Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma
Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma
This phase II trial studies how well nivolumab and brentuximab vedotin work in treating older
 patients with untreated Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as
 nivolumab, may help the body's immune system attack the cancer, and may interfere with the
 ability of tumor cells to grow and spread. Biological therapies, such as brentuximab vedotin,
 use substances made from living organisms that may stimulate or suppress the immune system in
 different ways and stop cancer cells from growing. Nivolumab and brentuximab vedotin may work
 better in treating older patients with untreated Hodgkin lymphoma.
PRIMARY OBJECTIVE:

 I. To determine the efficacy based on overall metabolic response rate (partial metabolic
 response [PMR] + complete metabolic remission [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.

 SECONDARY OBJECTIVES:

 I. The complete metabolic response (CMR) rate. II. Safety and tolerability of the regimen in
 this patient population. III. Duration of response (DOR). IV. Progression-free survival
 (PFS). V. Overall survival (OS).

 CORRELATIVE RESEARCH OBJECTIVES:

 I. T-cell/cytokine - peripheral blood specimens will be used to assess T-cell activation and
 cytokine up regulation as measures of treatment effect.

 II. 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.

 OUTLINE:

 Patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over
 60 minutes on day 1. Treatment repeats every 21 days for 7 cycles and 6-8 weeks in cycle 8 in
 the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 30 days for 90 days,
 every 90 days for 2.5 years, and then every 6 months until 5 years from registration.
Inclusion Criteria:

 -  Classical Hodgkin lymphoma determined by local hematopathology review

 -  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

 -  Requirement for systemic chemotherapy: all stages except IA (not bulky disease), if
 involved field is considered radiotherapy (RT) curative

 -  Previously untreated with either chemotherapy, radiation therapy or either brentuximab
 vedotin or nivolumab, or another check point inhibitor

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

 -  Absolute neutrophil count (ANC) >= 1500/mm^3, unless secondary to bone marrow
 involvement; obtained =< 7 days prior to registration

 -  Leukocytes >= 3,000/mm^3, obtained =< 7 days prior to registration

 -  Platelet count >= 100,000/mm^3, obtained =< 7 days prior to registration

 -  Hemoglobin > 9.0 g/dL - unless determined by treating physician to be disease related,
 obtained =< 7 days prior to registration

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN), obtained =< 7 days prior to
 registration

 -  Aspartate aminotransferase (aspartate transaminase [AST]) =< 2.5 x ULN, obtained =< 7
 days prior to registration

 -  Alanine aminotransferase (alanine transaminase [ALT]) =< 2.5 x ULN, obtained =< 7 days
 prior to registration

 -  Creatinine =< 2.0 mg/dL, obtained =< 7 days prior to registration

 -  Amylase and/or lipase =< 1.5 x ULN, obtained =< 7 days prior to registration

 -  Women of childbearing potential must have a negative serum or urine pregnancy test
 (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
 [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
 (i.e., 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

 -  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

 -  Ability to understand and willingness to sign an informed written consent

 -  Provide blood and tissue samples for mandatory correlative research purposes

 Exclusion Criteria:

 -  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

 -  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

 -  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

 -  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

 -  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 antibody [Ab]+ then polymerase chain reaction [PCR]+)
 indicating acute or chronic infection, and/or history of interstitial lung disease

 -  Allergy to brentuximab vedotin and/or nivolumab

 -  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

 -  Receiving any other investigational agent which would be considered as a treatment for
 the primary neoplasm

 -  Have had prior chemotherapy or radiotherapy for Hodgkin lymphoma

 -  Have received either of the study drugs

 -  < 60 years who are considered candidates for standard chemotherapy

 -  >= grade 2 peripheral neuropathy

 -  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

 -  Active central nervous system (CNS) involvement or leptomeningeal metastases
 involvement

 -  Known history of pancreatitis