xeroderma (7%) 
Endocrine & metabolic: Weight loss (7% to 8%), hyperthyroidism (3% to 6%; including 
immune-mediated events), adrenocortical insufficiency (1%; including immune-mediated 
events), increased gamma-glutamyl transferase 
Gastrointestinal: Intestinal perforation (<10%), stomatitis (<10%), colitis (including 
immune-mediated events: ≤6%) 

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Hepatic: Hepatitis (immune-mediated: 2% to 3%) 
Immunologic: Sjogren's syndrome (<10%) 
Infection: Sepsis (≥2%, systemic inflammatory response) 
Neuromuscular & skeletal: Myopathy (<10%), rheumatism (spondyloarthropathy: <10%) 
Renal: Acute renal failure (≥2%), nephritis (≤1%; immune-mediated), renal insufficiency 
(≤1%; immune-mediated) 
Respiratory: Interstitial pulmonary disease (6%), pneumonitis (≤6%; including immune-
mediated events), pleural effusion (1% to 5%), respiratory failure (≥2%) 
 
Frequency not defined: 
Central nervous system: Migraine 
Dermatologic: Acneiform eruption, bullous dermatitis, dermatitis, erythematous rash, 
exfoliative dermatitis, maculopapular rash, morbilliform rash, palmar-plantar 
erythrodysesthesia, psoriasiform eruption, pustular rash, Stevens-Johnson syndrome, toxic 
epidermal necrolysis 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Abdominal distress 
Neuromuscular & skeletal: Limb pain 
 
Rare known potential toxicities (<1%), postmarketing, and/or case reports:  
Demyelinating disease (immune-mediated), diabetic ketoacidosis, duodenitis 
(immune-mediated), encephalitis (limbic/lymphocytic/viral; may be immune-
mediated), facial nerve paralysis (immune-mediated), gastritis (immune-mediated), 
Guillain-Barré syndrome, hepatic sinusoidal obstruction syndrome, hypophysitis 
(including immune-mediated events), immunological signs and symptoms 
(hemophagocytic lymphohistiocytosis) (Hantel 2018), iritis (immune-mediated), 
lymphadenitis (immune-mediated; histiocytic necrotizing lymphadenitis [Kikuchi 
lymphadenitis]), motor dysfunction (immune-mediated), myasthenia (myasthenic 
syndrome), myocarditis (immune-mediated), myositis (immune-mediated), 
neuropathy (autoimmune; immune-mediated), pancreatitis (immune-mediated), 
pituitary insufficiency (immune-mediated), pneumonia due to Pneumocystis 
jirovecii, polymyalgia rheumatica (immune-mediated), rhabdomyolysis (immune-
mediated), sarcoidosis (immune-mediated), sixth nerve palsy (abducens nerve palsy; 
immune-mediated), type I diabetes mellitus (immune-mediated event), uveitis 
(immune-mediated), vasculitis, Vogt-Koyanagi-Harada syndrome 
 
15.28 Drug procurement:  Investigational nivolumab is provided free of charge to 
patients by Bristol-Myers Squibb Research and Development. 
 
15.281 Nivolumab will be provided free of charge from Bristol-Myers Squibb for 
investigational use to Clinical Research Services, a division of Rx Crossroads by 
McKesson. Each participating ACCRU treating location will order the drug from 
Clinical Research Services, a division of Rx Crossroads by McKesson.   
 
Fax the Drug Order Request Form (found as a stand alone document) to: 
 
 
  
 
  
 
 
 
Each participating ACCRU treating location will be responsible for  
 
 
monitoring the supply of Nivolumab and will use the appropriate Drug   
 
Order Request Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures  in place at each 
institution. 

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15.29 Nursing Guidelines 
15.291 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 off 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. 
 
15.292 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.  
 
15.293 Rash/pruirits/dermatitis is seen. Patients should report any rash to the study team. 
Treat per section 8.0 and monitor for effectiveness. 
  
