Asciminib Treatment Optimization in ≥ 3rd Line CML-CP.

Study Overview
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Brief Summary
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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). Patients for this study will be identified based on warning criteria and resistance definition following European Leukemia Network (ELN) 2020 recommendations. In addition, the study will investigate the use of two different posologies. For this, patients will receive asciminib 40 mg (twice-daily) BID or of 80 mg (once daily) once daily (QD).

Detailed Description
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This study is an international, multi-center, non-comparative, phase IIIb, treatment optimization study of daily 80 mg asciminib (as either as 40 mg BID of asciminib or as 80 mg QD) in adult patients previously treated with 2 or more TKIs. Up to 30 patients who are intolerant to ongoing TKI treatment but in major molecular response (MMR) will also be allowed to enter the trial. Enrollment will be used to have a balance in the allocation of treatment into either asciminib 40 mg b.i.d. or 80 mg q.d. Although this trial will not be powered to compare both treatments, descriptive data from both treatment groups is expected to provide additional insight into the optimal patient management In patients not achieving MMR at 48 weeks or losing the response after the week 48 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 planned duration of treatment is up to 144 weeks unless patient discontinue from treatment due to unacceptable toxicity, disease progression and/or if treatment is discontinued at the discretion of the investigator or the participant prior to week 144.

Official Title
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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.

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: ABL001 40mg BID
* Drug: ABL001 80mg QD
* Drug: ABL001 200mg QD


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients with a diagnosis of CML-CP ≥ 18 years of age Patients must meet all the following laboratory values at the screening visit: < 15% blasts in peripheral blood and bone marrow < 30% blasts plus promyelocytes in peripheral blood and bone marrow < 20% basophils in the peripheral blood ≥ 50 x 109/L (≥ 50,000/mm3) platelets Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior to screening) is acceptable No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly Prior treatment with a minimum of 2 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 Warning is defined as: Three months after the initiation of treatment: BCR-ABL1 > 10% IS Six months after the initiation of treatment: BCR-ABL1 >1-10% IS Twelve months after the initiation of treatment BCR-ABL1>0,1-1% IS At any time after the initiation of therapy BCR-ABL1 >0.1-1% IS, loss of MMR (>0.1% with 5-fold increase of BCR-ABL1 transcripts). In addition, patients with failure of treatment according to the ELN 2020 recommendations will be eligible: Three months after the initiation of treatment: BCR-ABL1 > 10% IS if confirmed within 1-3 months Six months after the initiation of treatment: BCR-ABL1 >10% IS Twelve months after the initiation of treatment BCR-ABL1 >1% IS At any time after the initiation of therapy BCR-ABL1 >1% IS, emergence of resistance mutations, high-risk ACA Intolerance is defined as: Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer Exclusion criteria: Known presence of the BCR-ABL1 T315I mutation at any time prior to study entry. Known history of AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment 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, permanent pace maker) QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) 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 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, pulmonary hypertension) History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis History of active ongoing acute or chronic liver disease Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of asciminib. Other Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABL001<br>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. | Drug: ABL001 40mg BID<br>* One tablet of 40 mg will be taken orally twice a day (BID)<br>* Other names: asciminib;Drug: ABL001 80mg QD<br>* Two tablets of 40 mg will be taken orally once a day (QD)<br>* Other names: asciminib;Drug: ABL001 200mg QD<br>* Five tablets of 40 mg will be taken orally once a day (QD)<br>* Other names: asciminib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major molecular response (MMR) rate at Week 48 for all patients with no evidence of MMR at baseline. | To estimate the molecular response rate at week 48 of all patients (40 mg BID asciminib and 80 mg QD) with CML-CP following two or more prior TKI treatments and with no evidence of MMR at baseline. A patient will be counted as having achieved MMR at week 48 if he/she meets the MMR criterion (BCR-ABL1 ≤ 0.1% IS) at week 48 while on study treatment and without meeting any treatment failure criteria prior to week 48. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMR rate at baseline at Week 12, 24, 36, 72, 96 and 144 for patients with no MMR at baseline. | To assess the rate of MMR in patients without MMR at Baseline. MMR is defined as BCR-ABL ratio ≤0.1%. | Week 12, 24, 36, 72, 96 and 144. | 
| MMR rate at Week 48 for patients with MMR at baseline | To assess the rate of MMR for patients with MMR at Baseline. MMR is defined as BCR-ABL ratio ≤0.1%. | Week 48. | 
| Time to MMR. | To assess the time to MMR. MMR is defined as BCR-ABL ratio ≤0.1%. | From the date of enrollment to the date of first documented MMR, assessed up to 144 weeks | 
| Rate of BCR-ABL1 ≤ 10% | To assess the rate of early responses of BCR-ABL1 ≤10%. | Week 12, 24, 36 and 48. | 
| Rate of BCR-ABL1 ≤1% | To assess the rate of early responses of BCR-ABL1 ≤1%. | Week 12, 24, 36 and 48. | 
| MR4 rate. | To assess the rate of deep molecular responses MR4. MR4 is defined as BCR-ABL ratio ≤0.01%. | Week 12, 24, 36, 48, 72, 96 and 144. | 
| MR4.5 rate. | To assess the rate of deep molecular responses MR4.5. MR4.5 is defined as BCR-ABL ratio ≤0.0032%. | Week 12, 24, 36, 48, 72, 96 and 144. | 
| Rate of complete cytogenetic response (CCyR). | To assess the rate of complete cytogenetic response (CCyR). CCyR is defined as 0% Ph+ metaphases in the bone marrow. | Week 48 and end of treatment (up to 144 weeks) | 
| Occurrence of high-risk additional chromosomal abnormalities (ACA) | Occurrence of high-risk ACA to characterize the impact of additional cytogenetic abnormalities on efficacy. | Up to 144 weeks | 
| Cumulative molecular response rate of BCR-ABL1 ≤ 10%. | To assess cumulative molecular responses (BCR-ABL1 ≤ 10%) by all-time points. | From enrollment to end of treatment up to 144 weeks. | 
| Cumulative molecular response rate of BCR-ABL1 ≤1%. | To assess cumulative molecular responses (BCR-ABL1 ≤1%) by all-time points. | From enrollment to end of treatment up to 144 weeks. | 
| Cumulative molecular response rate of MMR. | To assess cumulative molecular responses of MMR by all-time points. MMR is defined as BCR-ABL ratio ≤0.1%. | From enrollment to end of treatment up to 144 weeks. | 
| Cumulative molecular response rate of MR4. | To assess cumulative molecular responses of MR4 by all-time points. MR4 is defined as BCR-ABL ratio ≤0.01%. | From enrollment to end of treatment up to 144 weeks. | 
| Cumulative molecular response rate of MR4.5. | To assess cumulative molecular responses of MR4.5 by all-time points. MR4.5 is defined as BCR-ABL ratio ≤0.0032%. | From enrollment to end of treatment up to 144 weeks. | 
| Duration of MMR. | Duration of MMR is defined as the time from the date of first documented MMR to the earliest date of loss of MMR, progression to accelerated phase (AP) or blast crisis (BC), or CML-related death. MMR is defined as BCR-ABL ratio ≤0.1%. | 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. | Duration of MR4 is the time from the date of the 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. MR4 is defined as BCR-ABL ratio ≤0.01%. | 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. | 
| Progression-Free survival (PFS) | PFS is defined as the time from treatment assignment the earliest occurrence of documented disease progression to AP/BC or the date of death from any cause, assessed up to approximately 144 weeks. | Up to 144 weeks. | 
| Overall Survival (OS) | OS is defined as the time from treatment assignment to death due to any cause during study, assessed up to 144 weeks. | Up to 144 weeks. | 
| Treatment failure (TTF) | Time from treatment assignment to treatment failure defined as BCR-ABL1>10%, assessed up to 144 weeks. | Up to 144 weeks. | 
| Change in symptom burden and interference from baseline over time according to the MDASI-CML PRO instrument. | To evaluate patient reported outcomes and quality of life by using QoL scale. The MD Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) is a 26 item self-administered questionnaire for adult CML patients. Twenty of the items measure the severity of disease-related symptoms (symptom burden) and are scored from 0 (not present) to 10 (as bad as you can imagine) and 6 items that measure symptom interference with daily life (interference) scored from 0 (did not interfere) to 10 (interfered completely). For symptom burden, total scores range from 0 to 200 and for interference range from 0 to 60, with higher scores indicates high impact on severity of chronic myeloid leukemia-related symptoms and on impact of these symptoms on daily functioning for the patient. | Week 4, 12, 24, 48, 72, 96, 120 and at end of treatment (up to 144 weeks). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABL001, Phase 3, Chronic Myelogenous Leukemia, CML, tyrosine kinase inhibitor, Chronic myelogenous leukemia (CML), chronic myeloid leukemia (CML), chronic myelocytic leukemia (CML), chronic granulocytic leukemia (CGL), cancer of the white blood cells, clonal bone marrow stem cell disorder, proliferation of mature granulocytes