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 (CRISTALLO)

A Prospective, Open-Label, Multicenter Randomized Phase III 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

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).

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia (CLL)
• Intervention / Treatment: Drug: Venetoclax; Drug: Obinutuzumab; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Bendamustine

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Canberra Hospital
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Port Macquarie, New South Wales, Australia, 2444
      • Port Macquarie - Mid North Coast Cancer Institute
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health;Haematology Research
    • Melbourne, Victoria, Australia, 3050
      • Peter MacCallum Cancer Centre;Clinical Haematology
    • Melbourne, Victoria, Australia, 3076
      • Northern Hospital;Oncology and/or Hematology
• France
  • Caen, France, 14000
    • Centre Hospitalier Universitaire de Caen Normandie
  • Le Mans, France, 72000
    • Clinique Victor Hugo- CCS du Mans
  • Poitiers, France, 86021
    • Centre Hospitalier Universitaire de Poitiers
  • Reims, France, 51092
    • Centre Hospitalier Universitaire de Reims - Hôpital Robert Debré;Hématologie Clinique
  • Aquitaine
    • Pessac, Aquitaine, France, 33600
      • Hopital Haut Leveque Chu de Bordeaux
  • Indre-et-Loire
    • Tours, Indre-et-Loire, France, 37032
      • Centre Hospitalier Régional Universitaire de Tours - Hôpital Bretonneau;Hématologie et Thérapie Cellulaire
  • Languedoc-Roussillon
    • Perpignan, Languedoc-Roussillon, France, 66046
      • Centre Hospitalier de Pérpignan;hématologie
  • Nord
    • Lille, Nord, France, 59037
      • Hopital Claude Huriez - CHU de Lille;service maladies appareil digestif
  • Provence-Alpes-Côte d'Azur Region
    • Toulon, Provence-Alpes-Côte d'Azur Region, France, 83100
      • Centre Hospitalier intercommunal de Toulon La Seyne sur Mer
  • Rhône
    • Pierre-Bénite, Rhône, France, 69310
      • centre hospitalier lyon sud;Service Hématologie
  • Val-de-Marne
    • Créteil, Val-de-Marne, France, 94000
      • HENRI MONDOR HOSPITAL;Centre d'investigation clinique
• Italy
  • Apulia
    • Bari, Apulia, Italy, 70124
      • Instituto Tumori Giovanni Paolo II;ONCOLOGIA MEDICA
    • Lecce, Apulia, Italy, 73100
      • Ospedale Vito Fazzi;U.O. Ematologia IV Piano Polo Oncologico
  • Emilia-Romagna
    • Modena, Emilia-Romagna, Italy, 41125
      • Azienda Ospedaliero Universitaria;Ematologia
  • Lazio
    • Rome, Lazio, Italy, 168
      • Fondazione Policlinico Universitario Agostino Gemelli
    • Rome, Lazio, Italy, 161
      • Policlinico Umberto I
  • Liguria
    • Genoa, Liguria, Italy, 16132
      • Ospedale San Martino;U.O. Clinica Ematologica
  • Lombardy
    • Milan, Lombardy, Italy, 20122
      • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico;U.O.C Ematologia
    • Milan, Lombardy, Italy, 20162
      • ASST Grande Ospedale Metropolitano Niguarda;Ematologia
  • Piedmont
    • Novara, Piedmont, Italy, 28100
      • Azienda Ospedaliero Universitaria Maggiore della Carità;SCDU Ematologia
  • Umbria
    • Perugia, Umbria, Italy, 6132
      • AO Santa Maria della Misericordia
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron;Hematology
  • Madrid, Spain, 28015
    • Hospital Universitario La Paz;Hematología
  • Murcia, Spain, 30008
    • Hospital General Universitario Morales Meseguer;Hematologia y Oncologia médica
  • Seville, Spain, 41009
    • Hospital Universitario Virgen del Rocío;Unidad Onco-Hematología Pediátrica
  • Toledo, Spain, 45007
    • Hospital Universitario de Toledo
  • Barcelona
    • Badalona, Barcelona, Spain, 8916
      • Hospital Germans Trias i Pujol
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • COMPLEJO HOSPITALARIO DE NAVARRA;Servicio de Hematología
• United States
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Medical Center of Aurora
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center;Office of Clinical Trials
  • Virginia
    • Roanoke, Virginia, United States, 24014
      • Oncology & Hematology Associates of Southwest Virginia, Inc._Goldschmidt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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.; Other Names: Venclexta; GDC-0199; RO5537382; Drug: 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.; Other Names: Gazyva; RO5072759; GA101
Active Comparator: 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.	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.; Drug: Cyclophosphamide; Cyclophosphamide will be administered in a dosage of 250 mg/m^2, IV, on Days 1, 2, and 3 Cycles 1-6.; 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.; Other Names: Rituxan; MabThera; Drug: Bendamustine; Bendamustine will be administered at a dose of 90 mg/m^2, IV, on 2 consecutive days of Cycles 1-6.; Other Names: Treanda; Levact; Ribomustin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS)	MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point.	At Month 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit	MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point.	VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit	MRD response rate=percentage of participants with MRD-negativity measured in BM using NGS (cutoff of <10^-4). MRD negativity=<1 CLL cell in 10,000 leukocytes. MRD in BM was assessed for participants with complete response (CR)/CR with incomplete blood count recovery (CRi) & partial response (PR). CR=PB lymphocytes <4x10^9 /L; Absence of significant lymphadenopathy (nodes <1.5 cm in longest diameter); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi=fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR= ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy (sum of longest diameter of up to 6 largest lymph nodes by physical exam & 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.	VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
