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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 — Phase 1 / Phase 2, Terminated, 29 participants, Hoffmann-La Roche

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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

RegistryNCT03135262
StatusTerminated - Sponsor's decision to terminate the study after Phase 1; will not proceed with Phase 2.
PhasePhase 1 / Phase 2
Study typeInterventional; non randomized, parallel, masking: none, treatment
Enrollment29 (Actual)
SponsorHoffmann-La Roche (Industry)
ConditionsFollicular Lymphoma, Lymphoma, Large B-Cell, Diffuse
InterventionsIdasanutlin, Obinutuzumab, Venetoclax, Rituximab (Drug)
Datesstart 2017-06-15, primary completion 2020-04-30, completion 2020-04-30, first posted 2017-05-01, last updated 2021-12-07
Locations21 sites in United States, Australia, Germany, New Zealand, South Korea

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-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.

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+Arms and interventions

ArmTypeInterventionsDescription
Dose-Escalation Cohort: FLExperimentalDrug: Idasanutlin; Drug: Obinutuzumab; Drug: VenetoclaxInduction 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.
Dose-Escalation Cohort: DLBCLExperimentalDrug: Idasanutlin; Drug: Obinutuzumab; Drug: Venetoclax; Drug: RituximabInduction 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.
Expansion Cohort: FLExperimentalDrug: Idasanutlin; Drug: Obinutuzumab; Drug: VenetoclaxInduction 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.
Expansion Cohort: DLBCLExperimentalDrug: Idasanutlin; Drug: Venetoclax; Drug: RituximabInduction 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 (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.
  • 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).
  • 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.
  • 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.

+Outcome measures

Primary outcomes

  • RP2D of Idasanutlin When Given in Combination With Obinutuzumab or Rituximab [Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)]: 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.
  • RP2D of Venetoclax When Given in Combination With Obinutuzumab or Rituximab [Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)]: 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.
  • Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)]: 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.
  • Percentage of Participants With Adverse Events (AEs) [From Baseline up to approximately 48 months]: 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.
  • 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 [At end of Induction (EOI) (within 6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days])]: 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.

Secondary outcomes

  • 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]]: The investigator evaluated responses at the end of induction treatment using Lugano 2014 criteria for malignant lymphoma for a PET-CT based complete response (CR), which required a complete metabolic response with a score of 1, 2 or 3 with or without a residual mass in lymph nodes and extralymphatic sites on the PET 5-point scale for 18-fluorodeoxyglucose (FDG) uptake (1 = no uptake above background; 2 = uptake less than or equal to \[<=\] mediastinum; 3 = uptake greater than \[>\] mediastinum and <= liver; 4 = uptake moderately > liver; 5 = uptake markedly > liver and/or new lesions). The CR criteria were slightly modified to require normal bone marrow by morphology (if intermediate, immunohistochemistry negative). PET-CT scans were performed at end of induction only on participants who had received at least 2 cycles of induction treatment; those without a post-baseline tumor assessment were considered non-responders.
  • 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]]: The IRC was to evaluate responses at the end of induction treatment using the Lugano 2014 response criteria for malignant lymphoma for a computed tomography (CT)-based complete response (CR). The CR criteria required to complete radiologic response with all of the following: target nodal masses must regress to less than or equal to 1.5 centimeters in the longest transverse diameter of a lesion \[LDi\]; no extralymphatic sites of disease; no non-measured or new lesions; enlarged organs regressing to normal size; and bone marrow normal by morphology (if indeterminate, immunochemistry negative). CT scans were performed at end of induction only on participants who had received at least 2 cycles of induction treatment; those without a post-baseline tumor assessment were to be considered non-responders. Therefore the result data not derived and not reported.
  • 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]]: The investigator evaluated responses at the end of induction treatment using the Lugano 2014 response criteria for malignant lymphoma for a computed tomography (CT)-based complete response (CR). The CR criteria required a complete radiologic response with all of the following: target nodes/nodal masses must regress to less than or equal to 1.5 centimeters in the longest transverse diameter of a lesion (LDi); no extralymphatic sites of disease; no non-measured or new lesions; enlarged organs regressing to normal size; and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative). CT scans were performed at end of induction only on participants who received at least 2 cycles of Induction treatment; those without a post-baseline tumor assessment were to be considered non-responders. This outcome measure therefore not derived and not reported.
  • 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]]: The IRC was to evaluate responses at the end of induction treatment using Luagno 2014 criteria for malignant lymphoma for a PET-CT based objective response: either a complete (CR) or partial response (PR). A CR required a complete metabolic response with a score of 1, 2 or 3 on the PET 5-point scale (5PS) for 18-fluorodeoxyglucose (FDG) uptake (scores range from 1 \[no uptake above background\] to 5 \[uptake markedly higher than liver and/or new lesions\]), with or without a residual mass in lymph nodes and extralymphatic sites; and a PR required a partial metabolic response with a score 4 or 5 on the 5PS with reduced 18-FDG uptake compared with baseline and residual mass(es) of any size. For bone marrow involvement, the CR criteria required no evidence of FDG-avid disease, and the PR criteria required residual uptake higher than in normal marrow but reduced compared with baseline. Therefore the result data not derived and not reported. The study was pre-maturely terminated.
  • 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]]: The investigator was to evaluate responses at end of induction treatment using Lugano 2014 criteria for malignant lymphoma for a PET-CT based objective response: either a complete (CR) or partial response (PR). A CR required a complete metabolic response with a score of 1, 2, or 3 on the PET 5-point scale (5PS) for 18-fluorodeoxyglucose (FDG) uptake (scores range from 1 \[no uptake above background\] to 5 \[uptake markedly higher than liver and/or new lesions\]), with or without a residual mass in lymph nodes and extralymphatic sites; and a PR required a partial metabolic response with a score of 4 or 5 on the 5PS with reduced 18-FDG uptake compared with baseline and residual mass(es) of any size. For bone marrow involvement, the CR criteria required no evidence of FDG-avid disease, and the PR criteria required residual uptake higher than in normal marrow but reduced compared with baseline. Participants without a post-baseline tumor assessment were to be considered non-responders.
