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)

NCT03135262 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: BH391472016-002480-34
• Study Type: interventional
• Target: 29
• Locations: 5 countries
• Sites: 21

Brief Summary

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.

Conditions

Follicular Lymphoma; Lymphoma, Large B-Cell, Diffuse

Outcome Measures

Primary Outcomes (5)

• RP2D of Idasanutlin When Given in Combination With Obinutuzumab or Rituximab

  It was planned to be identified in escalation and carried over in expansion phases. However the expansion phase did not take place. phases. The study was closed because at escalation doses 100 (in combination with venetoclax 400 mg) and 150 mg (in combination with venetoclax 200 mg) Idasanutlin, the benefit was mild. The study was terminated at the escalation phase with DLTs showing AEs in all cohorts. The subpopulations of DLBCL and FL were showed no difference in their genetic subtype make-up, therefore, Cohorts Safety, 1, 2, 3 contain both populations. The safety cohort had a different venetoclax schedule of 5 days to ensure safety. Remaining cohorts used a 10 days schedule. No RP2D was identified in the Cohorts 1 and 3.

  Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)

• RP2D of Venetoclax When Given in Combination With Obinutuzumab or Rituximab

  It was planned to be identified in escalation and carried over in expansion phases. However the expansion phase did not take place. The study was closed because at escalation doses 200 (in combination with 150 mg idasanutlin) and 400 (in combination with 100 mg idasanutlin) mg Venetoclax, the benefit was mild. The study was terminated at the escalation phase with DLTs showing AEs in all cohorts. The safety cohort had a different venetoclax schedule of 5 days to ensure safety. Remaining cohorts used a 10 days schedule. No RP2D was identified in the Cohorts 1 and 3.

  Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)

• Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  DLT is defined as any one of the following events occurring during first two Cycles of treatment and assessed by the investigator as clearly not related to patient's underlying disease: - Any Grade 5 adverse event (AE) unless unequivocally due to the underlying malignancy or extraneous causes; - AE of any grade that leads to a delay of more than 14 days at the start of next treatment cycle; - Hematologic AEs (neutropenia, thrombocytopenia); - Non-hematologic AE, except IRRs, laboratory TLS without manifestations of clinical TLS, AST or ALT, diarrhea, nausea or vomiting, fatigue, asthenia, anorexia, or constipation, hepatic transaminase.

  Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)

• Percentage of Participants With Adverse Events (AEs)

  An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a casual relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

  From Baseline up to approximately 48 months

• Percentage of Participants With Complete Response (CR), Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography-Computed Tomography (PET-CT) Scans Using Modified Lugano 2014 Criteria

  The study plan was for the IRC to analyze the efficacy results in participants from the expansion phase (Part II), but the expansion phase was not opened (i.e., no enrollment) because the sponsor decided to terminate the study early due to the modest benefit achieved with the maximum tolerated dose during the dose escalation phase (Part I). Therefore the result data not derived and not reported.

  At end of Induction (EOI) (within 6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days])

Secondary Outcomes (16)

• Percentage of Participants With CR, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria

  At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]

• Percentage of Participants With CR, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria

  At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]

• Percentage of Participants With CR, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria

  At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]

• Percentage of Participants With Objective Response, Determined by the IRC on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria

  At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]

• Percentage of Participants With Objective Response, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria

  At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]

Study Arms (4)

Dose-Escalation Cohort: FL

EXPERIMENTAL

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.

Drug: Idasanutlin; Drug: Obinutuzumab; Drug: Venetoclax

Dose-Escalation Cohort: DLBCL

EXPERIMENTAL

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.

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

Expansion Cohort: FL

EXPERIMENTAL

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.

Drug: Idasanutlin; Drug: Obinutuzumab; Drug: Venetoclax

Expansion Cohort: DLBCL

EXPERIMENTAL

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.

Drug: Idasanutlin; Drug: Venetoclax; Drug: Rituximab

Interventions

Idasanutlin DRUG

Induction Treatment: Idasanutlin tablets will be administered orally once daily at escalated doses (starting dose 100 milligrams \[mg\], maximum 600 mg). Post-Induction Treatment: The dose and regimen will be determined by the Sponsor after review of all relevant data. The dose for maintenance/consolidation will not exceed the dose the participant received during induction.

Dose-Escalation Cohort: DLBCL; Dose-Escalation Cohort: FL; Expansion Cohort: DLBCL; Expansion Cohort: FL

Obinutuzumab DRUG

Participants will receive a fixed dose of obinutuzumab, 1000 mg by intravenous (IV) infusion on Days 1, 8 and 15 of Cycle 1 and on Day 1 of each subsequent cycle (Cycles 2 to 6) (each cycle = 28 days) during induction treatment, and on Day 1 of every other month during maintenance treatment (eligible participants with FL only) or during consolidation treatment (eligible participants with DLBCL only).

Dose-Escalation Cohort: DLBCL; Dose-Escalation Cohort: FL; Expansion Cohort: FL

Venetoclax DRUG

Induction Treatment: Venetoclax tablets will be administered orally once daily at escalated doses (starting dose 200 mg, maximum 800 mg). Post-Induction Treatment: The dose and regimen will be determined by the Sponsor after review of all relevant data. The dose for maintenance/consolidation will not exceed the dose the participant received during induction.

Dose-Escalation Cohort: DLBCL; Dose-Escalation Cohort: FL; Expansion Cohort: DLBCL; Expansion Cohort: FL

Rituximab DRUG

Rituximab will be administered by IV infusion at a dose of 375 milligrams per square meter (mg/m\^2) on Day 1 of Cycles 1-6 during induction treatment and on Day 1 of every other month during consolidation treatment.

Dose-Escalation Cohort: DLBCL; Expansion Cohort: DLBCL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (21)

University of Colorado

Aurora, Colorado, 80045-2517, United States

Location

The University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Norton Cancer Institute - Dutchmans

Louisville, Kentucky, 40207, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Guthrie Clinic

Sayre, Pennsylvania, 18840, United States

Location

Swedish Cancer Inst.

Seattle, Washington, 98104, United States

Location

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Linear Clinical Research Limited

Nedlands, Western Australia, 6009, Australia

Location

Klinikum Augsburg

Augsburg, 86156, Germany

Location

Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden

Dresden, 01307, Germany

Location

SLK-Kliniken Heilbronn GmbH

Heilbronn, 74078, Germany

Location

Klinikum rechts der Isar der TU München

München, 81675, Germany

Location

Universitätsklinikum Würzburg; Studienzentrale Hämatologie/Onkologie

Würzburg, 97080, Germany

Location

Christchurch Hospital

Christchurch, 8011, New Zealand

Location

Auckland Clinical Studies Limited

Grafton, 1010, New Zealand

Location

Keimyung University Dongsan Medical Center

Daegu, 41931, South Korea

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

MeSH Terms

Conditions

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

Interventions

RG7388; obinutuzumab; venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Dose expansion part of the study did not take place. AEs were not differentiated for DLBCL and FL arms since these are sub mutations of disease which does nor show differences in AEs.

Results Point of Contact

• Title: Reference Study ID Number: BH39147
• Organization: www.roche.com/about_roche/roche_worldwide.htm

global-roche-genentech-trials@gene.com

888-662-6728 (U.S. Only)

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2017
• First Posted: May 1, 2017
• Study Start: June 15, 2017
• Primary Completion: April 30, 2020
• Study Completion: April 30, 2020
• Last Updated: December 7, 2021
• Results First Posted: July 27, 2021

Record last verified: 2021-12

Locations

US (7); AU (3); NZ (2); DE (5); KR (4)