A Study to Compare the Efficacy and Safety of a Combined Regimen of Venetoclax and Obinutuzumab Versus Fludarabine, Cyclophosphamide, and Rituximab (FCR)/ Bendamustine And Rituximab (BR) in FIT Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without DEL (17P) or TP53 Mutation

NCT ID: NCT04285567

Last Updated: 2025-10-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 166 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-28
• Study Completion Date: 2025-03-19

Brief Summary

This study will evaluate the efficacy and safety of venetoclax and obinutuzumab (VEN + G) compared with fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (FCR/BR) in FIT participants (FIT is defined by a cumulative illness rating scale [CIRS]/score of ≤6 and a normal creatinine clearance of ≥70 mL/min) with previously untreated CLL without DEL(17P) or TP53 mutation requiring treatment. Eligible participants will be randomly assigned in a 1:1 ratio to receive either VEN + G (Arm A) or FCR/BR (Arm B).

Conditions

Chronic Lymphocytic Leukemia (CLL)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

VEN + G

Participants will receive 12 cycles of treatment (each cycle is 28 days). Venetoclax (VEN) will be administered orally, daily, with a 5-week ramp-up period, starting on Cycle 1, Day 22 and administration will continue until the end of Cycle 12. Obinutuzumab (G) will be administered intravenously (IV) on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Group Type: EXPERIMENTAL

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab 1000 milligrams (mg) will be administered IV on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Venetoclax

Intervention Type: DRUG

Venetoclax 20 mg will be administered orally, once daily starting on Day 22 of Cycle 1 for 7 days, then ramp up from 50 to 400 mg/day during Cycle 2 and continue at 400 mg/day from Day 1 of Cycle 3 till end of Cycle 12.

FCR/BR

Participants will receive 6 cycles of Fludarabine + Cyclophosphamide + Rituximab (FCR) consisting of a single cycle of a single infusion of rituximab on Day 1 and fludarabine and cyclophosphamide infusions on Days 1-3 of each 28-day cycle or bendamustine (B) as infusions on Days 1 and 2 and a single cycle of rituximab on Day 1 of each 28-day cycle.

Group Type: ACTIVE_COMPARATOR

Fludarabine

Intervention Type: DRUG

Fludarabine will be administered in a dosage of 25 milligram per meter squared (mg/m\^2), IV, on days 1, 2, and 3 of Cycles 1-6.

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide will be administered in a dosage of 250 mg/m\^2, IV, on Days 1, 2, and 3 Cycles 1-6.

Rituximab

Intervention Type: DRUG

Rituximab will be administered at a dose of 375 mg/m\^2, IV, on Cycle 1, Day 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6.

Bendamustine

Intervention Type: DRUG

Bendamustine will be administered at a dose of 90 mg/m\^2, IV, on 2 consecutive days of Cycles 1-6.

Interventions

Obinutuzumab

Obinutuzumab 1000 milligrams (mg) will be administered IV on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Intervention Type: DRUG

Venetoclax

Venetoclax 20 mg will be administered orally, once daily starting on Day 22 of Cycle 1 for 7 days, then ramp up from 50 to 400 mg/day during Cycle 2 and continue at 400 mg/day from Day 1 of Cycle 3 till end of Cycle 12.

Intervention Type: DRUG

Fludarabine

Fludarabine will be administered in a dosage of 25 milligram per meter squared (mg/m\^2), IV, on days 1, 2, and 3 of Cycles 1-6.

Intervention Type: DRUG

Cyclophosphamide

Cyclophosphamide will be administered in a dosage of 250 mg/m\^2, IV, on Days 1, 2, and 3 Cycles 1-6.

Intervention Type: DRUG

Rituximab

Rituximab will be administered at a dose of 375 mg/m\^2, IV, on Cycle 1, Day 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6.

Intervention Type: DRUG

Bendamustine

Bendamustine will be administered at a dose of 90 mg/m\^2, IV, on 2 consecutive days of Cycles 1-6.

Intervention Type: DRUG

Other Intervention Names

Gazyva; RO5072759; GA101; Venclexta; RO5537382; GDC-0199; MabThera; Rituxan; Treanda; Levact; Ribomustin

Eligibility Criteria

Inclusion Criteria

• Ability to comply with the study protocol, in the investigator's judgment
• Aged 18 years or older
• Have previously untreated documented Chronic Lymphocytic Leukemia (CLL) according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
• CLL requiring treatment according to the iwCLL criteria
• Cumulative Illness Rating Scale (CIRS) score ≤ 6 and creatinine clearance (CrCl) ≥ 70 mL/min
• Hematology values within the following limits, unless cytopenia is caused by the underlying disease (i.e., no evidence of additional bone marrow (BM) dysfunction; e.g., myelodysplastic syndrome, hypoplastic BM):

• Absolute neutrophil count ≥ 1.0 x 109/L, unless there is BM involvement
• Platelet count ≥ 75 x 109/L and more than 7 days since last transfusion, or ≥ 30 x 109/L if there is BM involvement
• Adequate liver function as indicated by a total bilirubin, aspartate aminotransferase, and Alanine transaminase ≤ 2 times the institutional upper limit of normal (ULN) value, unless directly attributable to the participant's CLL
• Life expectancy >6 months
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm

Exclusion Criteria

• Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL)
• Participants with Small Lymphocyclic Lymphoma (SLL) only
• Known central nervous system involvement
• Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)
• Detected del(17p) or TP53 mutation (valid test within 6-months from screening is required for randomisation)
• An individual organ/system impairment score of 4 as assessed by the Cumulative Illness Rating Scale (CIRS) definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
• Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
• History of prior malignancy
• Participants with infections requiring IV treatment (Grade 3 or 4) within the last 8 weeks prior to enrollment
• Evidence of other clinically significant uncontrolled conditions including but not limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or fungal)
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Hypersensitivity to fludarabine, bendamustine, cyclophosphamide, rituximab, obinutuzumab, or venetoclax or to any of the excipients (e.g., trehalose)
• Pregnant women and nursing mothers
• Vaccination with a live vaccine ≤ 28 days prior to randomization
• Prisoners or participants who are institutionalized by regulatory or court order or persons who are in dependence to the Sponsor or an investigator
• History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
• Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology)
• Positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
• Participants with known infection with HIV or Human T-Cell Leukemia Virus 1 (HTLV-1)
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study
• Received any of the following agents within 28 days prior to the first dose of study treatment:

• Immunotherapy
• Radiotherapy
• Hormone therapy
• Any therapies intended for the treatment of lymphoma/leukemia whether approved or experimental
• Participants who have received the following agents:

• Strong and moderate CYP3A inhibitors/inducers within 7 days prior to the initiation of study treatment
• Steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids within 7 days prior to the first dose of study drug administration
• Consumed grapefruit, grapefruit products, Seville oranges(including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration
• Inability to swallow a large number of tablets.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical trial

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Medical Center of Aurora

Aurora, Colorado, United States

American Oncology Partners of Maryland, PA

Bethesda, Maryland, United States

University of Tennessee Medical Center;Office of Clinical Trials

Knoxville, Tennessee, United States

Oncology & Hematology Associates of Southwest Virginia, Inc._Goldschmidt

Roanoke, Virginia, United States

Canberra Hospital

Canberra, Australian Capital Territory, Australia

Liverpool Hospital

Liverpool, New South Wales, Australia

Port Macquarie - Mid North Coast Cancer Institute

Port Macquarie, New South Wales, Australia

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Royal Hobart Hospital

Hobart, Tasmania, Australia

Monash Health;Haematology Research

Clayton, Victoria, Australia

Peter MacCallum Cancer Centre;Clinical Haematology

Melbourne, Victoria, Australia

Northern Hospital;Oncology and/or Hematology

Melbourne, Victoria, Australia

Hopital Haut Leveque Chu de Bordeaux

Pessac, Aquitaine, France

Centre Hospitalier Régional Universitaire de Tours - Hôpital Bretonneau;Hématologie et Thérapie Cellulaire

Tours, Indre-et-Loire, France

Centre Hospitalier de Pérpignan;hématologie

Perpignan, Languedoc-Roussillon, France

Hopital Claude Huriez - CHU de Lille;service maladies appareil digestif

Lille, Nord, France

Centre Hospitalier intercommunal de Toulon La Seyne sur Mer

Toulon, Provence-Alpes-Côte d'Azur Region, France

centre hospitalier lyon sud;Service Hématologie

Pierre-Bénite, Rhône, France

HENRI MONDOR HOSPITAL;Centre d'investigation clinique

Créteil, Val-de-Marne, France

Centre Hospitalier Universitaire de Caen Normandie

Caen, , France

Clinique Victor Hugo- CCS du Mans

Le Mans, , France

Centre Hospitalier Universitaire de Poitiers

Poitiers, , France

Centre Hospitalier Universitaire de Reims - Hôpital Robert Debré;Hématologie Clinique

Reims, , France

Instituto Tumori Giovanni Paolo II;ONCOLOGIA MEDICA

Bari, Apulia, Italy

Ospedale Vito Fazzi;U.O. Ematologia IV Piano Polo Oncologico

Lecce, Apulia, Italy

Azienda Ospedaliero Universitaria;Ematologia

Modena, Emilia-Romagna, Italy

Policlinico Umberto I

Rome, Lazio, Italy

Fondazione Policlinico Universitario Agostino Gemelli

Rome, Lazio, Italy

Ospedale San Martino;U.O. Clinica Ematologica

Genoa, Liguria, Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico;U.O.C Ematologia

Milan, Lombardy, Italy

ASST Grande Ospedale Metropolitano Niguarda;Ematologia

Milan, Lombardy, Italy

Azienda Ospedaliero Universitaria Maggiore della Carità;SCDU Ematologia

Novara, Piedmont, Italy

AO Santa Maria della Misericordia

Perugia, Umbria, Italy

Hospital Germans Trias i Pujol

Badalona, Barcelona, Spain

COMPLEJO HOSPITALARIO DE NAVARRA;Servicio de Hematología

Pamplona, Navarre, Spain

Hospital Universitari Vall d'Hebron;Hematology

Barcelona, , Spain

Hospital Universitario La Paz;Hematología

Madrid, , Spain

Hospital General Universitario Morales Meseguer;Hematologia y Oncologia médica

Murcia, , Spain

Hospital Universitario Virgen del Rocío;Unidad Onco-Hematología Pediátrica

Seville, , Spain

Hospital Universitario de Toledo

Toledo, , Spain

Countries

United States; Australia; France; Italy; Spain

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2019-003327-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2023-504036-17-00

Identifier Type: OTHER

Identifier Source: secondary_id

CO41685

Identifier Type: -

Identifier Source: org_study_id