Clinical trial NCT04925479: Study to Determine the Dose and Safety of Asciminib in Pediatric Patients With Chronic Myeloid Leukemia
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myeloid Leukemia, Philadelphia Positive
Keywords: Asciminib
pediatric patients
Philadelphia chromosome positive chronic myeloid leukemia in chronic phase
Ph+ CML-CP
ABL001
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-06-14
Enrollment: 34
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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 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.

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 or a BCR::ABL mutation with known resistance to study treatment any time 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.

Primary outcomes:
measure: Primary Pharmacokinetic (PK) parameter: AUClast
timeFrame: 52 weeks
measure: Primary PK parameter: AUCtau
timeFrame: 52 weeks
measure: Secondary PK parameter: Cmax
timeFrame: 52 weeks
measure: Secondary PK parameter: Tmax
timeFrame: 52 weeks
measure: Secondary PK parameter: Ctrough
timeFrame: 52 weeks
Secondary outcomes:
measure: Hematologic responses
timeFrame: 52 weeks
measure: Molecular responses
timeFrame: 52 weeks
measure: Questionnaire on acceptability and palatability after first dose, 4 and 52 weeks
timeFrame: after first dose at Week 1 Day 1, 4 weeks, 52 weeks
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana UH Riley H for CIU
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New York
country: United States
facility: Columbia University Medical Center New York Presbyterian
state: New York
city: Cincinnati
country: United States
facility: Cinn Children Hosp Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Childrens Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Uni Of Texas MD Anderson Cancer Ctr
state: Texas
city: Salt Lake City
country: United States
facility: University Of Utah
state: Utah
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Yokohama
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
state: CS
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Muang
country: Thailand
facility: Novartis Investigative Site
city: Bursa
country: Turkey
facility: Novartis Investigative Site
state: Gorukle
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: