Clinical trial NCT02187861: A Study Evaluating the Safety and Efficacy of Venetoclax (GDC-0199) Plus Bendamustine + Rituximab (BR) in Comparison With BR or Venetoclax Plus Rituximab in Participants With Relapsed and Refractory Follicular Non-Hodgkin's Lymphoma (fNHL)
Official title: A Phase II, Open-Label Study Evaluating the Safety and Efficacy of GDC-0199 (ABT-199) Plus Bendamustine Plus Rituximab (BR) in Comparison With BR Alone or GDC-0199 Plus Rituximab (R) in Patients With Relapsed and Refractory Follicular Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Follicular Lymphoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
First posted: 2014-07-11
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This open-label, international, multicenter study will investigate the safety and efficacy of venetoclax (GDC-0199) in combination with bendamustine plus rituximab (venetoclax + BR) compared with BR alone in participants with relapsed and refractory fNHL, comparing two chemotherapy-containing regimens (Chemotherapy-Containing Cohort). In addition, an exploratory analysis of the safety and efficacy of venetoclax in combination with rituximab (venetoclax + rituximab), a chemotherapy-free regimen, will be performed (Chemotherapy-Free Cohort). Assignment to the Chemotherapy-Containing or Chemotherapy-Free Cohort will be decided at the discretion of the Investigator, unless one of the cohorts is not open to enrollment; in which case, participants may be enrolled only to the open cohort. The first 6 participants enrolled in the Chemotherapy-Containing Cohort (or more if required) will comprise the Safety Run-In group for Treatment Arm B, dosing venetoclax at 600 milligrams (mg) in combination with BR. Once a dose has been chosen from the Safety Run-In Period, randomization to the two treatment arms of the Chemotherapy-Containing Cohort (Arms B and C) will begin.


Eligibility criteria: Inclusion Criteria:

* Participants must have histologically confirmed follicular lymphoma (FL) of Grade 1, 2, or 3a
* Participants must have received at least one prior therapy for FL
* For participants potentially receiving chemotherapy: if the participant has received prior bendamustine, response duration must have been greater than (\>) 1 year
* At least one bi-dimensionally measurable lesion on imaging scan defined as \>1.5 centimeters (cm) in its longest dimension
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
* Adequate hematologic function
* For female participants of childbearing potential and male participants with female partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception throughout the course of study treatment and for at least 30 days after the last dose of venetoclax and 12 months after the last dose of rituximab, whichever is longer
* Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined specifications prior to study enrollment

Exclusion Criteria:

* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
* Contraindication to potential treatment agents
* Ongoing corticosteroid use \>30 milligrams per day (mg/day) of prednisone or equivalent. Participants receiving corticosteroid treatment with less than equal to (\</=) 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to randomization (Cycle 1 Day 1)
* Primary central nervous system (CNS) lymphoma
* Vaccination with live vaccines within 28 days prior to treatment
* Chemotherapy or other investigational therapy within five half-lives of a biologic agent with a minimum of 28 days prior to the start of Cycle 1
* History of other malignancy that could affect compliance with the protocol or interpretation of results
* Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the participant
* Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1
* Requires the use of warfarin
* Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
* Presence of positive test results for hepatitis B surface antigen or hepatitis C virus (HCV) antibody
* Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
* Participants with occult or prior hepatitis B virus (HBV) infection may be included if HBV deoxyribonucleic acid (DNA) is undetectable at screening. These participants must be willing to undergo monthly HBV DNA test until at least 12 months after the last treatment cycle
* Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1)
* Pregnant or lactating
* Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1), other than for diagnosis

