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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
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.
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).
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 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.
University of Colorado
Aurora, Colorado, United States
The University of Chicago Medical Center
Chicago, Illinois, United States
Norton Cancer Institute - Dutchmans
Louisville, Kentucky, United States
Mount Sinai Medical Center
New York, New York, United States
Allegheny General Hospital
Pittsburgh, Pennsylvania, United States
Guthrie Clinic
Sayre, Pennsylvania, United States
Swedish Cancer Inst.
Seattle, Washington, United States
Prince of Wales Hospital
Randwick, New South Wales, Australia
Westmead Hospital
Westmead, New South Wales, Australia
Linear Clinical Research Limited
Nedlands, Western Australia, Australia
...and 11 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: At end of Induction (EOI) (within 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 PET-CT Scans Using Modified Lugano 2014 Criteria
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.
Time frame: 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
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.
Time frame: 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
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.
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Time frame: 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
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.
Time frame: 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
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.
Time frame: 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 CT Scans Alone Using Modified Lugano 2014 Criteria
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.
Time frame: 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 at EOI, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
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.
Time frame: 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 During the Study, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
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.
Time frame: From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months
Observed Serum Concentration of Obinutuzumab in Participants With FL
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.
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)
Observed Serum Concentration of Obinutuzumab in Participants With DLBCL
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.
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)
Observed Serum Concentration of Rituximab in Participants With FL
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.
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)
Observed Serum Concentration of Rituximab in Participants With DLBCL
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.
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)
Observed Plasma Concentration of Idasanutlin in Participants With FL
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
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)
Observed Plasma Concentration of Idasanutlin in Participants With DLBCL
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
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)
Observed Plasma Concentration of Venetoclax in Participants With FL
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.
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)
Observed Plasma Concentration of Venetoclax in Participants With DLBCL
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.
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)