A Phase 3b, Multi-center, Open-label, Treatment Optimization Study of Oral Asciminib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Previously Treated With 2 or More Tyrosine Kinase Inhibitors
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 199
- 试验地点
- 48
- 主要终点
- Major Molecular Response (MMR) Rate at Week 48 for All Patients With no Evidence of MMR at Baseline
研究概览
简要总结
The purpose of the study is to optimize the treatment of asciminib in patients with chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with 2 or more Tyrosine Kinase Inhibitors (TKIs).
详细描述
This study consists of a screening period of up to 28 days, a treatment period of 144 weeks and a post-treatment safety follow-up period of 4 weeks.
Patients will receive asciminib as study treatment continuously for up to 144 weeks or until disease progression, treatment failure or intolerance to treatment. At treatment initiation, asciminib will be provided to all trial patients at a total daily dose of 80 mg. All patients will be randomly assigned 1:1 to 2 groups with 80 mg given either as 40 mg b.i.d. or 80 mg q.d., using IRT to avoid any selection bias.
In patients not achieving Major Molecular Responses (MMR) at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation. In addition, there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management.
The trial will enroll a total of approximately 186 patients:
- 156 patients with CML-CP not in MMR at baseline who were treated with two or more TKIs and who were either resistant (ELN 2020 warning or failure) or intolerant to the last treatment will be enrolled. For this population, the primary endpoint for MMR at 48 weeks will be assessed.
- Up to 30 additional patients intolerant only to their last TKI treatment and in MMR at baseline will also be enrolled. This patient population will not be part of primary endpoint analysis; however, all assessments will be done as with the 156 patients from the population of the primary endpoint analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent must be obtained prior to participation in the study
- •Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
- •Treatment with a minimum of 2 or more prior TKIs (i.e. imatinib, nilotinib, dasatinib, bosutinib, radotinib or ponatinib)
- •Warning or failure (adapted from the 2020 ELN Recommendations) or intolerance to the most recent TKI therapy at the time of screening
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
- •Adequate end organ function (as per central laboratory tests)
排除标准
- •Known presence of the BCR::ABL1 T315I mutation at any time prior to study entry
- •Known second chronic phase of CML after previous progression to AP/BC
- •Previous treatment with a hematopoietic stem-cell transplantation
- •Patient planning to undergo allogeneic hematopoietic stem cell transplantation
- •Uncontrolled cardiac repolarization abnormality
- •Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol
- •History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
- •Testing for Hepatitis B surface antigen (HbsAg) and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening. Patients with active Hepatitis B Virus (HBV) infection (hepatitis B surface antigen [HbsAg] positive) will be excluded
- •Other Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
ABL001
Participants will be treated with 80 mg of ABL001 (40 mg BID or 80mg QD). In patients not achieving MMR at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation.
干预措施: ABL001 40mg BID (Drug)
ABL001
Participants will be treated with 80 mg of ABL001 (40 mg BID or 80mg QD). In patients not achieving MMR at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation.
干预措施: ABL001 80mg QD (Drug)
ABL001
Participants will be treated with 80 mg of ABL001 (40 mg BID or 80mg QD). In patients not achieving MMR at 48 weeks or losing the response after the week 48 assessment up to week 108, asciminib dose may be escalated to 200 mg q.d. if in the investigator's opinion the patient may benefit from the escalation.
干预措施: ABL001 200mg QD (Drug)
结局指标
主要结局
Major Molecular Response (MMR) Rate at Week 48 for All Patients With no Evidence of MMR at Baseline
时间窗: Week 48
Major Molecular Response (MMR) is defined as a significant reduction in the level of BCR::ABL1 transcripts, which are the genetic markers of chronic myeloid leukemia (CML). Specifically, MMR is achieved when there is a ≥ 3.0 log reduction in BCR::ABL1 transcripts compared to a standardized baseline, which corresponds to a BCR::ABL1/ABL1 ratio of ≤ 0.1% on the international scale (IS). The Major Molecular Response (MMR) rate at Week 48 for all patients with no evidence of MMR at baseline refers to the percentage of patients who achieve MMR after 48 weeks of treatment, despite not having MMR at the start.
次要结局
- MMR Rate at Week 12, 24, 36, 72, 96 and 144 for Patients With no MMR at Baseline(Week 12, 24, 36, 72, 96 and 144)
- Major Molecular Response (MMR) Rate at Week 48 for Patients With MMR at Baseline(Week 48.)
- Time to MMR for Subjects Without MMR at Baseline(From the date of enrollment to the date of first documented MMR, assessed up to 144 weeks)
- Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline(Week 12, 24, 36 and 48)
- Rate of BCR::ABL1 ≤ 1% for Subjects Without MMR at Baseline(Week 12, 24, 36 and 48.)
- Deep Molecular Responses (MR4) Rate for Subjects Without MMR at Baseline(Week 12, 24, 36, 48, 72, 96 and 144.)
- Deep Molecular Responses (MR4.5) Rate for Subjects Without MMR at Baseline(Week 12, 24, 36, 48, 72, 96 and 144.)
- Rate of Complete Cytogenetic Response (CCyR) for Subjects Without MMR at Baseline(Week 48 and end of treatment (up to 144 weeks))
- Occurrence of High-risk Additional Chromosomal Abnormalities (ACA) for Subjects Without MMR at Baseline(Up to 144 weeks)
- Cumulative Molecular Response Rate of BCR::ABL1 ≤ 10% for Subjects Without MMR at Baseline(From enrollment to end of treatment up to 144 weeks.)
- Cumulative Molecular Response Rate of BCR::ABL1 ≤1% for Subjects Without MMR at Baseline(From enrollment to end of treatment up to 144 weeks.)
- Cumulative Molecular Response Rate of MMR for Subjects Without MMR at Baseline(From enrollment to end of treatment up to 144 weeks.)
- Cumulative Molecular Response Rate of MR4 for Subjects Without MMR at Baseline(From enrollment to end of treatment up to 144 weeks.)
- Cumulative Molecular Response Rate of MR4.5 for Subjects Without MMR at Baseline(From enrollment to end of treatment up to 144 weeks.)
- Duration of MMR(From the date of the first documented molecular response at MMR level to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.)
- Duration of MR4 Without Loss of MMR(From the date of first documented MR4 without loss of MMR to the date of first documented loss of the response level or death due to any cause, whichever occurs first, assessed up to 144 weeks.)
- Overall Survival (OS) for Subjects Without MMR at Baseline(Up to 144 weeks.)
- Time to Treatment Failure (TTF) for Subjects Without MMR at Baseline(Up to 144 weeks.)
- Progression-Free Survival (PFS) for Subjects Without MMR at Baseline(Up to 144 weeks.)
- Change in Symptom Burden and Interference From Baseline Over Time According to the MDASI-CML PRO Instrument(Week 4, 12, 24, 48, 72, 96, 120 and at end of treatment (up to 144 weeks).)