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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04925479

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

1.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myeloid Leukemia, Philadelphia Positive	Drug: Asciminib Pediatric formulation group Drug: Asciminib Adult formulation group	Phase 1/Phase 2

Detailed Description

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 follow a two-part study design consisting of a dose determination part (Part 1) and a cohort expansion (Part 2).

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 remaining patients will be enrolled in Part 2 until at least 30 participants, including those who were included in Part 1, have been enrolled (15 per age group) in the pediatric formulation group.

Due to the fact that the pediatric formulation is currently in development and not yet available, this study will start with the recruitment of adolescent patients. These participants aged 14 to <18 years, weighing at least 40 kg will 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 is planned after all participants have completed at least 52 weeks of study treatment or discontinued earlier.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 27, 2021

Anticipated Primary Completion Date :

Dec 4, 2025

Anticipated Study Completion Date :

Dec 27, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Asciminib 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 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) BID 15 mg (15x 1 mg tablets in capsule) 20 mg (20x 1 mg tablets in capsule) BID 30 mg (30x 1 mg tablets in capsule) BID Other Names: ABL001 Drug: Asciminib Adult formulation group Asciminib Adult formulation group: 40 mg tablets BID, taken orally. 20 mg tablets BID, taken orally. Other Names: ABL001

Arm

Intervention/Treatment

Experimental: Asciminib

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

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) BID 15 mg (15x 1 mg tablets in capsule) 20 mg (20x 1 mg tablets in capsule) BID 30 mg (30x 1 mg tablets in capsule) BID

Other Names:

ABL001

Drug: Asciminib Adult formulation group

Asciminib Adult formulation group: 40 mg tablets BID, taken orally. 20 mg tablets BID, taken orally.

Other Names:

ABL001

Outcome Measures

Primary Outcome Measures

Primary Pharmacokinetic (PK) parameter: AUClast [52 weeks]
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Primary PK parameter: AUCtau [52 weeks]
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Cmax [52 weeks]
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Tmax [52 weeks]
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Ctrough [52 weeks]
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

Secondary Outcome Measures

Hematologic responses [52 weeks]
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
Molecular responses [52 weeks]
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.
Questionnaire on acceptability and palatability after first dose, 4 and 52 weeks [after first dose at Week 1 Day 1, 4 weeks, 52 weeks]
To assess acceptability and palatability of the pediatric formulation

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute Dept.of DFCI	Boston	Massachusetts	United States	02215
2	Columbia University Medical Center- New York Presbyterian	New York	New York	United States	10032
3	Novartis Investigative Site	Bordeaux Cedex		France	33076
4	Novartis Investigative Site	Lille		France	59000
5	Novartis Investigative Site	Poitiers		France	86021
6	Novartis Investigative Site	Erlangen		Germany	91054
7	Novartis Investigative Site	Essen		Germany	45147
8	Novartis Investigative Site	Hamburg		Germany	20246
9	Novartis Investigative Site	Athens		Greece	115 27
10	Novartis Investigative Site	Budapest		Hungary	1094
11	Novartis Investigative Site	Genova	GE	Italy	16147
12	Novartis Investigative Site	Monza	MB	Italy	20900
13	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	232-8555
14	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160 8582
15	Novartis Investigative Site	Osaka		Japan	534-0021
16	Novartis Investigative Site	Wrocław		Poland	50367
17	Novartis Investigative Site	Moscow		Russian Federation	117198
18	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
19	Novartis Investigative Site	Bangkok		Thailand	10400
20	Novartis Investigative Site	Khon Kaen		Thailand
21	Novartis Investigative Site	Bursa	Gorukle	Turkey	16059
22	Novartis Investigative Site	Istanbul		Turkey	34093