A Phase 2, Multi-center, Open-label, Randomized Study of Oral Asciminib Added to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients With CML-CP Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 104
- 试验地点
- 33
- 主要终点
- Molecular Response (MR)^4.5 Rate at 48 Weeks
研究概览
简要总结
To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib in pre-treated patients with Chronic Myeloid Leukemia in chronic phase (CML-CP). An asciminib single agent arm (80 mg daily) was added after the primary analysis to evaluate if asciminib alone could lead to MR4.5 patients in Imatinib for at least one year who have never achieved deep molecular response (DMR).
详细描述
The study was a Phase 2, multi-center, open-label, randomized study of asciminib in two different doses (40 mg or 60 mg) in combination with imatinib 400 mg versus continued imatinib versus switch to nilotinib in participants with chronic myeloid leukemia in chronic phase (CML-CP) who had been previously treated with imatinib first line therapy for at least one year and had not achieved deep molecular response (DMR). Eligible participants were randomized 1:1:1:1 to receive asciminib 60 mg once daily (QD) as add-on therapy to imatinib 400 mg QD, or 40 mg QD as add-on therapy to imatinib 400 mg QD, or to continue imatinib 400 mg QD, or to switch to nilotinib 300 mg twice a day (BID). During the trial, there was no switch allowed. It was just at the moment of the randomization that the participants were selected to asciminib add-on arms or nilotinib.
Participants on the imatinib continuation arm who had not achieved MR4.5 at 48 weeks were allowed to cross-over ((CO) to receive the add-on treatment within 4 weeks after week 48 visit to receive the asciminib 60 mg combination add-on treatment, as this dose provided higher exposure. The cross-over was at the discretion of the investigator and the participant. Apart from a polymerase chain reaction (PCR) result of below MR4.5 at Week 48 visit, there were no other entry criteria for the cross-over part. Participants on nilotinib were not allowed to cross-over to receive the add-on treatment.
Participants on the study continued on the allocated treatment until treatment failure, intolerability, or for up to 96 weeks (in arms 1 to 4) after the last participant had received the first dose of treatment. After the last dose was received, every participant was followed up for safety for 30 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients ≥ 18 years of age with a confirmed diagnosis of CML-CP.
- •Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 400 mg QD at randomization and had no dose change in the past three months).
- •For Korea only:
- •(i) a minimum of one year (12 calendar months) of prior treatment with imatinib for patients with BCR::ABL1 levels > 0.1%, ≤ 1% IS at the time of randomization.
- •(ii) a minimum of two years (24 calendar months) of prior treatment with imatinib for patients with BCR::ABL 1 levels > 0.01%, ≤ 0.1% IS at the time of randomization.
- •BCR::ABL1 levels > 0.01% IS (International Scale) and ≤ 1% IS at the time of randomization as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) confirmed by 2 consecutive tests at any time during prior imatinib treatment. An isolated, single test result with BCR::ABL1 levels < 0.01 % (MR4 IS) is allowed, however, it should not have been observed within the 9 months prior to randomization
- •Patient must meet the following laboratory values before randomization:
- •Absolute Neutrophil Count ≥ 1.5 x 10E9/L
- •Platelets ≥ 75 x 10E9/L
- •Hemoglobin ≥ 9 g/dL
- •Serum creatinine < 1.5 mg/dL
- •Total bilirubin ≤ 1.5 x ULN (Upper Limit of Normal) except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN
- •Aspartate transaminase (AST) ≤ 3.0 x ULN
- •Alanine transaminase (ALT) ≤ 3.0 x ULN
- •Alkaline phosphatase ≤ 2.5 x ULN
- •Serum lipase ≤ 1.5 x ULN
- •Participants must have the following laboratory values ≥ Lower Limit of Normal or corrected to within normal limits with supplements prior to randomization: potassium increase of up to 6.0 mmol/L is acceptable if associated with creatinine clearance within normal limits ; calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with creatinine clearance* within normal limits) ; magnesium increase up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance within normal limits.
排除标准
- •Treatment failure according to European Leukemia Network (ELN) criteria 2013 during imatinib treatment.
- •Known second chronic phase of CML after previous progression to Accelerated Phase (AP)/Blast Crisis (BC).
- •Previous treatment with any tyrosine kinase inhibitors (TKIs) other than imatinib.
- •History or current diagnosis of ECG abnormalities indicating significant risk or safety for participants participating in the study such as:
- •History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to randomization
- •Concomitant clinically significant arrhythmias
- •Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization
- •Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- •Risk factors for Torsades de Pointes
- •Concomitant medications with a "known" risk of Torsades de Pointes
- •inability to determine the QTcF interval
- •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 (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant hyperlipidemia and high serum amylase)
- •History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis; on-going acute liver disease or history of chronic liver disease
- •History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively.
研究组 & 干预措施
Asciminib 60mg QD + Imatinib 400mg QD
Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily
干预措施: Asciminib add-on (Drug)
Asciminib 60mg QD + Imatinib 400mg QD
Asciminib 60 mg taken once daily in combination with Imatinib 400 mg taken once daily
干预措施: Imatinib (Drug)
Asciminib 80mg QD (ASAC)
Asciminib 80 mg taken once daily
干预措施: Asciminib 80mg QD (asciminib single agent (ASAC)) (Drug)
Asciminib 40mg QD + Imatinib 400mg QD
Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily
干预措施: Asciminib add-on (Drug)
Asciminib 40mg QD + Imatinib 400mg QD
Asciminib 40 mg taken once daily in combination with Imatinib 400 mg taken once daily
干预措施: Imatinib (Drug)
Imatinib 400mg QD
Imatinib 400 mg taken once daily
干预措施: Imatinib (Drug)
Nilotinib 300mg BID
Nilotinib 300 mg taken twice daily
干预措施: Nilotinib (Drug)
结局指标
主要结局
Molecular Response (MR)^4.5 Rate at 48 Weeks
时间窗: at Week 48
Percentage of participants still treated with the randomized treatment at 48 weeks and are in MR4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all participants in the asciminib add-on arms vs imatinib arm.