15.294 Monitor LFT’s 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. 
 
15.295 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. 
 
15.296 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 and decreased activity tolerance. 
Instruct patients to report these signs or symptoms immediately and obtain 
appropriate labs as ordered by MD.  
 
15.297  Pancreatitis is possible with nivolumab. Instruct patients to report abdominal pain, 
nausea and vomiting to the study team. 
 
15.298 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.  
 
15.199a Monitor renal function 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  
 

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16.1 
Overview 
 
This is a phase II study of nivolumab and brentuximab vedotin in patients with untreated Hodgkin 
lymphoma ≥ 60 years old or under 60 and unable to receive standard ABVD chemotherapy. The 
study is designed to assess the overallmetabolic response rate using a single stage phase II study 
design with an interim analysis. Accrual will be halted after 6 patients to assess safety (see Section 
16.4). We do not plan to halt accrual during the interim analysis (see Section 16.214). 
 
16.11 
Primary Endpoint: The primary endpoint of this trial is the rate of overall metabolic 
response. A metabolic response is defined as a patient who has achieved an objective status 
of PMR or CMR at the end of cycle 8. Throughout Section 16.0, metabolic response 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, unless they are determined to be a major violation or are 
replaced in the safety analysis phase per Section 13.6.  If the safety analysis determines 
that a reduction to the starting dose is warranted, only patients treated at the final dose level 
will be included when evaluating the decision rules in Sections 16.211 and 16.212. Patients 
treated at other dose levels will be summarized separately.   
 
16.2 
Statistical Design:  
16.21 Decision Rule:    
In a single-agent front-line phase II study of HL patients > 60 years-old treated with 
brentuximab vendotin, the interim analysis of 27 patients reported rate of 93%6 .  This 
study will look at responses maintained until the end of cycle 8 and will utilize an updated 
response criteria that assesses metabolic response (Cheson 2014).  Considering these 
factors, along with heterogeneity of disease in patients with HL and a broader eligibility 
criteria that includes patients < 60 years old with other co-morbidities, an overall metabolic 
response rate of greater than 65% for brentuximab vendotin with the addition of nivolumab 
would be of interest for this study.    
The largest success proportion where the proposed treatment regimen would be considered 
ineffective in this population is 65%, and the smallest success proportion that would 
warrant subsequent studies with the proposed regimen in this patient population is 80%. 
The following one–stage design with an interim analysis is based on a two-stage Simon 
optimum design and requires 56 evaluable patients to test the null hypothesis that the true 
success proportion in this patient population is at most 65%.  
 
16.211 Interim Analysis: Enter 25 evaluable patients into the study. If 17 or fewer 
successes are observed in the first 25 evaluable patients, we will consider this 
regimen ineffective in this patient population and terminate the study. Otherwise, if 
the number of successes is at least 18, we will continue accrual. 
 
16.212  Final Decision Rule: Enter an additional 31 evaluable patients into the study. If 40 
or fewer successes are observed in the first 56 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 41, this will be considered 
evidence of promising activity and the treatment may be recommended for further 
testing 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 16.313. 
 
16.214 NOTE: We will not suspend accrual at the interim analysis to allow the first 25 
patients to become evaluable, unless undue toxicity is observed.  Given the limited 

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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: The one stage study design with an interim analysis to be used is fully 
described above. A minimum of 25 and a maximum of 56 evaluable patients will be 
accrued onto this phase II study at the final dose level determined in the safety analysis 
phase, unless undue toxicity is encountered.  An additional one or two cohorts of 6 patients 
will be accrued if the early safety analysis determines that a reduction to the starting dose is 
warranted for up to 12 additional evaluable patients.   We anticipate accruing up to an 
additional 7 patients (2 safety analysis, 5 phase II) to account for ineligibility, cancellation, 
major treatment violation, or other reasons (i.e. replacement of a safety analysis patient) for 
a total of 75 patients overall.   
 
