Brentuximab Vedotin Plus Lenalidomide and Rituximab for the Treatment of Relapsed/Refractory DLBCL

Study Overview
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Brief Summary
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Participants in this study will have diffuse large B-cell lymphoma (DLBCL) that has come back or not gotten better with treatment. The trial will study whether brentuximab vedotin plus two drugs works better to treat this type of cancer than the two drugs alone. Participants will be randomly assigned to get either brentuximab vedotin or placebo. The placebo will look like brentuximab vedotin, but has no medicine in it. Since the study is blinded, participants and their doctors will not know whether a participant gets brentuximab vedotin or placebo. All participants in the study will get rituximab and lenalidomide. These are drugs that can be used to treat DLBCL.

Official Title
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A Randomized, Double-blind, Placebo-Controlled, Active-Comparator, Multicenter, Phase 3 Study of Brentuximab Vedotin or Placebo in Combination With Lenalidomide and Rituximab in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Brentuximab vedotin
* Drug: Rituximab
* Drug: Lenalidomide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with relapsed or refractory diffuse and transformed large B-cell lymphoma (R/R DLBCL). DLBCL and cell of origin (GCB versus non-GCB) will be histologically determined by local pathology assessment for the purposes of study eligibility and stratification. Participants must have R/R disease following 2 or more lines of prior systemic therapy. For participants with transformed DLBCL, at least the last systemic therapy used must have been for DLBCL Participants must be HSCT or CAR-T ineligible according to the investigator and must meet at least one of the following criteria: One or more co-morbidities, including cardiac, pulmonary, renal or hepatic dysfunction that in the opinion of the Investigator make the participant medically unfit to received HSCT or CAR-T therapy Active disease following induction and salvage chemotherapy Inadequate stem cell mobilization (for HSCT) Relapse following prior HSCT or CAR-T Unable to receive CAR-T therapy due to financial, geographic, insurance, or manufacturing issues Participants must have tumor tissue submitted to the central pathology lab. The tumor tissue submitted should be from the most recent biopsy that contains DLBCL. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2 Participants must have fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist within 28 days of Day 1. Exclusion Criteria: History of another malignancy within 2 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy History of progressive multifocal leukoencephalopathy (PML) Active cerebral/meningeal disease related to the underlying malignancy. Participants with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been effectively treated and without progression for at least 3 months. Any uncontrolled Grade 3 or higher (per NCI CTCAE version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 3 weeks prior to first dose of study drug, unless underlying disease has progressed on treatment Previous treatment with brentuximab vedotin or lenalidomide. Previous treatment with other vedotin-based ADCs is permitted if the last dose is at least 6 months prior to Day 1. Current therapy with immunosuppressive medications (including steroids), other systemic anti-neoplastic, or investigational agents a) Prednisone (or equivalent) ≤10 mg/day may be used for non-lymphomatous purposes 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 (NYHA) Class III-IV within 6 months prior to the first dose of study drugs Congestive heart failure, Class III or IV, by the NYHA criteria Grade 2 or higher peripheral sensory or motor neuropathy at baseline

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Brentuximab vedotin + lenalidomide + rituximab | Drug: Brentuximab vedotin<br>* 1.2 mg/kg administered into the vein (IV; intravenously) infusion every 3 weeks<br>Drug: Rituximab<br>* 375 mg/m^2 administered via intravenous infusion on Cycle 1 Day 1. 1400 mg injected under the skin (subcutaneous) permitted every 3 weeks from Cycle 2 Day 1 through end of treatment.<br>Drug: Lenalidomide<br>* 20 mg given by mouth (orally) daily<br>|
| Active Comparator: Control Arm<br>Placebo + lenalidomide + rituximab | Drug: Rituximab<br>* 375 mg/m^2 administered via intravenous infusion on Cycle 1 Day 1. 1400 mg injected under the skin (subcutaneous) permitted every 3 weeks from Cycle 2 Day 1 through end of treatment.<br>Drug: Lenalidomide<br>* 20 mg given by mouth (orally) daily<br>Other: Placebo<br>* Administered via intravenous infusion every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is defined as the time from the date of randomization to date of death due to any cause | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. Assessment of PD will be performed by the investigator based on the Lugano Criteria for Response Assessment (Cheson 2014) | Approximately 1 year | 
| Objective response rate (ORR) | Proportion of participants with best response of complete response (CR) or partial response (PR) according to investigator assessment per the Lugano Criteria for Response Assessment (Cheson 2014). | Approximately 1 year | 
| Complete response (CR) rate | Proportion of participants with best response of CR according to investigator assessment per the Lugano Criteria for Response Assessment (Cheson 2014) | Approximately 1 year | 
| Duration of response (DOR) | Time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of tumor progression by investigator assessment per the Lugano Criteria for Response Assessment (Cheson 2014) or death due to any cause, whichever occurs first. | Approximately 1 year | 
| Incidence of adverse events | Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Approximately 1 year | 
| OS in CD30+ participants | Time from the date of randomization to date of death due to any cause. | Approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seattle Genetics