  • Percentage of Participants With Objective Response, 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]]: The IRC was to evaluate responses at the end of induction treatment using the Lugano 2014 response criteria for malignant lymphoma for a CT-based objective response: either a complete (CR) or partial response (PR). The CR criteria required a complete radiologic response with all of the following: target nodes/nodal masses must regress to less than or equal to 1.5 cm in the LDi; no extralymphatic sites of disease; no non-measured or new lesions; enlarged organs regressing to normal size; and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative). The PR criteria required all of the following: a >=50% decrease in sum of the product of perpendicular diameters of up to 6 target measurable nodes and extranodal sites; no new lesions; non-measured lesion that is absent/nomal, regressed, but no increase; and spleen must have regressed by >50% in length. Therefore the result data not derived and not reported. The study was pre-maturely terminated.
  • Percentage of Participants With Objective Response at EOI, 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]]: The investigator was to evaluate responses at the end of induction treatment using Lugano 2014 response criteria for malignant lymphoma for a CT-based objective response: either a complete (CR) or partial response (PR). The CR criteria required a complete radiologic response with all of the following: target nodes/nodal masses must regress to less than or equal to 1.5 cm in LDi; no extralymphatic sites of disease; no non-measured or new lesions; enlarged organs regressing to normal size; and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative). The PR criteria required all of the following: a >=50% decrease in sum of the product of perpendicular diameters up to 6 target measurable nodes and extranodal sites; no new lesions; non-measured lesion that is absent/normal, regressed, but no increase; and spleen must have regressed by >50% in length. The study was pre-maturely terminated at escalation phase.
  • 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 [From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months]: The investigator was to evaluate responses at the end of induction treatment using Lugano 2014 response criteria for malignant lymphoma for a CT-based objective response: either a complete (CR) or partial response (PR). The CR criteria required a complete radiologic response with all of the following: target nodes/nodal masses must regress to less than or equal to 1.5 cm in LDi; no extralymphatic sites of disease; no non-measured or new lesions; enlarged organs regressing to normal size; and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative). The PR criteria required all of the following: a >=50% decrease in sum of the product of perpendicular diameters up to 6 target measurable nodes and extranodal sites; no new lesions; non-measured lesion that is absent/normal, regressed, but no increase; and spleen must have regressed by >50% in length. The study was pre-maturely terminated at escalation phase.
  • Observed Serum Concentration of Obinutuzumab in Participants With FL [From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)]: Observed Serum Concentration of Obinutuzumab in Participants With FL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived, therefore no result was reported. The result data not derived due to early termination of the study by the sponsor's decision and did not reach the end of study.
  • Observed Serum Concentration of Obinutuzumab in Participants With DLBCL [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)]: Observed Serum Concentration of Obinutuzumab in Participants With DLBCL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived, therefore no result was reported.
  • Observed Serum Concentration of Rituximab in Participants With FL [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)]: Observed Serum Concentration of Rituximab in Participants With FL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived, therefore no result was reported.
  • Observed Serum Concentration of Rituximab in Participants With DLBCL [From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)]: Observed Serum Concentration of Rituximab in Participants With DLBCL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived, therefore no result was reported.
  • Observed Plasma Concentration of Idasanutlin in Participants With FL [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)]: Observed Plasma Concentration of Idasanutlin in Participants With FL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived therefore no result was reported
  • Observed Plasma Concentration of Idasanutlin in Participants With DLBCL [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)]: Observed Plasma Concentration of Idasanutlin in Participants With DLBCL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated. No result data was derived therefore no result was reported
  • Observed Plasma Concentration of Venetoclax in Participants With FL [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)]: Observed Plasma Concentration of Venetoclax in Participants With FL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated.
  • Observed Plasma Concentration of Venetoclax in Participants With DLBCL [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)]: Observed Plasma Concentration of Venetoclax in Participants With DLBCL was planned to be determined as part of the pharmacokinetics analyses during the expansion phase which did not take place. The study was prematurely terminated because of the overall modest benefit achieved with MTD during the escalation phase (Part 1); Phase II of the study (expansion) was never initiated.