16.23 Accrual Rate and Study Duration: The anticipated accrual rate is 25-30 evaluable patients 
per year. At this rate, it will likely take about 3 years to enroll all patients. The maximum 
total study duration is expected to be approximately 3.5 years, or until the last patient 
accrued has been observed for at least 6 months.   
 
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) and the probability of stopping at the interim analysis 
under various success proportions can be tabulated as a function of the true success 
proportion as shown in the following table. 
 
 
If the true success proportion is... 
0.65 
0.70 
0.75 
0.80 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.29 
0.59 
0.85 
And the probability of stopping at 
the interim analysis is… 
0.69 
0.49 
0.27 
0.11 
 
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 
 
The analysis for this trial will commence at planned time points (see 16.2) and at the time the 
patients have become evaluable for the primary endpoint. The Statistician and Study Chair will 
make the decision, in accord with ACCRU Standard Operating Procedures, availability of data for 
secondary endpoints (e.g., laboratory correlates), and the level of data maturity. It is anticipated 
that the earliest date in which the results will be made available via manuscript, abstract, or 
presentation format is when last patient has been followed for at least 6 months. 
 
16.31 Primary Outcome Analyses: 
 
16.311 Definition: The primary endpoint of this trial is the rate of overall metabolic 
response. A metabolic response is defined as a patient who has achieved an 
objective status of PMR or CMR at the end of cycle 8. All patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment will 

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be evaluable for metabolic response, unless they are determined to be a major 
violation or are replaced in the safety analysis phase per Section 13.6.   If the 
safety analysis determines that a reduction to the starting dose is warranted, only 
patients treated at the final dose level will be included when evaluating the 
decision rules in Sections 16.211 and 16.212.   Patients treated at other dose levels 
will be summarized separately. 
 
16.312 Estimation: The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. Ninety-five percent 
confidence intervals for the true success proportion will be calculated according to 
the approach of Duffy and Santner. 
 
16.313 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 point estimates 
and confidence intervals. 
 
16.32 Secondary Outcome Analyses 
 
16.321 The complete metabolic response rate will be estimated by the total number of 
complete metabolic responses (CMR) divided by the total number of evaluable 
patients. All evaluable patients will be used for this analysis. Exact binomial 95% 
confidence intervals for the true complete metabolic response rate will be 
calculated. 
 
16.322   Duration of response is defined for all evaluable patients who have achieved a 
response as the date at which the patient’s objective status is first noted to be a 
CMR or PMR to the earliest date progression (PMD or PD) is documented. If a 
patient has not had disease progression, they will be censored on the date of their 
last disease assessment The distribution of duration of response will be estimated 
using the method of Kaplan-Meier. 
 
16.322 Progression-free survival is defined as the time from registration to the earliest 
date of documentation of disease progression (PMD or PD) or death due to any 
cause. If a patient is alive and has not had disease progression, they will be 
censored on the date of their last disease assessment.  The distribution of 
progression-free survival will be estimated using the method of Kaplan-Meier. 
16.323 Overall survival time is defined as the time from registration to death due to any 
cause. If a patient is still alive, they will be censored on the date of their last 
follow-up.  The distribution of overall survival will be estimated using the method 
of Kaplan-Meier. 
 
16.324 Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). Adverse events will be 
assessed using CTCAE version 4.0 per Section 10.0. 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.  
 
16.33 Correlative Outcome Analyses:  Due to the small overall sample size, the results of these 
analyses will be considered exploratory and hypothesis-generating in nature. 
 
16.331 Biomarkers including intratumoral cell populations, genetic variability, serum 
cytokines, and T-cell activation will be evaluated both before and during treatment.  
Baseline values and changes in these parameters over time will be both graphically 

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and quantitatively summarized and explored. Standard paired comparisons 
methodologies (paired t-tests, Wilcoxon signed rank tests and Fisher’s exact tests 
for interval, ordinal and nominal level data, respectively) will be used to assess 
changes in these variables before and after therapy. In addition, baseline values and 
changes over time in each measure will be explored in relation to clinical outcome 
to explore any differences between responders and non-responders and by depth of 
response (CMR vs. PMR) to identify potential biomarkers. 
 