Objective Response Rate (ORR)	ORR was defined as the percentage of participants with overall response (OR) of CR, CRi, and PR as determined by the investigator according to the iwCLL guidelines. CR was defined as PB lymphocytes <4x10^9 /L; absence of significant lymphadenopathy (nodes <1.5 cm in longest diameter [LD]); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR was defined as ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy sum of longest diameter of up to 6 largest lymph nodes by physical exam and 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.	At Month 15
CR Rate	CR rate was defined as the percentage of participants with CR or CRi. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes (evaluated by blood and differential count) below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.	At Month 15
MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit	MRD response rate was determined as the percentage of participants (with a CR/CRi) with MRD-negativity measured in the PB using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.	At Month 15
MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit	MRD response rate was determined as the percentage of participants (with CR/CRi) with MRD-negativity measured in the BM using NGS using a cutoff of < 10^-4. MRD was considered negative if the result was < 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10^9 /L; absence of significant lymphadenopathy (nodes < 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria with CR but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.	VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
Best Overall Response (BOR)	BOR=percentage of participants with CR/CRi/PR/stable disease (SD)/PD per the investigator. Participants with best response as CR/CRi/PR were considered responders while those reaching SD/PD were non-responders. SD=participants who have not achieved a CR or a PR, or who have not exhibited PD. PD=any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. CR, CRi and PR were defined as outlined in the description for ORR, OM number 5.	At Month 15
VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate	TLS risk reduction rate in the VEN + G arm was defined as the reduction in the percentage of participants who were TLS high-risk after 3 doses of obinutuzumab compared to the percentage of participants who were TLS high-risk at baseline. Risk for developing TLS were categorised into: Low - All measurable lymph nodes with the LD < 5 cm and < 25x10^9/L absolute lymphocyte count (ALC); Medium - Any measurable lymph node with the LD ≥5 cm but <10 cm OR ≥25x10^9/L ALC; High - Any measurable lymph node with the LD ≥10 cm or the presence of both ≥25x10^9/L ALC and any measurable lymph node with the LD ≥5 cm but <10 cm. Percentages have been rounded off to the nearest decimal point.	Baseline up to Cycle 1 Day 22 (1 cycle=28 days)
VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up	Reduction in mandatory hospitalizations during venetoclax ramp-up in the VEN + G arm participants was defined as the actual number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab compared to the number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up expected at baseline. Ramp-up period for venetoclax was defined as period from Cycle 1, Days 22-28, and Cycle 2, Day 1-Day 7 where the 20 mg and 50 mg daily doses of venetoclax, were administered for participants at TLS-high risk requiring mandated hospitalizations (the hospitalizations at 100, 200 and 400 was only needed if the participant had a TLS event at one of the lower doses). Total number of hospitalizations in high-risk TLS participants at baseline (expected to be N=2 hospitalization) was compared with the number of protocol mandated hospitalizations during the first 2 doses of the ramp-up.	Cycle 1 Days 22-28 up to Cycle 2 Days 1-7 (1 cycle=28 days)
Progression-free Survival (PFS)	PFS was defined as the time from randomization to the first occurrence of disease progression (PD), or death from any cause. PD was assessed by the investigators using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. PD was defined as any one of the following: Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 centimeters [cm]); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/litres (L) B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; post treatment: progression of any cytopenia, documented by a decrease of hemoglobin (Hb) ≥ 2 grams per deciliter (g/dL) or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. Kaplan-Meier (K-M) method was used to determine PFS.	Up to approximately 56.4 months
Duration of Objective Response (DOR)	DOR=time from first occurrence of a documented objective response (CR, CRi & PR) to the time of PD as determined by the investigator, or death from any cause, whichever occurred first. CR, CRi, PR, & PD were defined per the iwCLL guidelines. PD = any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. CR, CRi & PR were defined as outlined in the description for ORR outcome measure. K-M method was used to determine DOR.	Up to approximately 56.4 months
