PRIMARY OBJECTIVE:
I. Determine the 18-month progression free survival (PFS) for each arm of therapy stratified
by positron emission tomography (PET)/computed tomography (CT)-2 response.
SECONDARY OBJECTIVES:
I. Assess safety, tolerability, and quality of life (QOL) for each arm of therapy.
II. Measure PET/CT-2 negativity rate after 2 lead-in cycles of standard of care doxorubicin,
bleomycin, vinblastine, dacarbazine (ABVD).
III. Evaluate the 3-year PFS and overall survival (OS) for each arm of treatment.
EXPLORATORY OBJECTIVES:
I. Evaluate if a baseline antitumor immune response, as assessed by a Nanostring gene panel,
correlates with PFS.
II. Evaluate if minimal residual disease (MRD) status, as monitored by cancer personalized
profiling by deep sequencing (CAPP-Seq) of circulating tumor (ct) deoxyribonucleic acid
(DNA), can be correlated with PFS.
OUTLINE: Patients are assigned to 1 of 2 groups based on their PET/CT-2 scans.
GROUP I (PET/CT-2 NEGATIVE): Patients without bulky disease are randomized to either Arm A or
B and patients with bulky disease are assigned to Arm B.
ARM A: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab
IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients receive doxorubicin IV, bleomycin IV, vinblastine IV, dacarbazine IV on days
1 and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease
progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on
day 1. Treatment with nivolumab repeats every 14 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity.
GROUP II (PET/CT-2 POSITIVE): Patients receive doxorubicin IV, vinblastine IV, dacarbazine,
IV and brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28
days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Patients that are PET/CT negative receive nivolumab IV over 60 minutes on day 1. Treatment
with nivolumab repeats every 14 days for up to 6 cycles in the absence of disease progression
or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for 3 years.
Inclusion Criteria:
- Documented informed consent of the participant and/or legally authorized
representative.
- Assent, when appropriate, will be obtained per institutional guidelines.
- Eastern Cooperative Oncology Group (ECOG) =< 2.
- Histologically confirmed diagnosis of classical Hodgkin lymphoma (cHL) by current
World Health Organization classification (nodular sclerosis, mixed cellularity,
lymphocyte rich, lymphocyte depleted, or classical Hodgkin lymphoma, NOS [not
otherwise specified]) at local enrolling center. Nodular lymphocyte-predominant
Hodgkin lymphoma is excluded
- Stage IA, IB, IIA, or IIB cHL by Cotswold modified Ann Arbor staging done prior to any
treatment with ABVD.
- Must have prior to standard of care ABVD treatment at least one lesion that is > 1.5
cm in the longest diameter on cross-sectional imaging and measureable in two
perpendicular dimensions on CT and fludeoxyglucose (FDG) avid by PET.
Exclusion Criteria:
- Patients must be naive in terms of any prior therapy for Hodgkin lymphoma (including
immunotherapy, chemotherapy or radiation therapy) with the exception that they may
have received up to 2 cycles of ABVD as standard of care therapy prior to enrollment,
as long as they can start protocol therapy (therapy administered in Arms A, B1/B2, or
C) within timelines specified by the trial.
- Peripheral sensory neuropathy > grade 1 or any peripheral motor neuropathy.
- History of another primary malignancy that has not been in remission for at least 3
years. (The following are exempt from the 3-year limit: nonmelanoma skin cancer, fully
excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, and
cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on
Papanicolau [PAP] smear)
- Known cerebral/meningeal disease.
- History of progressive multifocal leukoencephalopathy (PML).
- Known history of pancreatitis.
- Documented history of a cerebral vascular event (stroke or transient ischemic attack),
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York
Heart Association class III-IV within 6 months prior to enrollment
- Uncontrolled cardiac disease including ventricular dysfunction, left ventricular
ejection fraction < 45%, coronary artery disease, or arrhythmias.
- Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient
contained in the drug formulation of brentuximab vedotin, nivolumab, or any component
of ABVD.
- Known active infection with hepatitis B or hepatitis C. Patients who are hepatitis B
carriers can enroll if have a negative hepatitis B polymerase chain reaction (PCR) DNA
test and are on hepatitis B suppressive medication management with entecavir or
lamivudine. Patients with past active hepatitis C virus (HCV) infection are eligible
if they are PCR negative after curative therapy. Testing to be done only in patients
suspected of having infections or exposures.
- Known active infection with human immunodeficiency virus (HIV). Patients who are HIV
positive can enroll if CD4 count is > 200/uL and have an undetectable or
unquantifiable HIV viral load within 28 days of enrollment, have concurrent management
with infectious disease specialists, and are on stable combination antiretroviral
therapy. Participants are required to be on antiretroviral regimens that are in
accordance with the current International acquired immune deficiency syndrome (AIDS)
Society guidelines concurrently with chemotherapy. The specific agents are at the
discretion of the Investigator and the use of investigational agents currently
available on an expanded access basis is allowed. Use of experimental antiretroviral
agents or those containing zidovudine (including Combivir and Trizivir) or ritonavir
(includes Norvir or Kaletra), Cobicistat, Didanosine (Videx or Videx EC), or similar
potent CYP3 inhibitors are prohibited. In order to be eligible, participants taking
zidovudine or ritonavir, Cobicistat, Didanosine, or other CYP3 inhibitors must change
to a different regimen 7 days prior to therapy initiation. Changes to highly active
antiretroviral therapy (HAART) therapy during the study may be made if medically
necessary (toxicity, failure of regimen, etc.). Participants must be on HAART for at
least 7 days prior to therapy. HIV testing to be done only in patients suspected of
having infections or exposures
- Subjects with active interstitial pneumonitis.
- 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.
- Females only: pregnant or breastfeeding.
- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures.
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics).
