This phase II trial compares the impact of brentuximab vedotin and nivolumab after radiation to standard of care high dose chemotherapy (HDT)-autologous stem cell transplant (ASCT) in standard-risk patients with classic Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). In addition, the phase III trial will compare the effect of pembrolizumab after HDT-ASCT to standard of care HDT-ASCT alone in high-risk patients with relapsed or refractory classic Hodgkin lymphoma. Brentuximab vedotin is in a class of medications called antibody-drug conjugates. It is made of a monoclonal antibody called brentuximab that is linked to a cytotoxic agent called vedotin. Brentuximab attaches to CD30 positive lymphoma cells in a targeted way and delivers vedotin to kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. An ASCT is a procedure in which blood-forming stem cells (cells from which all blood cells develop) are removed, stored, and later given back to the same person. Giving HDT before an ASCT helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Radiation therapy (RT) uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving brentuximab vedotin and nivolumab after radiation may be safe, tolerable and more effective than standard of care HDT-ASCT in treating patients with standard risk relapsed or refractory classic Hodgkin lymphoma. In addition, giving pembrolizumab after standard of care HDT-ASCT may be safe and tolerable and more effective than HDT-ASCT alone in treating high-risk patients with relapsed or refractory classic Hodgkin lymphoma.
PRIMARY OBJECTIVES: I. Demonstrate the non-inferiority (and possible superiority) in progression free survival (PFS) amongst patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after checkpoint inhibitor-based maintenance and localized radiation in comparison to standard of care HDT-ASCT. (Phase III Standard-Risk) II. Demonstrate the superiority of checkpoint inhibitor-based maintenance after HDT-ASCT in improving PFS among patients with R/R cHL in comparison to standard of care HDT-ASCT. (Phase II High-Risk) SECONDARY OBJECTIVES: I. To assess overall survival (OS) in the treatment arms in the standard risk as well as high-risk groups. II. To assess safety and toxicity of the treatment regimens in the standard risk as well as high risk groups. EXPLORATORY OBJECTIVES: I. To evaluate prognostic factors (lactate dehydrogenase \[LDH\], erythrocyte sedimentation rate \[ESR\], time to relapse, B symptoms, extranodal disease, stage, bulk, treatment with a checkpoint inhibitor, response at the time of ASCT) associated with risk of progression following HDT-ASCT (Arms B and D). II. To compare the impact of various radiation therapy modalities utilized (e.g., 3-dimensional conformal radiation therapy \[3D-CRT\], intensity-modulated radiation therapy \[IMRT\], proton therapy) and its association with dosimetric and clinical outcomes, including toxicity assessment, (grade 2+), at the end of radiation. III. To assess PFS for patients in partial metabolic response (PMR) receiving radiation therapy, compared to those patients in complete metabolic response (CMR), for all arms of the study. OUTLINE: Patients in the standard risk cohort are assigned to Arm S and patients in the high risk cohort are assigned to Arm H. ARM S: Patients receive standard of care salvage therapy for up to 2-4 cycles per investigator choice. After completing salvage therapy, patients without stable disease (SD) or progressive metabolic disease (PMD) are randomized to Arm A or Arm B. ARM A: Patients undergo photon RT with either 3DCRT, IMRT, volume modulated arc therapy (VMAT), or tomotherapy or proton RT with either passive scattering, uniform scanning, or pencil beam scanning over 15-17 fractions. Starting 4-8 weeks after completing radiation therapy, patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab for an additional 2 cycles in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive HDT and undergo ASCT per standard of care in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment with brentuximab vedotin for up to 16 cycles in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization. ARM H: Patients receive 2-4 cycles of standard of care salvage therapy per investigator choice. After completing salvage therapy, patients without SD or PMD are randomized to Arm C or Arm D. ARM C: Patients receive HDT and undergo ASCT per standard of care. Starting 4-8 weeks after transplant, patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment with brentuximab vedotin for up to 16 cycles in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization. ARM D: Patients receive HDT and undergo ASCT per standard of care in the absence of disease progression or unacceptable toxicity. Starting within 4-8 weeks after transplant, patients with CMR may also undergo RT as in arm A over 15-17 fractions and patients with PMR may also undergo RT over 20-22 fractions per investigator. Starting 30-45 days after transplant, patients may also receive maintenance treatment as in arm B in the absence of disease progression or unacceptable toxicity as determined per investigator at time of randomization. Additionally, patients may undergo blood sample collection, computed tomography (CT), and positron emission tomography (PET)/CT throughout the study. After completion of study treatment, patients are followed every 6 months for the first 2 years then annually for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
374
Undergo 3DCRT
Undergo ASCT
Undergo blood sample collection
Given IV
Undergo CT and PET/CT
Receive HDT
Undergo IMRT
Given IV
Given IV
Undergo pencil beam proton RT
Undergo PET/CT
Receive standard of care salvage therapy
Undergo passive scattering proton RT
Undergo tomotherapy
Undergo uniform scanning proton RT
Undergo VMAT
Progression-free survival (PFS) (Standard risk cohort)
The analysis will be performed using the repeated confidence intervals methodology. Two-sided repeated confidence interval will be constructed using the partial likelihood estimate from stratified Cox proportional hazards model and the critical value based on the Lan-DeMets error-spending function that corresponds to the truncated O'Brien-Fleming boundaries. Sensitivity analysis will be performed to assess the possible impact of treatment non-compliance. The actual treatment received may be considered in a multivariable Cox model where possible effects of clinical and biological characteristics on outcome are assessed.
Time frame: From randomization to progression or death without documented progression, assessed up to 15 years
PFS (High-risk cohort)
Stratified log-rank test will be used for the primary analysis to compare the PFS between arms D and C.
Time frame: From randomization to progression or death without documented progression, assessed up to 15 years
Overall survival (OS) (Standard risk cohort)
The analysis will be performed using the stratified log-rank test. To preserve the overall type I error rate, critical values at the interim efficacy analyses will be determined using a truncated version of the Lan-DeMets error spending function corresponding to the O'Brien-Fleming boundary.
Time frame: From randomization to death due to any cause, assessed up to 15 years
OS (High risk cohort)
Stratified log-rank test will be used to compare the OS between the two arms.
Time frame: From randomization to death due to any cause, assessed up to 15 years
Incidence of adverse events
Will be measured using the most recent version of the Common Terminology Criteria for Adverse Events.
Time frame: Up to 30 days after last dose of study treatment
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