+Eligibility

Sex: All, ages: 18 Years to any

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

+Posted results

Participant flow

MilestoneDose Escalation DLBCL and FL Safety CohortDose Escalation DLBCL and FL Cohort 1Dose Escalation DLBCL and FL Cohort 2Dose Escalation DLBCL and FL Cohort 3Not Defined for DLBCL or FL Subgroups Cohort 3
Started96761
Completed00000
Not completed96761

Outcome results

  • RP2D of Idasanutlin When Given in Combination With Obinutuzumab or Rituximab (Primary), Number, mg: Dose Escalation DLBCL and FL Safety Cohort NA; Dose Escaltion DLBCL and FL Cohort 1 NA; Dose Escaltion DLBCL and FL Cohort 2 150; Dose Escalation DLBCL and FL Cohort 3 NA; Not Defined for DLBCL or FL Subgroups Cohort 3 NA
  • RP2D of Venetoclax When Given in Combination With Obinutuzumab or Rituximab (Primary), Number, mg: Dose Escalation DLBCL and FL Safety Cohort NA; Dose Escalation DLBCL and FL Cohort 1 NA; Dose Escaltion DLBCL and FL Cohort 2 200; Dose Escalation DLBCL and FL Cohort 3 NA; Not Defined for DLBCL or FL Subgroups Cohort 3 NA
  • Percentage of Participants With Dose-Limiting Toxicities (DLTs) (Primary), Number, Percentage of Participants: Dose Escaltion DLBCL and FL Safety Cohort 0; Dose Escaltion DLBCL and FL Cohort 1 16.7; Dose Escaltion DLBCL and FL Cohort 2 28.6; Dose Escalation DLBCL and FL Cohort 3 16.7; Not Defined for DLBCL or FL Subgroups Cohort 3 0
  • Percentage of Participants With Adverse Events (AEs) (Primary), Number, Percentage of Participants: Dose Escaltion DLBCL and FL Safety Cohort 100; Dose Escalation DLBCL and FL Cohort 1 100; Dose Escalation DLBCL and FL Cohort 2 100; Dose Escalation DLBCL and FL Cohort 3 100; Not Defined for DLBCL or FL Subgroups Cohort 3 0
  • 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 (Primary)
  • Percentage of Participants With CR, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria (Secondary), Number, Percentage of Participants: Dose Escaltion DLBCL and FL Safety Cohort 22.2 (4.10 to 54.96); Dose Escalation DLBCL and FL Cohort 1 16.7 (0.85 to 58.18); Dose Escalation DLBCL and FL Cohort 2 28.6 (5.34 to 65.87); Dose Escalation DLBCL and FL Cohort 3 16.7 (0.85 to 58.18); Not Defined for DLBCL or FL Subgroups Cohort 3 0 (0.00 to 95.00)
  • Percentage of Participants With CR, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria (Secondary)
  • Percentage of Participants With CR, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria (Secondary)
  • Percentage of Participants With Objective Response, Determined by the IRC on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria (Secondary)
  • Percentage of Participants With Objective Response, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria (Secondary), Number, Percentage of Participants: Dose Escalation DLBCL and FL Safety Cohort 33.3 (9.77 to 65.51); Dose Escalation DLBCL and FL Cohort 1 16.7 (0.85 to 58.18); Dose Escalation DLBCL and FL Cohort 2 28.6 (5.34 to 65.87); Dose Escalation DLBCL and FL Cohort 3 33.3 (6.28 to 72.87); Not Defined for DLBCL or FL Subgroups Cohort 3 0 (0.00 to 95.00)
  • Percentage of Participants With Objective Response, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria (Secondary)
  • Percentage of Participants With Objective Response at EOI, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria (Secondary)
  • 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 (Secondary)
  • Observed Serum Concentration of Obinutuzumab in Participants With FL (Secondary)
  • Observed Serum Concentration of Obinutuzumab in Participants With DLBCL (Secondary)
  • Observed Serum Concentration of Rituximab in Participants With FL (Secondary)
  • Observed Serum Concentration of Rituximab in Participants With DLBCL (Secondary)
  • Observed Plasma Concentration of Idasanutlin in Participants With FL (Secondary)
  • Observed Plasma Concentration of Idasanutlin in Participants With DLBCL (Secondary)
  • Observed Plasma Concentration of Venetoclax in Participants With FL (Secondary)
  • 1 more outcome measures not shown.

Adverse events

Time frame: From Baseline Up to Approximately 3 Years

ArmDeathsSerious adverse eventsOther adverse events
Dose Escalation DLBCL and FL Safety Cohort6/9 (66.7%)3/9 (33.3%)9/9 (100.0%)
Dose Escalation DLBCL and FL Cohort 12/6 (33.3%)3/6 (50.0%)6/6 (100.0%)
Dose Escalation DLBCL and FL Cohort 22/7 (28.6%)4/7 (57.1%)7/7 (100.0%)
Dose Escalation DLBCL and FL Cohort 32/6 (33.3%)4/6 (66.7%)6/6 (100.0%)
Not Defined for DLBCL or FL Subgroups Cohort 30/1 (0.0%)0/1 (0.0%)0/1 (0.0%)

