A(B)VD Followed by Nivolumab as Frontline Therapy for Higher Risk Patients With Classical Hodgkin Lymphoma (HL)
A(B)VD Followed by Nivolumab as Frontline Therapy for Higher Risk Patients With Classical Hodgkin Lymphoma (HL)
The aim of this study is to improve the chance of cure for people with higher risk Hodgkin
 lymphoma. The purpose of the Phase I study is to test any good and bad effects of the study
 drug called Nivolumab when combined with ABVD for the front-line treatment of HL.The purpose
 of this Phase II study is to test whether including nivolumab in treatment for untreated
 Hodgkin lymphoma can improve the chance of cure for patients with abnormal PET scans after 2
 cycles of ABVD.
The phase II portion of cohort A will enroll patients with untreated stage III or IV Hodgkin
 lymphoma. All patients will begin with 2 cycles of ABVD as standard of care treatment. A PET
 scan will be performed after 2 cycles of ABVD. Enrollment at MSK may occur at any point
 during the first two cycles of ABVD treatment. Enrollment at non-MSK locations will occur
 after the PET scan is performed. MSK patients with a PET-negative response (defined by
 Deauville 1, 2 or 3) will proceed with 4 additional cycles of ABVD or AVD (per treating
 physician preference) on-study. Non-MSK patients with a PET-negative response are not
 eligible for this study. Patients with a PET-positive response (Deauville 4 or 5) will
 proceed with 4 cycles of AVD plus nivolumab on-study. Non-MSK patients must have a
 PET-positive response to enroll on this study
Inclusion Criteria:

 -  Cohort A overview: Patients age less than 60 with untreated stage III or IV classical
 Hodgkin lymphoma will be eligible for cohort A. In phase I, patients could enroll onto
 cohort A if they had have a baseline IPS ≥3 OR if their PET scan after 2 cycles of
 ABVD is positive (Deauville 4 or 5). Enrollment onto phase I has now ceased and
 enrollment will begin for phase II.

 In phase II, patients less than 60 years of age with stage III or IV HL are eligible. MSK
 patients may enroll anytime within the first 2 cycles of ABVD Non-MSK patients must enroll
 after positive PET-2 scan.

 -  Cohort B overview: Patients 60 or older with untreated classical Hodgkin lymphoma
 (regardless of stage) will be eligible for cohort B.

 The following eligibility criteria applies to both cohort A and B except when stated
 otherwise:

 -  Histologic diagnosis of classical Hodgkin lymphoma

 -  FDG-avid disease by FDG-PET/CT

 -  Non-MSK patients ONLY: PET-2 positive disease (Cohort A only)

 -  Ann Arbor Stage III or IV disease (Cohort A only)

 -  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
 IU/L or equivalent units of HCG) within 2 weeks prior to the start of study drug.
 Women who undergo fertility preservation within 2 weeks of beginning chemotherapy
 are expected to have false-positive pregnancy tests and therefore testing may be
 waived for these patients.

 -  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
 IU/L or equivalent units of HCG) within 24 hours prior to the start of study
 drug. Women who undergo fertility preservation within 2 weeks of beginning
 chemotherapy are expected to have false-positive pregnancy tests and therefore
 testing may be waived for these patients.

 -  Reliable methods of birth control include a double barrier method, oral
 contraceptive, implant, dermal contraception, long-term injectable contraceptive,
 intrauterine device, tubal ligation or total abstinence during the study

 -  Women must not be breastfeeding

 -  Men who are sexually active with WOCBP must agree to follow instructions for method(s)
 of contraception (i.e. use of a condom during intercourse) for the duration of
 treatment with study drug plus 5 half-lives of study drug plus 90 days (duration of
 sperm turnover) for a total of 31 weeks posttreatment completion

 -  Age ≥ 18

 -  Serum creatinine ≤ 1.5 x Upper limit of normal (ULN) or creatinine clearance (CrCl) ≥
 40 mL/min (measured using the Cockcroft-Gault formula

 -  AST/ALT ≤ 3 x ULN (5x ULN for those with lymphoma involvement of the liver)

 -  Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
 bilirubin < 3.0 mg/dL)

 Exclusion Criteria:

 -  Subjects with active brain metastases or leptomeningeal metastases.

 -  Subjects with nodular lymphocyte-predominant HL

 -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
 may increase the risk associated with study participation or study drug
 administration, impair the ability of the subject to receive protocol therapy, or
 interfere with the interpretation of study results.

 -  Prior malignancy active within the previous 3 years except for locally curable cancers
 that have been apparently cured, such as basal or squamous cell skin cancer,
 superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

 -  Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
 to enroll.

 -  Subjects with a condition requiring systemic treatment with systemic corticosteroids
 (equivalent of >10mg/day of prednisone). Patients may receive steroid therapy if
 steroids are tapered down to 10mg or less by 4 weeks after initiating A(B)VD to
 control lymphoma-related symptoms.

 -  Any of the following cardiovascular conditions or values within 6 months before the
 first dose of study drug:

 -  A left-ventricular ejection fraction < 50%

 -  Myocardial infarction within 2 years of randomization

 -  New York Heart Association (NYHA) Class III or IV heart failure

 -  Evidence of current uncontrolled cardiovascular conditions, including cardiac
 arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence
 of acute ischemia or active conduction system abnormalities

 -  Any positive test for hepatitis B virus or hepatitis C virus indicating acute
 infection.

 -  Known history of testing positive for human immunodeficiency virus (HIV) or known
 acquired immunodeficiency syndrome (AIDS).

 -  History of severe hypersensitivity reaction to any monoclonal antibody.

 -  Adjusted DLCO <60% (if unadjusted DLCO is >/=60% then there is no need to calculate
 adjusted