A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
概览
- 阶段
- 3 期
- 干预措施
- Asciminib
- 疾病 / 适应症
- Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive
- 发起方
- Novartis Pharmaceuticals
- 入组人数
- 405
- 试验地点
- 123
- 主要终点
- Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI
- 状态
- 进行中（未招募）
- 最后更新
- 26天前
概览
简要总结
The study is designed to compare the efficacy of asciminib 80 mg QD versus Investigator selected Tyrosine Kinase Inhibitor (TKI) for the treatment of newly diagnosed, previously untreated patients with Ph+ CML-CP. The Investigator selected TKI will be one of the following treatment options for first-line treatment of CML-CP - imatinib 400 mg QD or nilotinib 300 mg BID or dasatinib 100 mg QD or bosutinib 400 mg QD.
This study has three periods: 1. Treatment period for all randomized participants, 2. Optional Treatment-Free Remission (TFR) period only for participants meeting TFR eligibility criteria and 3. Treatment Re-Initiation (TRI) period only for participants who relapsed after TFR attempt.
详细描述
This study is a phase III, multi-center, open-label, randomized study of oral asciminib 80 mg QD versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or bosutinib) in adult patients with newly diagnosed Ph+ CML-CP. All comparator TKIs will be made available, unless not permitted by local regulations or local Health Authority or not approved for the treatment of CML in the country. Approximately 402 patients will be randomized in a 1:1 ratio to asciminib and Investigator selected TKI to join the treatment period. Randomization will be stratified based on the following two stratification factors: * ELTS score (low versus intermediate versus high) * Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib)). Prior to randomization, the Investigator, in consultation with the patient, considering the current treatment paradigm and patient characteristics and comorbidities, will make a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or bosutinib) if the patient is randomized to the comparator arm. The stratified randomization based on these two stratification factors will help to achieve a balance across the treatment arms for the possible comorbidities and baseline characteristics of patients enrolled in the study. To further ensure that the distribution of patients, between imatinib and 2G TKIs (nilotinib or dasatinib or bosutinib), in the Investigator selected TKI arm is reflective of the use of these agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or dasatinib or bosutinib) based on the pre-randomization selection of TKI will be managed by Interactive Response Technology to be approximately 50% versus 50%. Treatment arms: The study will have 2 treatment arms: * Arm 1: asciminib 80 mg QD under fasting conditions * Arm 2: Investigator selected TKI that will include one of the below treatments: * Imatinib 400 mg QD administered with food * Nilotinib 300 mg BID administered under fasting conditions * Dasatinib 100 mg QD administered with or without meal * Bosutinib 400 mg QD administered with food. Apart from the treatment period described above, the present study comprises an optional Treatment-Free Remission (TFR) Period enrolling consenting participants of the treatment period (receiving asciminib or IS-TKI) who will discontinue their randomized treatment if they meet per protocol eligibility criteria. The optional TFR Period will last at least 2 years to assess the feasibility of TFR and TFR outcomes following discontinuation of their randomized treatment (asciminib or IS-TKI). In addition, during the TFR Period, participants who will lose major molecular response (MMR) must re-initiate treatment and will enter into a Treatment Reinitiation (TRI) Period. During the treatment period, no crossover of study treatment across arms and no change of study treatment within the Investigator selected TKI will be allowed. For specifically participants who must transition into the TRI Period, at the time of treatment re-initiation: a) participants who were previously treated with asciminib will resume asciminib at the same dose prior to entry into TFR. b) participants who were on IS-TKI may either continue with the same study treatment they were randomized to and at the same dose prior to entry into TFR or may switch to asciminib with a starting dose of 80 mg QD. Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, premature discontinuation due to treatment failure, disease progression or intolerance, due to Investigator or participant decision. or due to patient going to TFR Period and/or TRI Period. Duration of study: The End of Study will occur 8 years from the last patient first treatment in the study. Patients who discontinue study treatment prematurely due to any reason, will be followed up for survival and progression (to AP/BC) until the End of Study.
