A Study of Obinutuzumab in Combination With Idasanutlin and Venetoclax in Participants With Relapsed or Refractory (R/R) Follicular Lymphoma (FL) or Rituximab in Combination With Idasanutlin and Venetoclax in Participants With R/R Diffuse Large B-Cell Lymphoma (DLBCL)

Roche

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Follicular Lymphoma; Lymphoma, Large B-Cell, Diffuse

Treatments: Drug: Rituximab; Drug: Venetoclax; Drug: Obinutuzumab; Drug: Idasanutlin

Study type: Interventional

Funder types: Industry

Identifiers

NCT03135262

2016-002480-34 (EudraCT Number)

BH39147

Details and patient eligibility

About

This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will evaluate the safety, efficacy, and pharmacokinetics of obinutuzumab in combination with idasanutlin and venetoclax in participants with R/R FL and obinutuzumab or rituximab in combination with idasanutlin and venetoclax in participants with R/R DLBCL. The study will include an initial dose-escalation phase followed by an expansion phase. The dose-escalation phase is designed to determine the recommended phase II doses (RP2Ds) and regimen for idasanutlin and venetoclax in combination with obinutuzumab for FL participants and in combination with rituximab for DLBCL participants.

Enrollment: 29 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• B-cell lymphoma classified as either of the following: R/R FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-cluster of differentiation 20 (CD20) monoclonal antibody; R/R DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in participants who are not eligible for second line combination chemotherapy and autologous stem-cell transplantation, have failed second line combination chemotherapy, or experienced disease progression following autologous stem-cell transplantation
• Histologically documented CD20-positive lymphoma
• Fluorodeoxyglucose (FDG)-avid lymphoma (that is [i.e.], PET-positive lymphoma)
• At least one bi-dimensionally measurable lesion (greater than [>] 1.5 centimeters [cm] in its largest dimension by CT scan or magnetic resonance imaging [MRI])
• Availability of a representative tumor specimen and the corresponding pathology report for retrospective central confirmation of the diagnosis of FL or DLBCL

Exclusion criteria

• Known CD20-negative status at relapse or progression
• Prior allogeneic stem-cell transplantation (SCT)
• Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1
• Prior standard or investigational anti-cancer therapy as specified: Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1; Monoclonal antibody or antibody-drug conjugate within 4 weeks prior to Day 1 of Cycle 1; Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1
• Clinically significant toxicity (other than alopecia) from prior therapy that has not resolved to Grade less than or equal to (</=) 2 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) prior to Day 1 of Cycle 1
• Grade 3b FL
• History of transformation of indolent disease to DLBCL (expansion-phase only)
• Central nervous system lymphoma or leptomeningeal infiltration
• Treatment with systemic corticosteroids >20 mg/day, prednisone or equivalent
• Clinical conditions requiring treatment with oral or parenteral anticoagulants or antiplatelet agents unless treatment can be discontinued 7 days (or 5 half-lives) prior to initiation of study treatment (except used as flushes for indwelling catheters)
• History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies
• Known hypersensitivity or allergy to murine products or any component of the obinutuzumab, rituximab, idasanutlin, or venetoclax formulation
• Current or history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or HCV antibody at screening
• History of progressive multifocal leukoencephalopathy (PML)
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results
• Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by study treatment, such as severe hereditary coagulation disorders or insulin-dependent diabetes mellitus that is not optimally controlled with medical management (example, presence of ketoacidosis)
• Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1, or anticipation of a major surgical procedure during the study
• Inadequate hematologic function (unless due to underlying lymphoma), defined as follows: Hemoglobin less than (<) 9 grams per decilitre (g/dL), absolute neutrophil count (ANC) <1.5*10^9 cells per liter (cells/L), platelet count <75*10^9 cells/L
• Any of the following abnormal laboratory values (unless due to underlying lymphoma): International normalized ratio (INR) or prothrombin time (PT) >1.5*upper limit of normal (ULN) in the absence of therapeutic anticoagulation; partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) >1.5*ULN in the absence of a lupus anticoagulant
• Life expectancy <3 months

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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29 participants in 4 patient groups

Dose-Escalation Cohort: FL

Experimental group

Description:

Induction Treatment: Participants will receive either Regimen A or Regimen B. Regimen A: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Regimen B (in bridging cohort): Participants will receive obinutuzumab alone in Cycle 1 and obinutuzumab with idasanutlin and venetoclax (both at maximum tolerated dose \[MTD\] established from Regimen A) in Cycles 2 to 6. Post-Induction Treatment (Maintenance Treatment): Participants will receive obinutuzumab every 2 months for 24 months; idasanutlin and venetoclax for 6 months.

Treatment:

Drug: Venetoclax

Drug: Obinutuzumab

Drug: Idasanutlin

Dose-Escalation Cohort: DLBCL

Experimental group

Description:

Induction Treatment: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. In bridging cohort, participants will receive rituximab on Day 1 of Cycles 1 to 6 and idasanutlin and venetoclax (both at MTD) in Cycles 1 to 6. Post-Induction Treatment (Consolidation Treatment): Participants will receive obinutuzumab or rituximab (according to study treatment received in the induction) every 2 months for 6 months; idasanutlin and venetoclax for 6 months.

Treatment:

Drug: Rituximab

Drug: Venetoclax

Drug: Obinutuzumab

Drug: Idasanutlin

Expansion Cohort: FL

Experimental group

Description:

Induction Treatment: Participants will receive idasanutlin and venetoclax at the RP2D of the selected regimen (Regimen A or B) identified during the dose-escalation phase in combination with obinutuzumab. Regimen A: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Regimen B (in bridging cohort): Participants will receive obinutuzumab alone in Cycle 1 and obinutuzumab with idasanutlin and venetoclax in Cycles 2 to 6. Post-Induction Treatment (Maintenance Treatment): Participants will receive obinutuzumab every 2 months for 24 months; idasanutlin and venetoclax for 6 months.

Treatment:

Drug: Venetoclax

Drug: Obinutuzumab

Drug: Idasanutlin

Expansion Cohort: DLBCL

Experimental group

Description:

Induction Treatment: Participants will receive rituximab on Day 1 of Cycles 1 to 6; idasanutlin and venetoclax (both at RP2D) on Days 1 to 5 of Cycles 1 to 6 or rituximab on Day 1 of Cycles 1 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Post-Induction Treatment (Consolidation Treatment): Participants will receive rituximab every 2 months for 6 months; idasanutlin and venetoclax for 6 months.

Treatment:

Drug: Rituximab

Drug: Venetoclax

Drug: Idasanutlin