Clinical trial NCT03135262: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Follicular Lymphoma
Lymphoma, Large B-Cell, Diffuse
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-05-01
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: RP2D of Idasanutlin When Given in Combination With Obinutuzumab or Rituximab
timeFrame: Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)
measure: RP2D of Venetoclax When Given in Combination With Obinutuzumab or Rituximab
timeFrame: Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 Day 1 up to Cycle 2 Day 28 (each cycle = 28 days)
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: From Baseline up to approximately 48 months
measure: 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
timeFrame: 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:
measure: Percentage of Participants With CR, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
measure: Percentage of Participants With CR, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
measure: Percentage of Participants With CR, Determined by the Investigator on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
measure: Percentage of Participants With Objective Response, Determined by the IRC on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
measure: Percentage of Participants With Objective Response, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
measure: Percentage of Participants With Objective Response, Determined by the IRC on the Basis of CT Scans Alone Using Modified Lugano 2014 Criteria
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
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
timeFrame: At EOI (6 to 8 weeks after Cycle 6 Day 1 [up to approximately 28 weeks] [each cycle = 28 days]
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
timeFrame: From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months
measure: Observed Serum Concentration of Obinutuzumab in Participants With FL
timeFrame: From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)
measure: Observed Serum Concentration of Obinutuzumab in Participants With DLBCL
timeFrame: 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)
measure: Observed Serum Concentration of Rituximab in Participants With FL
timeFrame: 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)
measure: Observed Serum Concentration of Rituximab in Participants With DLBCL
timeFrame: From Day 1 of Cycle 1 (cycle length = 28 days) up to approximately 48 months (detailed timeframe is mentioned in outcome measure description)
measure: Observed Plasma Concentration of Idasanutlin in Participants With FL
timeFrame: 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)
measure: Observed Plasma Concentration of Idasanutlin in Participants With DLBCL
timeFrame: 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)
measure: Observed Plasma Concentration of Venetoclax in Participants With FL
timeFrame: 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)
measure: Observed Plasma Concentration of Venetoclax in Participants With DLBCL
timeFrame: 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)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute - Dutchmans
state: Kentucky
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Clinic
state: Pennsylvania
city: Seattle
country: United States
facility: Swedish Cancer Inst.
state: Washington
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Nedlands
country: Australia
facility: Linear Clinical Research Limited
state: Western Australia
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg; Studienzentrale Hämatologie/Onkologie
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies Limited
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: