Study Description
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. 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.
Interventions
Asciminib Adult formulation group
Asciminib Pediatric formulation group
Eligibility Criteria
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.
1. < 15% blasts in peripheral blood and bone marrow
2. < 30% combined blasts plus promyelocytes in peripheral blood and bone marrow
3. < 20% basophils in the peripheral blood
4. 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
5. 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.
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