Primary outcomes:
measure: Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA)
timeFrame: 6-8 weeks after Cycle 6 Day 1 (PRA) (Cycle length = 28 days)
Secondary outcomes:
measure: Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA
timeFrame: 4-10 weeks after Cycle 6 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1
timeFrame: 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1
timeFrame: 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan
timeFrame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan
timeFrame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan
timeFrame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan
timeFrame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan
timeFrame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan
timeFrame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
measure: Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan
timeFrame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
measure: Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan
timeFrame: From CMR or PMR until disease progression or death due to any cause (assessed up to approximately 2.5 years)
measure: Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death
timeFrame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
measure: Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan
timeFrame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
measure: Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy
timeFrame: Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years)
measure: Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan
timeFrame: Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years)
measure: Percentage of Participants Who Died Due to Any Cause
timeFrame: Baseline until death due to any cause (assessed up to approximately 2.5 years
measure: Overall Survival (OS)
timeFrame: Baseline until death due to any cause (assessed up to approximately 2.5 years)
measure: Apparent Clearance (CL) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
measure: Apparent Volume of Distribution (Vd) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
measure: Time to Maximum Plasma Concentration (Tmax) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
measure: Maximum Plasma Concentration (Cmax) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax
timeFrame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center, PC
state: Alabama
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: UCLA School of Medicine; Hematology/Oncology
state: California
city: Austell
country: United States
facility: Nothwest Georgia Oncology Centers P.C
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago College of Medicine
state: Illinois
city: Harvey
country: United States
facility: Primary Healthcare Associates SC - Harvey
state: Illinois
city: Westwood
country: United States
facility: University of Kansas; Medical Center & Medical pavilion
state: Kansas
city: Baltimore
country: United States
facility: Sidney Kimmel Comp Cancer Ctr
state: Maryland
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania; School of Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: VCU Massey Cancer Center
state: Virginia
city: Morgantown
country: United States
facility: West Virginia Uni Med. Center - Robert Byrd Health Science
state: West Virginia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital; Medical Oncology
state: New South Wales
city: Kogarah, New South Wales
country: Australia
facility: St George Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital; Haematology
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Douglas
country: Australia
facility: Townsville General Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Woodville South
country: Australia
facility: Queen Elizabeth Hospital; Haematology
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Brugge
country: Belgium
facility: AZ Sint Jan
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Kelowna
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Toronto
country: Canada
facility: University Health Network; Princess Margaret Hospital; Medical Oncology Dept
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve- Rosemont; Oncology
state: Quebec
city: Montreal
country: Canada
facility: Chum Hopital Notre Dame; Centre D'Oncologie
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre; Uni of Saskatoon Campus
state: Saskatchewan
city: Angers
country: France
facility: Institut de Cancerologie de l'Ouest
city: Clermont Ferrand cedex 1
country: France
facility: CHU Clermont Ferrand - Hôpital d'Estaing
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon - Hopital le Bocage
city: Le Mans
country: France
facility: Centre Jean Bernard
city: Montpellier
country: France
facility: CHU Montpellier
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud; Hematolgie
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH; Klinik f. Innere Medizin III
city: Dessau-Roßlau
country: Germany
facility: Städtisches Klinikum Dessau
city: Dresden
country: Germany
facility: BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie
city: Essen
country: Germany
facility: Universitätsklinik Essen; Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena; Klinik für Innere Medizin II
city: Koeln
country: Germany
facility: Universitätsklinikum Köln; Klinik I für Innere Medizin
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein / Campus Lübeck, Med. Klinik I, Hämatologie/Onkologie
city: Mainz
country: Germany
facility: Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm; Apotheke
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg; Medizinische Klinik und Poliklinik II; Hämatologie / Onkologie
city: Bologna
country: Italy
facility: A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna
state: Emilia-Romagna
city: Meldola
country: Italy
facility: IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
state: Emilia-Romagna
city: Ravenna
country: Italy
facility: Ospedale di Ravenna
state: Emilia-Romagna
city: Rimini
country: Italy
facility: Ospedale Infermi di Rimini
state: Emilia-Romagna
city: Bergamo
country: Italy
facility: Asst Papa Giovanni XXIII
state: Lombardia
city: Milano
country: Italy
facility: Ospedale Niguarda Milano
state: Lombardia
city: Pavia
country: Italy
facility: Irccs Policlinico San Matteo; Divisione Di Ematologia
state: Lombardia
city: Torino
country: Italy
facility: Azienda Ospedale San Giovanni
state: Piemonte
city: Firenze
country: Italy
facility: Az. Osp. Di Careggi; Divisione Di Ematologia
state: Toscana
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary; Dept. of Medical Oncology
city: London
country: United Kingdom
facility: University College London, Department of Haematology
city: London
country: United Kingdom
facility: Royal Marsden Nhs Trust; Consultant Cancer Physician
city: Manchester
country: United Kingdom
facility: Christie Hospital; Breast Cancer Research Office
city: Oxford
country: United Kingdom
facility: Churchill Hospital; Oxford Cancer and Haematology Centre
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Zinzani PL, Flinn IW, Yuen SLS, Topp MS, Rusconi C, Fleury I, Le Du K, Arthur C, Pro B, Gritti G, Crump M, Petrich A, Samineni D, Sinha A, Punnoose EA, Szafer-Glusman E, Spielewoy N, Mobasher M, Humphrey K, Kornacker M, Hiddemann W. Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma. Blood. 2020 Dec 3;136(23):2628-2637. doi: 10.1182/blood.2020005588.