16.4 
Early Safety Analysis: An early safety analysis will be performed after the first 6 patients have 
been accrued to the study at dose level 1 and observed for one cycle. If 2 or more of the first 6 
patients experience a DLT as defined in Section 7.12, then the starting dose level will be adjusted 
and additional cohorts may be evaluated at dose levels -1 and -2 as described below.  Accrual will 
be halted while evaluating each cohort in the early safety analysis. 
 
16.41 Dose level +1:  Six evaluable patients will be accrued onto dose level  +1 and observed 
until they complete one cycle treatment.  If 0 or 1 out of 6 patients experience a DLT, 
accrual will continue in the phase II portion at dose level 1.   If 2 or more patients 
experience a DLT on dose level +1, the toxicity level for dose level +1 will be considered 
unacceptable and six additional patients will be treated on dose level -1. 
 
16.42 Dose de-escalation to Dose level -1:  If dose level +1 has an unacceptable level of 
toxicity, six evaluable patients will be accrued onto dose level -1.  If 0 or 1 out of 6 
patients experience a DLT on dose level -1, accrual will continue in the phase II portion at 
dose level -1.  If 2 or more patients experience a DLT, the toxicity level for dose level -1 
will be considered unacceptable and six additional patients will be treated on dose level -
2.    
 
16.43 Dose escalation to Dose level -2:  If dose level -1 has an unacceptable level of toxicity, six 
evaluable patients will be accrued onto dose level -2.  If 0 or 1 out of 6 patients experience 
a DLT on dose level -2, accrual will continue in the phase II portion at dose level -2.  If 2 
or more patients experience a DLT, the toxicity level for dose level -2 will be considered 
unacceptable and accrual to the study will be temporarily closed, evaluated and potentially 
amended.    
 
16.5 
Data & Safety Monitoring: 
 
16.51 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. 
16.52 Adverse Event Stopping Rules (to include all patients treated at the dose level determined 
in the early safety analysis): 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 5 or more patients in the first 15 treated patients experience a grade 4 or higher non-
hematologic adverse event at least possibly related to treatment. 

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 
if after the first 15 patients have been treated, 30% 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.  
 
16.6  
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 
 For purposes of 
timing of the Results Reporting, the initial estimated completion date for the Primary Endpoint of 
this study is 3.5 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 6 months. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71 This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin. 
16.72 There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, 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 and gender groupings, the sample size is not 
increased in order to provide additional power for subset analyses. 
 
16.73 The geographical region served by ACCRU has a population which includes 
approximately 5-7% minorities. Based on prior ACCRU studies involving similar disease 
sites, we expect about 5-7% of patients will be classified as minorities by race and about 
50% of patients will be women. Expected sizes of racial by gender subsets are shown in the 
following table: 
 
 

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Accrual Estimates by Gender/Ethnicity/Race  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0 
2 
Not Hispanic or Latino 
36 
37 
0 
73 
Ethnic Category: Total of all subjects* 
37 
38 
0 
75 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
1 
0 
1 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
36 
36 
0 
72 
Racial Category: Total of all subjects* 
37 
38 
0 
75 
 
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.” 
Not Hispanic or Latino 
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 Tissue Biospecimen Submission 
 
 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Type of tissue 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to find 
specific 
details for  
biospecimen 
submission 
Formalin-fixed 
paraffin-embedded 
(FFPE) tissue blocks 
with corresponding 
H&E (OR (10) 5 
micron unstained 
slides with 
corresponding 
H&E)** 
Mandatory 
Within ≤14 days 
following 
registration 
Correlative biomarkers, 
tumor genetic variability 
and Banking 
Section 17.31 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides  
 
17.3 
Submit one formalin fixed paraffin-embedded (FFPE) tissue block Biopsy material obtained at the 
 
time of recurrence is preferred, but if not available, biopsy material obtained at the time of initial 
 
diagnosis of  Hodgkin Lymphoma may be submitted OR Please submit biopsy material from each 
 
surgery.)  A corresponding H&E slide for each submitted block must be provided to permit 
 
quality assessment of each tissue block.   
 
 
 
17.31 The FFPE tissue block is preferred; however, if an institution is unable   
 
 
 
 
to provide a tissue block, cut (11) 5 micron unstained slides and mount   
 
 
 
 
on charged glass slides.  Label the slides with ACCRU patient ID  
 
 
 
 
 
number, accession number, and order of sections. H&E stain the first   
 
 
 
 
slide (i.e., slides labeled 1, 11, etc.).  These H&E slides will be reviewed   
 
 
 
 
centrally under the research base’s protocol for assessing tissue quality.    
 
 
 
 
Do not bake or place covers slips on the slides. 
 
17.32  
The following materials below are mandatory and required for shipment: 
 
 
 
 
Paraffin embedded tissue blocks with corresponding H&E slide (OR (10) 5 
micron unstained slides with corresponding H&E(s)). 
 
17.33  
  
 
 
 
 
 
to notify Mayo Clinic Reference  
 
 
 
Laboratory when the specimen(s) are being shipped. 
 
17.34  
Specimens should be shipped to the following address: 
 
 
 
 
 
 
 
 
 
 

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17.4 
Tumor Assays  
 
17.41  Immunohistochemistry (IHC): Previous studies of tumor biomarkers have shown  that the 
 
tumor microenvironment in Hodgkin lymphoma is very important. These studies have 
 
shown that the number, phenotype and distribution of intratumoral immune cells  predicts 
 
response to therapy. To confirm the prognostic or predictive role of immune cells in 
 
patients with Hodgkin lymphoma treated with brentuximab vedotin and nivolumab, we 
 
will use submitted paraffin-embedded tissue to measure the T-cell and macrophage 
 
infiltrate and correlate cell numbers and location with patient response and progression –
 
free survival. As described above, 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. 
 
17.42  Fluorescence in situ hybridization (FISH): FISH will be performed on Hodgkin 
 
lymphoma tissue sections to assess copy number on 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. Malignant Reed–Sternberg cells will be 
 
identified by means of nuclear morphologic features, and all such cells will be analyzed. 
 
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. 
 
17.43  Molecular Signature: We will define the intratumoral molecular signature 
 
predictive of response to therapy in patients with Hodgkin lymphoma. We will use a 
 
previously described gene expression profile and optimize it for use in paraffin-embedded 
 
tissue [Sriedl et al]. The coefficients and the capture-based hybridization pipeline designed 
 
for formalin-fixed, paraffin-embedded tissues (FFPET) will be used. The genes include 
 
CSFR1, PD-L1, PD-L2, EZH2,  MEF2B, ARID1A, CARD11, FOXO1, CREBBP and 
 
EP300. In addition, gene signatures downstream of specific mutations will be explored 
 
using a paraffin-based approach that follows gene set enrichment analysis of mutated 
 
cases. The signature(s) will be used to explore their ability to select cases with inferior 
 
outcomes. 
 
 
 
 
 
 
 
 
 

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19.0  
Budget 
 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and  
 
 
 
regional coverage policies, to determine which items are standard of care and which are   
 
 
research at their site.  Refer to the payment synopsis for funding provided per accrual for   
 
 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
19.2 
Brentuximab vedotin and Nivolumab will be provided by Seattle  
 
 
 
Genetics and Bristol-Myers Squibb respectively, at no charge. 
 
 
19.3 
Tests to be research funded: 
 
 
 
19.31 Mandatory blood and tissue samples for research.