Study to Determine the Dose and Safety of Asciminib in Pediatric Patients With Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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The aim of this study is to support development of asciminib in the pediatric population (1 to <18 years) previously treated with one or more TKIs. Full extrapolation of the efficacy of asciminib from adult to pediatric patients will be conducted. Full extrapolation is based on the concept that CML in the pediatric population has the same pathogenesis, similar clinical characteristics and progression pattern as in adults.

Detailed Description
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The aim of this study is to support development of asciminib in the pediatric population (1 to <18 years) with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (PH+ CML-CP) previously treated with one or more Tyrosine kinase inhibitor (TKIs). The primary objective of this study is to characterize the pharmacokinetic (PK) profile of asciminib in pediatric patients with the goal of identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). The pediatric formulation group will include at least 15 participants in each of the following two age categories: 1 to <12 years and 12 to <18 years; leading to at least 30 participants enrolled treated with the pediatric formulation. It will consist of a dose determination part (Part 1) and a cohort expansion (Part 2 BID regimen and Part 3 QD regimen). In Part 1, 4-6 participants will be enrolled in order to obtain at least 4 participants evaluable for PK (these participants may be from either of the age categories described above). The initial starting dose will be based on body weight and will be administered BID with food. Once the body weight adjusted dose has been determined in Part 1 of the study, the patients will be enrolled in Part 2 until at least 20 participants, including those who were included in Part 1, have been enrolled (10 per age group) in the pediatric formulation group. Once the interim safety and PK analysis 2 is completed for one of the age groups, the Part 3 QD regimen will open for the respective age group to enroll 10 patients (5 patients by age group). Due to the fact that the pediatric formulation was in development and was not available, this study started with the recruitment of adolescent patients. These participants aged 14 to <18 years, weighing at least 40 kg receive the adult formulation at a flat dose of 40 mg BID under fasted conditions. The total duration of the treatment period of the study will be 5 years (260 weeks). Participants who, according to Investigator's judgement, are benefiting from study treatment will remain on treatment up to the completion of the treatment period (Week 260/5 years). The primary analysis for the BID regimen is planned after all participants in Part 1 and 2 have completed at least 52 weeks of study treatment or discontinued earlier. The primary analysis for combined regimen (BID+QD) is planned after all participants in Part 1, 2 and 3 have completed at least 52 weeks of study treatment or discontinued earlier.

Official Title
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A Multi-center, Open-label Study to Determine the Dose and Safety of Oral Asciminib in Pediatric Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP), Previously Treated With One or More Tyrosine Kinase Inhibitors

Conditions
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Myeloid Leukemia, Philadelphia Positive

Intervention / Treatment
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* Drug: Asciminib Pediatric formulation group
* Drug: Asciminib Adult formulation group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Male or female participants: Pediatric formulation group: ≥ 1 and less than 18 years of age at study entry. Adult formulation group: ≥ 14 and less than 18 years of age and body weight of ≥ 40 kg at study entry. Participants with Ph+ CML-CP must meet all of the following laboratory values at the screening visit. In the case where bone marrow blast and promyelocyte counts are available, these will be accepted if done within 56 days prior to the screening visit, to avoid unnecessary repetition of this test. < 15% blasts in peripheral blood and bone marrow < 30% combined blasts plus promyelocytes in peripheral blood and bone marrow < 20% basophils in the peripheral blood Neutrophils ≥ 1.5 x 10^9/L (or WBC ≥ 3 x 10^9/L if neutrophils are not available) and platelet count ≥ 100 x 10^9/L No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly Prior treatment with a minimum of one TKI Failure (adapted from the 2020 European Leukemia Net (ELN) Guidelines Hochhaus et al 2020 and 2013 ELN Guidelines Baccarani et al 2013) or intolerance to the most recent TKI therapy at the time of screening. Performance status: Karnofsky ≥ 50% for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age at the time of screening Participants must have adequate renal, hepatic, pancreatic and cardiac function Participants must have electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication: Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which are amenable to standardized RQ-PCR quantification. Exclusion Criteria: Known presence of the T315I mutation 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. Cardiac or 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. History of acute or chronic liver disease. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug Pregnant or nursing (lactating) females. Other protocol-defined inclusion/exclusion may apply.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 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: Asciminib<br>This arm consists of 2 groups: The pediatric formulation group where the dose is based on body weight (1.3mg/kg) The adult formulation group where participants will receive a flat dose of 40mg BID | Drug: Asciminib Pediatric formulation group<br>* Asciminib Pediatric formulation group: Mini-tablets will be supplied as size 0 capsules containing 1 mg mini-tablets, taken orally: 10 mg (10x 1 mg tablets in capsule) 15 mg (15x 1 mg tablets in capsule) 20 mg (20x 1 mg tablets in capsule) 30 mg (30x 1 mg tablets in capsule)<br>* Other names: ABL001;Drug: Asciminib Adult formulation group<br>* Asciminib Adult formulation group: 40 mg tablets BID, taken orally. 20 mg tablets BID, taken orally.<br>* Other names: ABL001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Pharmacokinetic (PK) parameter: AUClast | Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). | 52 weeks | 
| Primary PK parameter: AUCtau | Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). | 52 weeks | 
| Secondary PK parameter: Cmax | Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). | 52 weeks | 
| Secondary PK parameter: Tmax | Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). | 52 weeks | 
| Secondary PK parameter: Ctrough | Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted). | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic responses | Complete hematological response will be defined as all of the following present for ≥ 4 weeks: WBC count < 10 x 10^9/L Platelet count < 450 x 10^9/L Basophils < 5% No blasts and promyelocytes in peripheral blood Myelocytes + metamyelocytes < 5% in peripheral blood No evidence of extramedullary disease, including spleen and liver | 52 weeks | 
| Molecular responses | To assess pharmacodynamic markers of asciminib's anti-leukemic activity. Molecular response will be assessed by Breakpoint Cluster Region gene-Abelson proto-oncogene (BCR-ABL) 1 level. | 52 weeks | 
| Questionnaire on acceptability and palatability after first dose, 4 and 52 weeks | To assess acceptability and palatability of the pediatric formulation | after first dose at Week 1 Day 1, 4 weeks, 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asciminib, pediatric patients, Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, Ph+ CML-CP, ABL001