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

Primary Purpose

Myeloid Leukemia, Philadelphia Positive

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Asciminib Pediatric formulation group
Asciminib Adult formulation group
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myeloid Leukemia, Philadelphia Positive focused on measuring Asciminib, pediatric patients, Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, Ph+ CML-CP, ABL001

Eligibility Criteria

1 Year - 18 Years (Child, Adult)All SexesDoes not accept 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.

    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) 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.

Sites / Locations

  • Dana Farber Cancer Institute Dept.of DFCIRecruiting
  • Columbia University Medical Center- New York Presbyterian Herbert Irving Cancer CenterRecruiting
  • University of Utah Primary Childrens HospitalRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
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Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Asciminib

Arm Description

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

Outcomes

Primary Outcome Measures

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).
Primary PK parameter: AUCtau
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Cmax
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Tmax
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Secondary PK parameter: Ctrough
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
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
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
To assess acceptability and palatability of the pediatric formulation

Full Information

First Posted
May 18, 2021
Last Updated
July 26, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04925479
Brief Title
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 27, 2021 (Actual)
Primary Completion Date
September 14, 2026 (Anticipated)
Study Completion Date
October 4, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloid Leukemia, Philadelphia Positive
Keywords
Asciminib, pediatric patients, Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, Ph+ CML-CP, ABL001

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Asciminib
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Asciminib Pediatric formulation group
Other Intervention Name(s)
ABL001
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Asciminib Adult formulation group
Other Intervention Name(s)
ABL001
Intervention Description
Asciminib Adult formulation group: 40 mg tablets BID, taken orally. 20 mg tablets BID, taken orally.
Primary Outcome Measure Information:
Title
Primary Pharmacokinetic (PK) parameter: AUClast
Description
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Time Frame
52 weeks
Title
Primary PK parameter: AUCtau
Description
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Time Frame
52 weeks
Title
Secondary PK parameter: Cmax
Description
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Time Frame
52 weeks
Title
Secondary PK parameter: Tmax
Description
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Time Frame
52 weeks
Title
Secondary PK parameter: Ctrough
Description
Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Hematologic responses
Description
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
Time Frame
52 weeks
Title
Molecular responses
Description
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.
Time Frame
52 weeks
Title
Questionnaire on acceptability and palatability after first dose, 4 and 52 weeks
Description
To assess acceptability and palatability of the pediatric formulation
Time Frame
after first dose at Week 1 Day 1, 4 weeks, 52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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. < 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Dana Farber Cancer Institute Dept.of DFCI
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sara Galinko
Email
Sara_Galinko@DFCI.HARVARD.EDU
First Name & Middle Initial & Last Name & Degree
Jessica Pollard
Facility Name
Columbia University Medical Center- New York Presbyterian Herbert Irving Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
Phone
212-305-9770
First Name & Middle Initial & Last Name & Degree
Nobuko Hijiya
Facility Name
University of Utah Primary Childrens Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Keeley Best
Phone
801-213-3599
Email
Keeley.Best@imail2.org
First Name & Middle Initial & Last Name & Degree
Mallorie Heneghan
Facility Name
Novartis Investigative Site
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300020
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310005
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Shanghai
ZIP/Postal Code
200127
Country
China
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bordeaux Cedex
ZIP/Postal Code
33076
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Lille
ZIP/Postal Code
59000
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Paris Cedex
ZIP/Postal Code
75019
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Poitiers
ZIP/Postal Code
86021
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Essen
ZIP/Postal Code
45147
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Athens
ZIP/Postal Code
115 27
Country
Greece
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1094
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Genova
State/Province
GE
ZIP/Postal Code
16147
Country
Italy
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Monza
State/Province
MB
ZIP/Postal Code
20900
Country
Italy
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Yokohama-city
State/Province
Kanagawa
ZIP/Postal Code
232-8555
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
160 8582
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Osaka
ZIP/Postal Code
534-0021
Country
Japan
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
05505
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Utrecht
State/Province
CS
ZIP/Postal Code
3584
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Wrocław
ZIP/Postal Code
50367
Country
Poland
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
117198
Country
Russian Federation
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Saint Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Muang
State/Province
Chiangmai
ZIP/Postal Code
50200
Country
Thailand
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Khon Kaen
ZIP/Postal Code
40000
Country
Thailand
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bursa
State/Province
Gorukle
ZIP/Postal Code
16059
Country
Turkey
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Istanbul
ZIP/Postal Code
34093
Country
Turkey
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
IPD Sharing URL
https://www.clinicalstudydatarequest.com

Learn more about this trial

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

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