Evaluating the Addition of Maintenance Immunotherapy Compared to the Usual Treatment of Chemotherapy and Autologous Stem Cell Transplant Alone for High-risk Patients With Relapsed or Refractory Hodgkin Lymphoma
A Two Cohort Randomized Study for Patients With High Risk (Phase II) and Standard Risk (Phase III) Classical Hodgkin Lymphoma in First Relapse
3 other identifiers
interventional
374
0 countries
N/A
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Dec 2026
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 6, 2026
CompletedFirst Posted
Study publicly available on registry
May 7, 2026
CompletedStudy Start
First participant enrolled
December 4, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
March 31, 2029
Study Completion
Last participant's last visit for all outcomes
March 31, 2029
May 7, 2026
May 1, 2026
2.3 years
May 6, 2026
May 6, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
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.
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.
From randomization to progression or death without documented progression, assessed up to 15 years
Secondary Outcomes (3)
Overall survival (OS) (Standard risk cohort)
From randomization to death due to any cause, assessed up to 15 years
OS (High risk cohort)
From randomization to death due to any cause, assessed up to 15 years
Incidence of adverse events
Up to 30 days after last dose of study treatment
Other Outcomes (3)
Estimates of treatment effects by sex
Up to 15 years
Estimates of treatment effects by race
Up to 15 years
Estimates of treatment effects by ethnicity
Up to 15 years
Study Arms (4)
Arm A (salvage therapy, RT, brentuximab vedotin, nivolumab)
EXPERIMENTALPatients receive 2-4 cycles of standard of care salvage therapy per investigator choice. Patients undergo photon RT with either 3DCRT, IMRT, 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 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. Additionally, patients may undergo blood sample collection, CT, and PET/CT throughout the study.
Arm B (salvage therapy, HDT-ASCT, RT, brentuximab vedotin[BV])
EXPERIMENTALPatients receive 2-4 cycles of standard of care salvage therapy per investigator choice. 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. Additionally, patients may undergo blood sample collection, CT, and PET/CT throughout the study.
Arm C (salvage therapy, HDT-ASCT, pembrolizumab, RT, BV)
EXPERIMENTALPatients receive 2-4 cycles of standard of care salvage therapy per investigator choice. 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. Additionally, patients may undergo blood sample collection, CT, and PET/CT throughout the study.
Arm D (salvage therapy, HDT-ASCT, RT, brentuximab vedotin)
EXPERIMENTALPatients receive 2-4 cycles of standard of care salvage therapy per investigator choice. 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, CT, and PET/CT throughout the study.
Interventions
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
Eligibility Criteria
You may qualify if:
- STEP 0 REGISTRATION: Patient must have biopsy confirmed relapsed classical Hodgkin lymphoma
- STEP 0 REGISTRATION: Patient must be 5-75 years of age
- STEP 0 REGISTRATION: Patient must have relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after first line of chemotherapy
- STEP 0 REGISTRATION: Patients \> 17 years of age must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and patients ≤ 17 years of age must have a Lansky performance status 50-100
- STEP 0 REGISTRATION: Patient must have had a PET CT or magnetic resonance imaging (MRI) (PET1) confirming relapse. The PET1 must have been completed prior to starting any salvage therapy and must be obtained within 56 days prior to Step 0 registration
- NOTE: If patient received one cycle of salvage prior to study enrollment, PET1 confirming relapse must have been completed prior to the initiation of any salvage therapy
- STEP 0 REGISTRATION: Patient must be considered standard- or high-risk at the time of initial relapse. If a patient meets one the following criteria below, they are considered high risk:
- Primary refractory disease to frontline therapy
- Relapse in \< 3 months after completion of frontline non-checkpoint inhibitor containing therapy
- Relapse in \< 6 months after completion of frontline checkpoint inhibitor containing therapy
- \> 4 disease sites at relapse (as defined by the German Hodgkin Study Groups \[GHSG\] Criteria)
- Prior radiation that would result in overlapping fields that would exceed the RT dose to critical organs. For additional questions, contact the radiation oncology study co-chairs
- Patients with bone marrow involvement
- Patients who do not meet the criteria above are considered standard risk
- STEP 0 REGISTRATION: Patient must be considered eligible for high dose chemotherapy and autologous hematopoietic cell transplant
- +45 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Vaishalee P Kenkre
ECOG-ACRIN Cancer Research Group
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 6, 2026
First Posted
May 7, 2026
Study Start (Estimated)
December 4, 2026
Primary Completion (Estimated)
March 31, 2029
Study Completion (Estimated)
March 31, 2029
Last Updated
May 7, 2026
Record last verified: 2026-05
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.