This phase III trial compares chemotherapy versus an immune checkpoint inhibitor drug called pembrolizumab plus chemotherapy in treating patients with classical Hodgkin lymphoma that has come back (relapsed) or that does not respond to treatment (refractory). The usual approach for patients with classical Hodgkin lymphoma is treatment with standard chemotherapy, including drugs that are Food and Drug Administration (FDA)-approved. If this treatment puts a patient into remission, high dose chemotherapy and stem cell transplant may be used to increase the likelihood of a cure. Hodgkin lymphoma is capable of inhibiting the immune system from killing it. Pembrolizumab is a checkpoint inhibitor that may be able to stop this inhibition, allowing the immune system to attack the lymphoma.
PRIMARY OBJECTIVE: I. To assess the 2-year event free survival (EFS) of patients treated with pembrolizumab added to chemotherapy versus chemotherapy alone, in patients with relapsed/refractory (R/R) classical Hodgkin's lymphoma (cHL) who are intended to receive salvage therapy followed by high dose chemotherapy and autologous stem cell transplant (HDT-ASCT). PRIMARY IMAGING OBJECTIVE: I. To assess the diagnostic performance of baseline total metabolic tumor volume (TMTV) in predicting response (complete remission \[CR\] + partial remission \[PR\] versus \[vs\] no response) at pre-transplant/post-salvage for each arm separately and overall. SECONDARY OBJECTIVES: I. To assess the 2-year progression free survival (PFS) and overall survival (OS) in the transplanted population. II. To assess the complete remission (CR) rate to salvage therapy. III. To assess the CR rate post HDT-ASCT. IV. To assess the post HDT-ASCT partial remission (PR) to CR conversion rate. SECONDARY IMAGING OBJECTIVES: I. To assess the % change in TMTV (delta TMTV) from baseline to pre-transplant/post-salvage in predicting response (CR+PR vs no response) at pre-transplant/post-salvage for each arm separately and overall. II. To assess baseline TMTV and delta TMTV in predicting EFS/OS for each arm separately and overall. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: SALVAGE THERAPY: Patients receive 1 of 3 chemotherapy regimens as clinically indicated: 1) ifosfamide intravenously (IV), carboplatin IV, and etoposide IV; 2) gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin IV; or 3) brentuximab vedotin IV and bendamustine IV. Patients then undergo a positron emission tomography (PET)/computed tomography (CT) scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve stable disease (SD) or progressive disease (PD) come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo radiation therapy (RT) as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated. ARM B: SALVAGE THERAPY: Patients receive pembrolizumab IV plus 1 of 3 chemotherapy regimens specified in Arm A as clinically indicated. Patients then undergo a PET scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated. All patients undergo CT scans during follow-up.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Undergo ASCT
Given IV
Given IV
Given IV
Undergo PET/CT and CT
Given IV
Given IV
Given IV
Given IV
Given IV
Undergo PET/CT
Undergo RT
Receive standard preparative chemotherapy regimen
Given IV
Event free survival (EFS)
Events include: failure to achieve partial remission (PR) or complete remission (CR) to salvage chemotherapy, failure to achieve a CR post high dose chemotherapy and autologous stem cell transplant (HDT-ASCT), progression, receipt of unplanned radiation or brentuximab vedotin maintenance, or death. Patients who have not experienced any of these events will be censored at the date they are last known to be progression free. Kaplan-Meier method will be used to estimate EFS, including medians and confidence intervals. Comparison of EFS between treatment arms will be conducted based on intent-to-treat principle using a one-sided stratified log-rank test with the stratification factors.
Time frame: Time from randomization to the earlier of events listed in description field, assessed up to 15 years
Lugano-based response
Will be assessed using positron emission tomography/computed tomography (PET/CT) scan with Deauville score. Will assess the diagnostic performance of baseline metabolic tumor volume (TMTV) in predicting response (CR+PR vs no response) at pre-transplant/post-salvage, overall and by study arm. Diagnostic performance of baseline TMTV will be assessed using area under the receiver operator characteristic curve (ROC AUC) analysis, where the reference standard is pre-transplant/post-salvage response (CR/PR).
Time frame: Pre-transplant/post-salvage therapy
Percentage change in TMTV (delta TMTV)
Similar methods will be used as the primary imaging aim to assess the diagnostic performance of delta TMTV in predicting pre-transplant/post-salvage response (CR+PR vs no response). Delta TMTV will be defined as the percent change from baseline to pre-transplant/post-salvage \[(post-salvage/pre-transplant - baseline)/baseline X 100\].
Time frame: Baseline to pre-transplant/post-salvage therapy
Baseline TMTV and delta TMTV
Will assess baseline TMTV and delta TMTV in predicting EFS/overall survival (OS) for each arm separately and overall. The association between TMTV and EFS will be analyzed through a Cox regression model. TMTV will be analyzed individually as its absolute value and the percent change from baseline. We will also test if there is a difference by arm by including an interaction term in the model between TMTV and arm. The Kaplan-Meier method will be used to estimate EFS, including median survival times and confidence intervals. In addition to examining the TMTV, we will also analyze standard uptake value maximum (SUVmax) and total lesion glycolysis (TLG) with the same methods. The OS outcome will be analyzed in a similar manner.
Time frame: Baseline and pre-transplant/post-salvage therapy
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