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