Serious adverse events by term

TermOrgan systemDose Escalation DLBCL and FL Safety CohortDose Escalation DLBCL and FL Cohort 1Dose Escalation DLBCL and FL Cohort 2Dose Escalation DLBCL and FL Cohort 3Not Defined for DLBCL or FL Subgroups Cohort 3
NEUTROPENIABlood and lymphatic system disorders1/90/61/71/60/1
THROMBOCYTOPENIABlood and lymphatic system disorders0/90/60/71/60/1
ABDOMINAL PAINGastrointestinal disorders0/91/60/70/60/1
UPPER GASTROINTESTINAL HAEMORRHAGEGastrointestinal disorders0/90/61/70/60/1
NON-CARDIAC CHEST PAINGeneral disorders0/90/61/70/60/1
PYREXIAGeneral disorders0/91/60/70/60/1
CHOLECYSTITISHepatobiliary disorders0/90/61/70/60/1
HYPERBILIRUBINAEMIAHepatobiliary disorders0/91/60/70/60/1
DEVICE RELATED INFECTIONInfections and infestations0/90/60/71/60/1
PNEUMONIAInfections and infestations0/90/60/71/60/1
UPPER RESPIRATORY TRACT INFECTIONInfections and infestations1/90/60/70/60/1
INFUSION RELATED REACTIONInjury, poisoning and procedural complications0/91/60/70/60/1
ALANINE AMINOTRANSFERASE INCREASEDInvestigations1/90/60/70/60/1
TRANSAMINASES INCREASEDInvestigations0/91/60/70/60/1
OSTEOARTHRITISMusculoskeletal and connective tissue disorders1/90/60/70/60/1
HEADACHENervous system disorders1/90/60/70/60/1
SYNCOPENervous system disorders0/90/60/71/60/1

Other adverse events by term

TermOrgan systemDose Escalation DLBCL and FL Safety CohortDose Escalation DLBCL and FL Cohort 1Dose Escalation DLBCL and FL Cohort 2Dose Escalation DLBCL and FL Cohort 3Not Defined for DLBCL or FL Subgroups Cohort 3
ANAEMIABlood and lymphatic system disorders4/91/64/73/60/1
LEUKOPENIABlood and lymphatic system disorders3/91/63/71/60/1
LYMPHOPENIABlood and lymphatic system disorders0/90/60/72/60/1
NEUTROPENIABlood and lymphatic system disorders7/95/67/75/60/1
THROMBOCYTOPENIABlood and lymphatic system disorders7/94/67/75/60/1
ATRIAL FIBRILLATIONCardiac disorders0/91/60/71/60/1
HYPERTHYROIDISMEndocrine disorders0/90/61/70/60/1
EYE DISORDEREye disorders1/90/60/70/60/1
EYE PAINEye disorders1/90/60/70/60/1
PHOTOPHOBIAEye disorders1/90/60/70/60/1
VISION BLURREDEye disorders1/91/60/70/60/1
ABDOMINAL DISCOMFORTGastrointestinal disorders0/91/61/70/60/1
ABDOMINAL PAINGastrointestinal disorders3/90/60/70/60/1
ANAL INCONTINENCEGastrointestinal disorders0/91/60/70/60/1
CONSTIPATIONGastrointestinal disorders2/91/60/72/60/1
DIARRHOEAGastrointestinal disorders5/93/64/74/60/1
DYSPEPSIAGastrointestinal disorders0/90/60/71/60/1
FLATULENCEGastrointestinal disorders1/90/60/70/60/1
GASTROOESOPHAGEAL REFLUX DISEASEGastrointestinal disorders3/90/60/70/60/1
MOUTH ULCERATIONGastrointestinal disorders0/90/61/70/60/1
NAUSEAGastrointestinal disorders6/94/63/73/60/1
ODYNOPHAGIAGastrointestinal disorders1/90/60/70/60/1
STOMATITISGastrointestinal disorders1/90/60/70/60/1
TONGUE HAEMATOMAGastrointestinal disorders0/90/61/70/60/1
VOMITINGGastrointestinal disorders3/93/61/72/60/1
CHEST PAINGeneral disorders0/93/60/70/60/1
CHILLSGeneral disorders1/90/60/71/60/1
FATIGUEGeneral disorders1/93/63/71/60/1
NON-CARDIAC CHEST PAINGeneral disorders1/90/60/70/60/1
OEDEMAGeneral disorders0/91/60/70/60/1
PAINGeneral disorders1/90/60/70/60/1
PYREXIAGeneral disorders0/91/60/70/60/1
UNEVALUABLE EVENTGeneral disorders0/90/60/71/60/1
CELLULITISInfections and infestations0/90/60/71/60/1
CLOSTRIDIUM DIFFICILE COLITISInfections and infestations0/91/60/70/60/1
GASTROENTERITISInfections and infestations0/90/61/70/60/1
GASTROENTERITIS NOROVIRUSInfections and infestations0/91/60/70/60/1
HERPES ZOSTERInfections and infestations0/90/61/71/60/1
INFECTIONInfections and infestations0/91/60/70/60/1
MUCOSAL INFECTIONInfections and infestations1/90/61/70/60/1
ORAL CANDIDIASISInfections and infestations0/90/61/70/60/1
RESPIRATORY TRACT INFECTIONInfections and infestations1/90/61/70/60/1
SINUSITISInfections and infestations1/90/60/70/60/1
UPPER RESPIRATORY TRACT INFECTIONInfections and infestations3/91/60/70/60/1
WOUND INFECTIONInfections and infestations0/91/60/70/60/1
ACCIDENTAL OVERDOSEInjury, poisoning and procedural complications0/91/60/71/60/1
CONTUSIONInjury, poisoning and procedural complications1/90/60/70/60/1
INFUSION RELATED REACTIONInjury, poisoning and procedural complications3/90/60/71/60/1
MEDICATION ERRORInjury, poisoning and procedural complications0/90/61/70/60/1
PRODUCT ADMINISTRATION ERRORInjury, poisoning and procedural complications0/90/61/70/60/1
PRODUCT DOSE OMISSIONInjury, poisoning and procedural complications0/90/60/71/60/1
SKIN ABRASIONInjury, poisoning and procedural complications0/90/60/71/60/1
WOUND COMPLICATIONInjury, poisoning and procedural complications0/91/60/70/60/1
WRONG TECHNIQUE IN PRODUCT USAGE PROCESSInjury, poisoning and procedural complications0/90/60/71/60/1
ALANINE AMINOTRANSFERASEInvestigations0/90/60/71/60/1
ALANINE AMINOTRANSFERASE INCREASEDInvestigations1/90/61/70/60/1
AMYLASE INCREASEDInvestigations0/90/60/71/60/1
ASPARTATE AMINOTRANSFERASE INCREASEDInvestigations2/90/61/71/60/1
BLOOD ALKALINE PHOSPHATASE INCREASEDInvestigations1/90/60/70/60/1
BLOOD BILIRUBIN INCREASEDInvestigations1/90/61/70/60/1

