Study of Rituximab and Bendamustine With or Without Brentuximab Vedotin for CD30 Positive Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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This is a randomized, open-label, multicenter, Phase 2 clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin in combination with rituximab and bendamustine for the treatment of patients with relapsed or refractory CD30-positive diffuse large B-cell lymphoma (DLBCL) after failure of second-line salvage therapy or as second-line treatment in patients ineligible for autologous stem cell transplant (ASCT).

Detailed Description
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Patients will be randomized in a 1:1 manner to receive rituximab plus bendamustine with or without brentuximab vedotin. Patients who respond to combination treatment containing brentuximab vedotin and do not experience excessive toxicity may receive additional single-agent brentuximab vedotin following combination treatment, for up to an additional 10 cycles (up to 16 total cycles of treatment).

Official Title
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A Randomized, Open Label, Phase 2 Study of Rituximab and Bendamustine With or Without Brentuximab Vedotin for Relapsed or Refractory CD30-Positive Diffuse Large B-Cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma Refractory, Follicular B-cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Brentuximab Vedotin
* Drug: Rituximab
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with confirmed CD30-positive DLBCL or grade 3b follicular non-Hodgkin lymphoma (NHL). Patients must have relapsed or refractory disease following: second-line or greater salvage systemic therapy, or frontline cytotoxic systemic therapy, for patients who are ineligible for stem cell transplant (SCT). Age 18 years and older. Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET). An Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. Acceptable blood test results. Females of childbearing potential must have a negative pregnancy test result within 7 days prior to the first dose of study drug. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of brentuximab vedotin or 12 months following the last dose of rituximab, whichever is later. Patients must provide written informed consent. Exclusion Criteria: History of another invasive malignancy that has not been in remission for at least 1 year. (Exceptions are nonmelanoma skin cancer, curatively treated localized prostate cancer, ductal carcinoma, and cervical carcinoma or a squamous intraepithelial lesion on PAP smear). History of progressive multifocal leukoencephalopathy (PML). Cerebral/meningeal disease related to the underlying malignancy, unless definitively treated. Viral, bacterial, or fungal infection within 2 weeks prior to the first dose of treatment. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of study drug. Females who are pregnant or breastfeeding. Known allergy to any study drug or ingredient contained in the drug formulation of any of the study drugs. Known to be positive for hepatitis B. Known to have active hepatitis C infection or on antiviral therapy for hepatitis C within the last 6 months. Known to be positive for human immunodeficiency virus (HIV). Patients with previous allogeneic stem cell transplant. Previous treatment with brentuximab vedotin or bendamustine. Intolerable toxicity to prior rituximab therapy. Current therapy with other investigational agents. Lung disease unrelated to underlying malignancy. History of a stroke or transient ischemic attack, unstable angina, myocardial infarction, or cardiac symptoms within 6 months prior to the first dose of treatment. Congestive heart failure. Significant peripheral sensory or motor neuropathy at the start of the study.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brentuximab Vedotin<br>Subjects randomized to the brentuximab vedotin arm will receive IV infusions of brentuximab vedotin followed by bendamustine on day 1, and rituximab followed by bendamustine on day 2 of each 21 day cycle. | Drug: Brentuximab Vedotin<br> <br> * Other names: Adcetris;Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bendamustine<br> <br> * Other names: Treanda;|
| Active Comparator: Rituximab,Bendamustine control<br>Subjects randomized to the control arm will receive IV infusions of rituximab on day 1 or day 2 and bendamustine on both days 1 and 2 of each 21 day cycle. | Drug: Rituximab<br> <br> * Other names: Rituxan;Drug: Bendamustine<br> <br> * Other names: Treanda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients who achieve a Complete Response (CR) (including Complete Metabolic Response (CMR)) or Partial Response (PR) (including Partial Metabolic Response (PMR)) as best response to combination therapy on study | Approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is defined as the time from randomization to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first. | Up to 11.8 months | 
| Complete Remission (CR) Rate | CRR is the proportion of patients who achieve CR (including Complete Metabolic Response (CMR)) as best response to combination therapy on study. | Approximately 1 year | 
| Duration of Response (DOR) | DOR is defined as the time from first observation of response to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first. | Up to 10.5 months | 
| Overall Survival (OS) | OS is defined as the time randomization to death from any cause | Up to 1.5 years | 
| Number and Severity of Adverse Events (AEs) | All AEs are included in the summaries, unless treatment-emergent is specified. | Approximately 1 year |