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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Venetoclax
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Rituximab
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VEN + G<br>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: Obinutuzumab<br>* 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.<br>* Other names: GA101;Drug: Venetoclax<br>* 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.<br>* Other names: GDC-0199;|
| Active Comparator: FCR/BR<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<br>* 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.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered in a dosage of 250 mg/m^2, IV, on Days 1, 2, and 3 Cycles 1-6.<br>Drug: Rituximab<br>* 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.<br>* Other names: Rituxan;Drug: Bendamustine<br>* Bendamustine will be administered at a dose of 90 mg/m^2, IV, on 2 consecutive days of Cycles 1-6.<br>* Other names: Ribomustin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) Response Rate Using Next-generation Sequencing (NGS) |  | At Month 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) |  | From randomization up to the first occurrence of disease progression (PD), or death from any cause (up to 74 months) | 
| MRD Response Rate in Peripheral Blood (PB) at the End of Treatment Response Visit |  | At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR | 
| MRD Response Rate in Bone Marrow (BM) at the End of Treatment Response Visit |  | At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR | 
| Objective Response Rate (ORR) |  | At Month 15 | 
| Complete Response (CR) Rate |  | At Month 15 | 
| MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15 |  | At Month 15 | 
| MRD Response Rate in the BM of Participants With a CR/CRi at the End of Treatment Visit |  | At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR | 
| Duration of Objective Response (DOR) |  | From time of first response until PD, or death from any cause (up to 74 months) | 
| Best Overall Response |  | Up to and including the assessment at Month 15 | 
| Event-free Survival (EFS) |  | From randomization up to PD /relapse, death, or start of a new anti-leukemic therapy (up to 74 months) | 
| Overall Survival (OS) |  | From randomization up to death due to any cause (up to 74 months) | 
| Arm VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate |  | At screening and Cycle 1 Day 22 (cycle length= 28 days) | 
| Arm VEN + G: Reduction in Mandatory Hospitalisations During Venetoclax Ramp-up |  | On Cycle 1 Day 22 (cycle length= 28 days) | 
| Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score | The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is not present or did not interfere with the participant's activities and 10 indicating as bad as you can imagine or interfered completely. | Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 74 months) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) | The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from not at all to very much, and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from very poor to excellent. Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity). | Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 74 months) | 
| Number of Participants With Adverse Events (AEs) |  | Up to 28 days after last dose of study drug or until initiation of another anti-cancer therapy (up to 74 months) |