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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

Description:

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.

Related Conditions:
  • Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination With Idasanutlin and Venetoclax in Patients With Relapsed or Refractory Follicular Lymphoma and Obinutuzumab or Rituximab in Combination With Idasanutlin and Venetoclax in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: BH39147
  • SECONDARY ID: 2016-002480-34
  • NCT ID: NCT03135262

Conditions

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

Interventions

DrugSynonymsArms
IdasanutlinDose-Escalation Cohort: FL
ObinutuzumabDose-Escalation Cohort: FL
VenetoclaxDose-Escalation Cohort: FL
RituximabDose-Escalation Cohort: DLBCL

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose-Escalation Cohort: FLExperimentalInduction 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.
  • Idasanutlin
  • Obinutuzumab
  • Venetoclax
Dose-Escalation Cohort: DLBCLExperimentalInduction 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.
  • Idasanutlin
  • Obinutuzumab
  • Venetoclax
  • Rituximab
Expansion Cohort: FLExperimentalInduction 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.
  • Idasanutlin
  • Obinutuzumab
  • Venetoclax
Expansion Cohort: DLBCLExperimentalInduction 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.
  • Idasanutlin
  • Venetoclax
  • Rituximab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:RP2D of Idasanutlin When Given in Combination With Obinutuzumab or Rituximab
Time Frame:Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants With CR, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With CR, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With CR, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response, Determined by the IRC on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response at EOI, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
Time Frame:At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
Safety Issue:
Description:
Measure:Percentage of Participants With Objective Response During the Study, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
Time Frame:From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months
Safety Issue:
Description:
Measure:Observed Serum Concentration of Obinutuzumab in Participants With FL
Time Frame:From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Induction: Pre-dose (any time prior to dose on same day) and 30 minutes (min) post-dose on Day 1 of Cycle 1; Pre-dose (within 5 hours [hrs] prior to dose) and 30 min post-dose on Day 1 of Cycles 2, 4 and 6; Post-induction: Pre-dose (within 5 hrs prior to dose) on Day 1 of Months 1, 7, 13, 19; treatment discontinuation visit (up to 2 years); 120 days after last dose; and 1 to 2 years after last dose (up to approximately 48 months). Obinutuzumab infusion will be administered at a rate from 0.5 milligrams per kilogram per hour (mg/kg/hour) (maximum 50 milligrams per hour [mg/hour]) to a maximum rate of 400 mg/hour.
Measure:Observed Serum Concentration of Obinutuzumab in Participants With DLBCL
Time Frame:Induction: Pre-dose (any time prior to dose on same day) and 30 min post-dose on Day 1 of Cycle 1; Pre-dose (within 5 hrs prior to dose) and 30 min post-dose on Day 1 of Cycles 2, 4 and 6 (each cycle = 28 days)
Safety Issue:
Description:Obinutuzumab infusion will be administered at a rate from 0.5 mg/kg/hour (maximum 50 mg/hour) to a maximum rate of 400 mg/hour.
Measure:Observed Serum Concentration of Rituximab in Participants With FL
Time Frame:Induction: Pre-dose (any time prior to dose on same day) on Day 1 of Cycle 1; Pre-dose (within 5 hrs prior to dose) on Day 1 of Cycles 2, 4, 6; 30 min post-dose on Day 1 of Cycles 1 and 6 (each cycle = 28 days)
Safety Issue:
Description:Rituximab infusion will be administered at a rate from 0.5 mg/kg/hour (maximum 50 mg/hour) to a maximum rate of 400 mg/hour.
Measure:Observed Serum Concentration of Rituximab in Participants With DLBCL
Time Frame:From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Induction: Pre-dose (any time prior to dose on same day) and 30 min post-dose on Day 1 of Cycle 1; Pre-dose (within 5 hrs prior to dose) on Day 1 of Cycles 2, 4; Pre-dose (within 5 hrs prior to dose) and 30 min post-dose on Day 1 of Cycle 6; Post-induction: treatment discontinuation visit (up to 6 months); 120 days after last dose; and 1 to 2 years after last dose (up to approximately 48 months). Rituximab infusion will be administered at a rate from 0.5 mg/kg/hour (maximum 50 mg/hour) to a maximum rate of 400 mg/hour.
Measure:Observed Plasma Concentration of Idasanutlin in Participants With FL
Time Frame:From Day 1 of Cycle 1 up to Day 5 of Cycle 4 (each cycle = 28 days) (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Regimen A: Induction: Pre-dose (any time prior to dose on same day) and 6 hrs post-dose on Day 1 of Cycle 1; Pre-dose (within 1 hr prior to dose), and 2, 4, 6 hrs post-dose on Day 5 of Cycle 1; Pre-dose (within 1 hr prior to dose) and 6 hrs post-dose on Days 1 and 5 of Cycles 2 and 4 Regimen B: Induction: Pre-dose (any time prior to dose on same day) on Day 1 of Cycle 1; Pre-dose (any time prior to dose on same day) and 6 hrs post-dose on Day 1 of Cycle 2; Pre-dose (within 1 hr prior to dose), and 2, 4, 6 hrs post-dose on Day 5 of Cycle 2; Pre-dose (within 1 hr prior to dose) and 6 hrs post-dose on Days 1 and 5 of Cycle 4
Measure:Observed Plasma Concentration of Idasanutlin in Participants With DLBCL
Time Frame:From Day 1 of Cycle 1 up to Day 5 of Cycle 4 (each cycle = 28 days) (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Induction: Pre-dose (any time prior to dose on same day), 6 hrs post-dose on Day 1 of Cycle 1; Pre-dose (within 1 hr prior to dose), 2, 4, 6 hrs post-dose on Day 5 of Cycle 1; Pre-dose (within 1 hr prior to dose), 6 hrs post-dose on Days 1, 5 of Cycles 2, 4 (each cycle = 28 days)
Measure:Observed Plasma Concentration of Venetoclax in Participants With FL
Time Frame:From Day 1 of Cycle 1 up to Day 5 of Cycle 4 (each cycle = 28 days) (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Regimen A: Induction: Pre-dose (any time prior to dose on same day) and 6 hrs post-dose on Day 1 of Cycle 1; Pre-dose (within 1 hr prior to dose), and 2, 4, 6 hrs post-dose on Day 5 of Cycle 1; Pre-dose (within 1 hr prior to dose) and 6 hrs post-dose on Days 1 and 5 of Cycles 2 and 4 Regimen B: Induction: Pre-dose (any time prior to dose on same day) on Day 1 of Cycle 1; Pre-dose (any time prior to dose on same day) and 6 hrs post-dose on Day 1 of Cycle 2; Pre-dose (within 1 hr prior to dose), and 2, 4, 6 hrs post-dose on Day 5 of Cycle 2; Pre-dose (within 1 hr prior to dose) and 6 hrs post-dose on Days 1 and 5 of Cycle 4
Measure:Observed Plasma Concentration of Venetoclax in Participants With DLBCL
Time Frame:From Day 1 of Cycle 1 up to Day 5 of Cycle 4 (each cycle = 28 days) (detailed timeframe is mentioned in outcome measure description)
Safety Issue:
Description:Induction: Pre-dose (any time prior to dose on same day), 6 hrs post-dose on Day 1 of Cycle 1; Pre-dose (within 1 hr prior to dose), 2, 4, 6 hrs post-dose on Day 5 of Cycle 1; Pre-dose (within 1 hr prior to dose), 6 hrs post-dose on Days 1, 5 of Cycles 2, 4 (each cycle = 28 days)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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