Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 366
- 试验地点
- 120
- 主要终点
- Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)
研究概览
简要总结
This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Pathologically confirmed MCL (in tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
- •At least 1 measurable site of disease on cross-sectional imaging (CT).
- •At least 1, but no more than 5, prior treatment regimens for MCL.
- •Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen.
- •Subjects must have adequate fresh or paraffin embedded tissue.
- •Adequate hematologic, hepatic and renal function.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <= 2.
排除标准
- •History or current evidence of central nervous system lymphoma.
- •Concurrent enrollment in another therapeutic investigational study or prior therapy with ibrutinib or other BTK inhibitors.
- •Prior treatment with venetoclax or other BCL2 inhibitors.
- •Anticancer therapy including chemotherapy, radiotherapy, small molecule and investigational agents <= 21 days prior to receiving the first dose of study drug.
- •Treatment with any of the following within 7 days prior to the first dose of study drug: moderate to strong cytochrome P450 3A (CYP3A) inhibitors or strong CYP3A inducers.
- •Treatment Naïve Arm
- •Inclusion Criteria:
- •Pathologically confirmed treatment-naive MCL (tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
- •Men and women ≥18 years of age with a TP53 mutation.
- •At least 1 measurable site of disease by CT.
- •Must have adequate fresh or paraffin-embedded tissue.
- •Eastern Cooperative Oncology Group (ECOG) performance status score 0 to <=
- •Adequate hematologic, hepatic, and renal function.
- •Exclusion Criteria:
- •Blastoid variant of MCL
- •History or current evidence of CNS lymphoma.
- •Concurrent enrollment in another therapeutic investigational study or prior therapy including ibrutinib or other BTK inhibitors.
- •Prior treatment with venetoclax or other BCL2 inhibitors.
- •Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
- •Clinically significant infection requiring IV systemic treatment that was completed <=14 days before the first dose of study drug.
- •Any uncontrolled active systemic infection.
- •Known bleeding disorders (eg, von Willebrand's disease or hemophilia).
- •History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
- •History of HIV or active HCV or HBV.
- •Major surgery within 4 weeks of the first dose of study drug.
- •Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participant's safety or put the study outcomes at undue risk.
- •Currently active, clinically significant cardiovascular disease; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
- •Unable to swallow capsules or tablets, or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
- •Treatment with any of the following within 7 days prior to the first dose of study drug: Moderate or strong cytochrome P450 3A (CYP3A) inhibitors or moderate or strong CYP3A inducers.
- •Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects with known risk factors (as defined by high tumor burden and/or diminished renal function, as detailed in "Study Design" section above) for TLS.
- •Chronic liver disease with hepatic impairment Child-Pugh class B or C.
- •Unwilling or unable to participate in all required study evaluations and procedures.
- •Known hypersensitivity to the active ingredient or other components of one or more study drugs.
研究组 & 干预措施
Safety Run-in
Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period.
干预措施: Ibrutinib (Drug)
Safety Run-in
Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period.
干预措施: Venetoclax (Drug)
Randomization Phase: Ibrutinb + Venetoclax
Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment.
干预措施: Ibrutinib (Drug)
Randomization Phase: Ibrutinb + Venetoclax
Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment.
干预措施: Venetoclax (Drug)
Randomization Phase: Ibrutinib + Placebo
Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment.
干预措施: Ibrutinib (Drug)
Randomization Phase: Ibrutinib + Placebo
Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment.
干预措施: Placebo Oral tablet to match Venetoclax (Drug)
Treatment-naive Open-label Arm
Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.
干预措施: Ibrutinib (Drug)
Treatment-naive Open-label Arm
Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)
时间窗: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.
Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)
时间窗: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)
时间窗: From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months
AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Progression-free Survival (PFS) (Randomization Phase)
时间窗: For an overall median time on study of 61.34 months
PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Complete Response (CR) Rate (Treatment-Naive Arm)
时间窗: For an overall median time on study of 40.51 months
CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
次要结局
- Overall Survival (OS) (Safety Run-in)(For an overall median time on study of 74.78 months)
- Progression-free Survival (PFS) (Safety Run-in)(For an overall median time on study of 74.78 months)
- Duration of Response (DOR) (Safety Run-in)(For an overall median time on study of 74.78 months)
- Overall Response Rate (ORR) (Safety Run-in)(For an overall median time on study of 74.78 months)
- Percentage of Participants With a Complete Response (CR) (Randomization Phase)(For an overall median time on study of 61.34 months)
- Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)(For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm))
- MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)(For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm))
- Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)(For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm))
- Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)(For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm))
- Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm)(For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm))
- Number of Participants With TEAEs (Randomization Phase)(From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months)
- Number of Participants With TLS TEAEs (Randomization Phase)(From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months)
- Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Venetoclax: Cmax (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Venetoclax: AUC0-24 (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Steady-State PK of Venetoclax: CLss/F (Randomization Phase)(Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose)
- Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-related Quality of Life (Randomization Phase)(For an overall median time on study of 61.34 months (Randomization Phase))
- Duration of CR (Treatment-Naive Arm)(For an overall median time on study of 40.51 months)
- Progression-free Survival (PFS) (Treatment-Naive Arm)(For an overall median time on study of 40.51 months)