Molecular Response (MR)^4.5 Rate at 48 Weeks and Difference in Rate Between Asciminib + Imatinib and Imatinib Alone
时间窗: at Week 48
Percentage of participants still treated with the randomized treatment at 48 weeks and are in MR\^4.5 (BCR::ABL1 ratio of ≤ 0.0032%) at 48 weeks (± assessment window), among all participants in the asciminib add-on arms vs imatinib arm.
次要结局
- Rate of MR^4.5 at 48 Weeks (Asciminib add-on Arms vs Nilotinib)(at Week 48)
- Rate of MR^4.5 by 48 Weeks (Randomized Arms)(by 48 weeks)
- Rate of MR^4.5 at 96 Weeks (Randomized Arms) and Difference in Rate Between Asciminib + Imatinib and Nilotinib Alone(at Week 96)
- Rate of MR^4.5 by 96 Weeks (Randomized Arms)(by 96 weeks)
- Sustained MR^4.5 From at 96 Weeks (Randomized Arms)(at 96 weeks)
- Time to MR^4.5 (Randomized Arms)(96 weeks after the last participant received the first study dose)
- Duration of MR^4.5 (Randomized Arms)(96 weeks after the last participant received the first study dose)
- Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Cmax (Randomized Arms)(Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose; Week 4 Day 28: pre-dose (0h) 2h, 3h, 4h post-dose)
- Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Tmax (Randomized Arms)(Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose; Week 4 Day 28: pre-dose (0h) 2h, 3h, 4h post-dose)
- Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - Cmin (Randomized Arms)(Week 2 Day 14: pre-dose (0h), Week 4 Day 28: pre-dose (0h))
- Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - AUClast (Randomized Arms)(Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose)
- Pharmacokinetic Profile of Asciminib 40/60 mg and Imatinib When Administered in Combination - AUCtau (Randomized Arms)(Week 2 Day 14: pre-dose (0h), 1h, 2h, 3hr 4h and 8h post-dose)
- Molecular Response (MR) 4.5 Rate at 48 Weeks (Asciminib Single Agent Cohort (ASAC))(at Week 48)
- Time to MR^4.5 (ASAC)(48 weeks after the last enrolled participant (asciminib 80 mg cohort) received the first study dose)
- Duration of MR^4.5 (ASAC)(48 weeks after the last enrolled participant (asciminib 80 mg cohort) received the first study dose)
- Pharmacokinetic Profile of Asciminib 80mg QD - Cmax (ASAC)(Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose; Week 4 Day 28: 0h (pre-dose), 2h, 3h, 4h post-dose)
- Pharmacokinetic Profile of Asciminib 80mg QD - Tmax (ASAC)(Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose; Week 4 Day 28: 0h (pre-dose), 2h, 3h, 4h post-dose)
- Pharmacokinetic Profile of Asciminib 80mg QD - Cmin (ASAC)(Week 2 Day 14: 0h (pre-dose), Week 4 Day 28: 0h (pre-dose))
- Pharmacokinetic Profile of Asciminib 80mg QD - AUClast (ASAC)(Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose)
- Pharmacokinetic Profile of Asciminib 80mg QD - AUCtau (ASAC)(Week 2 Day 14: 0h (pre-dose), 1h, 2h, 3h, 4h, 8h post-dose)
- Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Cmax(up to 96 weeks)
- Time to MR^4.5(96/48 weeks after the last rand./enrolled (asciminib 80mg cohort) participant received the first study dose)
- Rate of MR^4.5 at 48 Weeks(at Week 48)
- Rate of MR^4.5 by 48 Weeks(by 48 weeks)
- Rate of MR^4.5 at 96 Weeks(at 96 weeks)
- Rate of MR^4.5 by 96 Weeks(by 96 weeks)
- Sustained MR^4.5 From 48 Weeks Until 96 Weeks(at 96 weeks)
- Duration of MR^4.5(96/48 weeks after the last rand./enrolled (asciminib 80mg cohort) participant received the first study dose)
- Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Tmax(up to 96 weeks)
- Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - Cmin(up to 96 weeks)
- Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - AUClast(up to 96 weeks)
- Pharmacokinetic Profile of Asciminib and Imatinib When Administered in Combination - AUCtau(up to 96 weeks)
- MR^4.5 Rate at 48 Weeks(at 48 weeks)
- Pharmacokinetic Profile of Asciminib 80mg QD - Cmax(up to 48 weeks)
- Pharmacokinetic Profile of Asciminib 80mg QD - Tmax(up to 48 weeks)
- Pharmacokinetic Profile of Asciminib 80mg QD - Cmin(up to 48 weeks)
- Pharmacokinetic Profile of Asciminib 80mg QD - AUClast(up to 48 weeks)
- Pharmacokinetic Profile of Asciminib 80mg QD - AUCtau(up to 48 weeks)