A Study Evaluating the Safety and Efficacy of Venetoclax (GDC-0199) Plus Bendamustine + Rituximab (BR) in Comparison With BR or Venetoclax Plus Rituximab in Participants With Relapsed and Refractory Follicular Non-Hodgkin's Lymphoma (fNHL)

Roche

Status and phase: Completed; Phase 2

Conditions: Follicular Lymphoma

Treatments: Drug: Venetoclax; Drug: Bendamustine; Drug: Rituximab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02187861

BO29337

2014-000576-26 (EudraCT Number)

Details and patient eligibility

About

This open-label, international, multicenter study will investigate the safety and efficacy of venetoclax (GDC-0199) in combination with bendamustine plus rituximab (venetoclax + BR) compared with BR alone in participants with relapsed and refractory fNHL, comparing two chemotherapy-containing regimens (Chemotherapy-Containing Cohort). In addition, an exploratory analysis of the safety and efficacy of venetoclax in combination with rituximab (venetoclax + rituximab), a chemotherapy-free regimen, will be performed (Chemotherapy-Free Cohort). Assignment to the Chemotherapy-Containing or Chemotherapy-Free Cohort will be decided at the discretion of the Investigator, unless one of the cohorts is not open to enrollment; in which case, participants may be enrolled only to the open cohort. The first 6 participants enrolled in the Chemotherapy-Containing Cohort (or more if required) will comprise the Safety Run-In group for Treatment Arm B, dosing venetoclax at 600 milligrams (mg) in combination with BR. Once a dose has been chosen from the Safety Run-In Period, randomization to the two treatment arms of the Chemotherapy-Containing Cohort (Arms B and C) will begin.

Enrollment: 163 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participants must have histologically confirmed follicular lymphoma (FL) of Grade 1, 2, or 3a
• Participants must have received at least one prior therapy for FL
• For participants potentially receiving chemotherapy: if the participant has received prior bendamustine, response duration must have been greater than (>) 1 year
• At least one bi-dimensionally measurable lesion on imaging scan defined as >1.5 centimeters (cm) in its longest dimension
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• Adequate hematologic function
• For female participants of childbearing potential and male participants with female partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception throughout the course of study treatment and for at least 30 days after the last dose of venetoclax and 12 months after the last dose of rituximab, whichever is longer
• Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined specifications prior to study enrollment

Exclusion criteria

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Contraindication to potential treatment agents
• Ongoing corticosteroid use >30 milligrams per day (mg/day) of prednisone or equivalent. Participants receiving corticosteroid treatment with less than equal to (</=) 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to randomization (Cycle 1 Day 1)
• Primary central nervous system (CNS) lymphoma
• Vaccination with live vaccines within 28 days prior to treatment
• Chemotherapy or other investigational therapy within five half-lives of a biologic agent with a minimum of 28 days prior to the start of Cycle 1
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the participant
• Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1
• Requires the use of warfarin
• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
• Presence of positive test results for hepatitis B surface antigen or hepatitis C virus (HCV) antibody
• Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
• Participants with occult or prior hepatitis B virus (HBV) infection may be included if HBV deoxyribonucleic acid (DNA) is undetectable at screening. These participants must be willing to undergo monthly HBV DNA test until at least 12 months after the last treatment cycle
• Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1)
• Pregnant or lactating
• Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1), other than for diagnosis

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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163 participants in 4 patient groups

Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR)

Experimental group

Description:

Participants will receive venetoclax no more than 600 milligrams (mg) orally once daily continuously along with rituximab 375 milligrams per square meter (mg/m\^2) intravenous (IV) infusion on Day 1 of 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of the 28-day cycle. Safety run-in will continue until first 9 participants complete the safety observation window of 28 days. Participants will continue receiving the same treatment as decided for Arm B.

Treatment:

Drug: Rituximab

Drug: Bendamustine

Drug: Venetoclax

Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab)

Experimental group

Description:

Participants will receive venetoclax 800 mg orally once daily for 1 year along with rituximab 375 mg/m\^2 IV infusion on Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 4, 6, 8, 10, and 12. Each cycle will be of 28 days.

Treatment:

Drug: Rituximab

Drug: Venetoclax

Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR)

Experimental group

Description:

Participants will receive venetoclax at doses decided from safety run-in orally once daily continuously for 1 year along with rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

Treatment:

Drug: Rituximab

Drug: Bendamustine

Drug: Venetoclax

Chemotherapy-Containing Cohort: Arm C (BR)

Active Comparator group

Description:

Participants will receive rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

Treatment:

Drug: Rituximab

Drug: Bendamustine