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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 166
- 试验地点
- 75
- 主要终点
- Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Obinutuzumab (Drug)
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.
干预措施: Venetoclax (Drug)
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.
干预措施: Fludarabine (Drug)
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.
干预措施: Cyclophosphamide (Drug)
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.
干预措施: Rituximab (Drug)
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.
干预措施: Bendamustine (Drug)
结局指标
主要结局
Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS)
时间窗: At Month 15
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.
次要结局
- MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit(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(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)(At Month 15)
- CR Rate(At Month 15)
- MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit(At Month 15)
- MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit(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)(At Month 15)
- VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate(Baseline up to Cycle 1 Day 22 (1 cycle=28 days))
- VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up(Cycle 1 Days 22-28 up to Cycle 2 Days 1-7 (1 cycle=28 days))
- Progression-free Survival (PFS)(Up to approximately 56.4 months)
- Duration of Objective Response (DOR)(Up to approximately 56.4 months)
- Event-free Survival (EFS)(Up to approximately 56.4 months)
- Overall Survival (OS)(Up to approximately 56.4 months)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to approximately 56.4 months)
- Number of Participants With Premature Withdrawals Due to AEs(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)(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(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(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)(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(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(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))