Phase 3
N=166
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
Chronic Lymphocytic Leukemia (CLL)
Bottom Line
View on ClinicalTrials.gov: NCT04285567 ↗Enrolled (actual)
166
Serious AEs
54.3%
Results posted
Apr 2025
Primary outcome: Primary: Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS) — 81.3; 54.7 percentage of participants — p=0.0004
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Obinutuzumab (Drug); Venetoclax (Drug); Fludarabine (Drug); Cyclophosphamide (Drug); Rituximab (Drug); Bendamustine (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Hoffmann-La Roche
- Primary completion
- Mar 2024
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS) |
81.3; 54.7 | 0.0004 sig |
| SECONDARY Progression-free Survival (PFS) |
NA; 53.3 | 0.3999 |
| SECONDARY MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit |
81.3; 60.5 | 0.0053 sig |
| SECONDARY MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit |
70.0; 38.4 | < .0001 sig |
| SECONDARY Objective Response Rate (ORR) |
88.8; 79.1 | 0.1119 |
| SECONDARY CR Rate |
50.0; 32.6 | 0.0154 sig |
| SECONDARY MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit |
97.5; 78.6 | 0.0054 sig |
| SECONDARY MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit |
87.5; 60.7 | 0.0038 sig |
| SECONDARY Duration of Objective Response (DOR) |
NA; 50.3 | 0.4100 |
| SECONDARY Best Overall Response (BOR) |
93.8; 90.7 | 0.4199 |
| SECONDARY Event-free Survival (EFS) |
NA; 53.3 | 0.2078 |
| SECONDARY Overall Survival (OS) |
NA; NA | 0.9468 |
| SECONDARY VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate |
23.8; 0 | — |
| SECONDARY VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up |
2 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |
76; 83; 46; 42 | — |
| SECONDARY Number of Participants With Premature Withdrawals Due to AEs |
1; 5 | — |
| SECONDARY 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) |
88.77; 88.33; -6.67; -0.92; 0.30; 8.89 | — |
| SECONDARY Change From Baseline in Role Functioning Assessed Using EORTC QLQC-30 |
85.67; 83.06; -33.33; -3.59; 3.79; 22.22 | — |
| SECONDARY Change From Baseline in GHS/QoL Assessed Using EORTC QLQC-30 |
73.10; 72.64; -25.00; 2.78; 1.85; 11.11 | — |
| SECONDARY Change From Baseline in Mean Core Symptom Severity Score as Measured by the M.D. Anderson Symptom Inventory (MDASI-CLL) |
1.75; 1.66; 0.46; -0.43; -0.20; 0.38 | — |
| SECONDARY Change From Baseline in Mean Module Symptom Severity Score as Measured by MDASI-CLL |
1.63; 1.43; -0.83; -0.67; -0.63; -0.58 | — |
| SECONDARY Change From Baseline in Mean Interference Score as Measured by MDASI-CLL |
2.11; 2.17; 1.33; -0.23; -0.29; 0.17 | — |
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).
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/indu
Data sourced from ClinicalTrials.gov (NCT04285567). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.