Event-free Survival (EFS)	EFS was defined as the time between the date of randomization and the date of PD/relapse, death, or the start of a new anti-leukemic therapy. PD was defined as any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10^9/L, which occurs at least 3 months after treatment. K-M method was used to determine EFS.	Up to approximately 56.4 months
Overall Survival (OS)	OS was defined as the time between the date of randomization and the date of death due to any cause. K-M method was used to determine OS.	Up to approximately 56.4 months
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that meets any of the following criteria: is fatal; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; is a significant medical event in the investigator's judgment.	Up to approximately 56.4 months
Number of Participants With Premature Withdrawals Due to AEs	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants who withdrew from the study due to AEs are being reported here.	Up to approximately 56.4 months
Change From Baseline in Physical Functioning Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30)	The EORTC QLQ-C30 consists of 30 questions incorporated into 5 functional scales (physical, role, cognitive, emotional and social scales), 3 symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global quality-of-life (GHS/QoL) scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range from 0-100. Higher scores=higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. Time frame continued: Day 28 After Completion/Early Termination (ET) of Combination Therapy (VEN+G)/Day 28 After Treatment Completion (TC)/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; Follow-up (FU) at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)
Change From Baseline in Role Functioning Assessed Using EORTC QLQC-30	The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint. Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)
Change From Baseline in GHS/QoL Assessed Using EORTC QLQC-30	The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The 2 GHS/QoL items were scored on a 7-point scale (1= Very poor to 7=Excellent). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. better QoL). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint. Time frame continued (TFC): Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately (approx) 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)
Change From Baseline in Mean Core Symptom Severity Score as Measured by the M.D. Anderson Symptom Inventory (MDASI-CLL)	MDASI-CLL=25 items over 3 scales assessing core cancer & CLL-related symptom severity &symptom interference that a participant may have experienced in past 24 hours. Participants rated severity of 13 symptoms called mean core symptom severity (pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting & numbness/tingling) to assess mean core symptom severity score. Each symptom is scored from 0 (not present)-10 (as bad as you can imagine). Total score across all questions(0-130) was divided by number of questions. Mean score, ranged from 0-10. Lower scores=lower symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. TFC: Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)
Change From Baseline in Mean Module Symptom Severity Score as Measured by MDASI-CLL	MDASI-CLL=25 items over 3 scales that assess core cancer & CLL-related symptom severity, as well as symptom interference a participant may have experienced in past 24 hours. Participants were asked to rate the severity of 6 disease-specific symptoms called mean module symptom severity (night sweats, fever & chills, lymph node swelling, diarrhea, easy bruising/bleeding & constipation). Each symptom is scored on scale from 0-10, where 0=not present & 10=as bad as you can imagine. The total score across all questions (0 to 60) was divided by the number of questions. The mean score, therefore, ranged from 0-10. Higher scores indicated more symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. Time frame continued: Day 28 After Completion/ET of VEN+G/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)
Change From Baseline in Mean Interference Score as Measured by MDASI-CLL	MDASI-CLL consists of 25 items over 3 scales that assess core cancer & CLL-related symptom severity, and symptom interference that a participant may have experienced in past 24 hours. Participants rated 6 mean interference on life questions (general activity, walking, work, mood, relations with other people & enjoyment of life) to derive the Mean Interference Score. These were scored on a scale from 0 (symptom did not interfere)-10 (symptom interfered completely). Total score across all questions (0 to 60) was divided by number of questions. Mean score, therefore, ranged from 0-10. Higher scores=higher symptom interference. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed=participants with data available for analysis at a given timepoint. Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx 11 months.	Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trial, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2020
• Primary Completion (Actual): March 19, 2024
• Study Completion (Actual): March 19, 2025

Study Registration Dates

• First Submitted: February 25, 2020
• First Submitted That Met QC Criteria: February 25, 2020
• First Posted (Actual): February 26, 2020

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Butyrates; Antibodies, Monoclonal, Murine-Derived; Bendamustine Hydrochloride; Rituximab; Cyclophosphamide; fludarabine; venetoclax; obinutuzumab
• Other Study ID Numbers: CO41685; 2019-003327-37 (EudraCT Number); 2023-504036-17-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical-trials/data-sharing).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No