研究者
入排标准
入选标准
- •for treatment period:
- •Participants eligible for inclusion in this study must meet all of the following criteria:
- •Male or female patients ≥ 18 years of age.
- •Participants with CML-CP within 3 months of diagnosis.
- •Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of Philadelphia chromosome
- •Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020):
- •\< 15% blasts in peripheral blood and bone marrow,
- •\< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
- •\< 20% basophils in the peripheral blood,
- •Platelet count ≥ 100 x 10\^9/L (≥ 100,000/mm\^3),
排除标准
- •for Treatment period:
- •Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib for ≤2 weeks is allowed, but no other treatment with other tyrosine kinase inhibitors prior to randomization is permitted.
- •Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
- •Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:
- •History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
- •Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
- •QTc ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
- •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 (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- •Concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.•Inability to determine the QTcF interval
研究组 & 干预措施
Asciminib
Patients will take asciminib 80 mg QD under fasting conditions on ongoing basis; Patients will be randomized 1:1 asciminib versus Investigator selected TKIs
干预措施: Asciminib
Investigator selected TKIs
Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food
干预措施: Imatinib
Investigator selected TKIs
Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food
干预措施: Nilotinib
Investigator selected TKIs
Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food
干预措施: Bosutinib
Investigator selected TKIs
Patients will take on ongoing basis the Investigator selected TKIs that will include one of the below treatments: Imatinib 400 mg QD administered with food Nilotinib 300 mg BID administered under fasting conditions Dasatinib 100 mg QD administered with or without a meal Bosotunib 400 mg QD administered with food
干预措施: Dasatinib
结局指标
主要结局
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI
时间窗: At 48 weeks
Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Asciminib (Imatinib Stratum) vs Investigator Selected TKI (Imatinib Stratum)
时间窗: At 48 weeks
Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL1/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
次要结局
- Major Molecular Response at Week 96(at 96 weeks (96 weeks after last patient first dose))
- Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE)(96 weeks after last patient first dose)
- Major Molecular Response at Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- Major Molecular Response by Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- MR4.0 at Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- MR4.5 at All Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- MR4.0 by Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- MR4.5 by All Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- Complete Hematological Response (CHR) at All Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- Complete Hematological Response (CHR) by All Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- Percentage of Participants With Complete Cytogenic Response (CCyR) by Week 48 & Week 96(By week 48 and by week 96 (48 weeks and 96 weeks after last patient first dose); data collection/analysis is ongoing for the 96 week time point, and the data will be reported later)
- Duration of MMR(Planned total follow-up duration of 5 years)
- Duration of MR4.0(Planned total follow-up duration of 5 years)
- Duration of MR4.5(Planned total follow-up duration of 5 years)
- Time to First MMR(Planned total follow-up duration of 5 years)
- Time to First MR4.0(Planned total follow-up duration of 5 years)
- Time to First MR4.5(Planned total follow-up duration of 5 years)
- BCR-ABL1≤1% at Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- BCR-ABL1≤1% by Scheduled Data Collection Time Points(Planned total follow-up duration of 5 years)
- Time to Treatment Failure (TTF)(Planned total follow-up duration of 5 years)
- Failure Free Survival (FFS)(Planned total follow-up duration of 5 years)
- Event Free Survival (EFS)(Planned total follow-up duration of 5 years)
- Progression Free Survival (PFS)(Planned total follow-up duration of 5 years)
- Overall Survival (OS)(Planned total follow-up duration of 5 years)
- Trough Plasma Concentrations.(Week 48)
- Pharmacokinetics (PK) of Asciminib: Cmax(Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose))
- PK of Asciminib: Tmax(Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose))
- PK of Asciminib: AUCtau and AUClast(Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose))
- PK of Asciminib: CL/F(Week 2 (0 hours (h) pre-dose, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose))
- Change From Baseline in Overall Scores (Global Health Status) and Individual Scales of the EORTC QLQ-C30 at Week 48 and Week 96(Baseline, week 48 and week 96)
- Change From Baseline in EORTC QLQ-CML24 Scales at Week 48 and Week 96(Baseline, week 48 and week 96.)
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