65 more terms not shown.

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.

+Locations (21)

FacilityCityCountryStatus
University of ColoradoAurora, ColoradoUnited States
The University of Chicago Medical CenterChicago, IllinoisUnited States
Norton Cancer Institute - DutchmansLouisville, KentuckyUnited States
Mount Sinai Medical CenterNew York, New YorkUnited States
Allegheny General HospitalPittsburgh, PennsylvaniaUnited States
Guthrie ClinicSayre, PennsylvaniaUnited States
Swedish Cancer Inst.Seattle, WashingtonUnited States
Prince of Wales HospitalRandwick, New South WalesAustralia
Westmead HospitalWestmead, New South WalesAustralia
Linear Clinical Research LimitedNedlands, Western AustraliaAustralia
Klinikum AugsburgAugsburgGermany
Universitätsklinikum "Carl Gustav Carus" der Technischen Universität DresdenDresdenGermany
SLK-Kliniken Heilbronn GmbHHeilbronnGermany
Klinikum rechts der Isar der TU MünchenMünchenGermany
Universitätsklinikum Würzburg; Studienzentrale Hämatologie/OnkologieWürzburgGermany
Christchurch HospitalChristchurchNew Zealand
Auckland Clinical Studies LimitedGraftonNew Zealand
Keimyung University Dongsan Medical CenterDaeguSouth Korea
Severance HospitalSeoulSouth Korea
Asan Medical CenterSeoulSouth Korea
Samsung Medical CenterSeoulSouth Korea

+Study documents

+Investigators

  • Clinical Trials, Study director, Hoffmann-La Roche

+Funding

NIH grants: 2016

My Notes