Genomics Study in CML Patients With Ponatinib Treatment (CAP)

The Comprehensive Assessment of BCR-ABL1 Gene Expression and Genetic Variations by qRT-PCR and NGS Assays in Chronic Myeloid Leukemia Patients Who Are Treated With Ponatinib (CAP Study)

This study will evaluate whether responsiveness and adverse events (AEs) to second-line or later ponatinib treatment are associated with genetic variations as measured by real-time quantitative polymerase chain reaction (qRT-PCR) and next-generation sequencing (NGS) in patients with CML of any stage who failed prior multiple targeted therapies except ponatinib.

Study Overview

• Status: Completed
• Conditions: Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Intervention / Treatment: Drug: Ponatinib

Detailed Description

Ponatinib treatment will be initiated per usual treatment procedure at 45 mg once daily p.o., which will be gradually decreased to 30 mg and 15 mg according to the predefined criteria based on responsiveness to treatment and AEs in the course of the treatment. A total of 100 subjects will be enrolled within 24 months after the first subject enrollment, and ponatinib treatment will continue for 24 months after the initial dosing of ponatinib in each enrolled subject. Routine ponatinib treatment will continue at the investigator's discretion until disease progression, the occurrence of unacceptable toxicity, subject's withdrawal of consent, or occurrence of any reason for discontinuation specified in the protocol.

All molecular analysis samples will be collected, transferred, and managed by the Catholic Leukemia Research Institute, and NGS will be performed.

<Eligibility>

1. Adults with BCR-ABL1-positive CML
2. Subjects who were resistant or intolerant to prior targeted therapy other than ponatinib and with an indication for ponatinib treatment according to the acceptance criteria by the Ministry of Food and Drug Safety (MFDS)
3. Women of childbearing potential (WOCBP) should have a negative serum or urine pregnancy test (with a sensitivity of at least 25 IU/L or equivalent to HCG) within 24 hours before initiating ponatinib treatment
4. Written informed consent to ponatinib treatment

<Outcome Measures>

1. Primary endpoint

   - 24 months dynamics of BCR-ABL1 gene expression by qRT-PCR

2. Secondary endpoints

   • Type and frequency of novel genetic variations (mutations, gene expressions, CNV, INDEL, etc.)
   • Cobll1/GCA/novel gene network identification: functional tests using Western blot/Knock-down assay

3. Safety endpoints : To explore the dynamics of adverse events according to dose changes up to 24 months

   • Frequency and severity of skin rash, fever, hypertension, pancreatitis and vascular events as common adverse events
   • Frequency and severity of rare adverse events
   • Treatment intolerance is defined as recurrence of a Grade ≥3 hematologic AE, or a Grade ≥2 non-hematologic AE requiring permanent discontinuation of ponatinib per protocol despite dose reduction

• Study Type: Observational
• Enrollment (Actual): 65

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 137-701
    • Seoul St. Mary's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study will involve 100 patients with BCR-ABL1-positive CML who failed to prior targeted therapy other than ponatinib. Patients receiving ponatinib 45 mg once daily as a second-line or later therapy will be enrolled.

Description

Inclusion Criteria:

• Patients who are willing to and capable of providing informed consent

• Adults with BCR-ABL1-positive CML

  1. Males and females aged 18 years and above
  2. Adequate organ function
• Subjects who were resistant or intolerant to prior targeted therapy other than ponatinib and with an indication for ponatinib treatment according to the acceptance criteria by the Ministry of Food and Drug Safety (MFDS)
• Women of childbearing potential (WOCBP) should have a negative serum or urine pregnancy test (with a sensitivity of at least 25 IU/L or equivalent to HCG) within 24 hours before initiating ponatinib treatment
• Female subjects who are not breastfeeding

Exclusion Criteria:

• Patients who were previously treated with ponatinib
• Patients aged below 18 years of age
• Diagnosis of severe comorbidity at baseline
• Any other cancers within 3 years

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CML patients failed to TKIs except Ponatinib; The study will involve 100 patients with BCR-ABL1-positive CML who failed to prior targeted therapy other than ponatinib. Patients receiving ponatinib 45 mg once daily as a second-line or later therapy will be enrolled.	Drug: Ponatinib; Ponatinib treatment will be initiated per usual treatment procedure at 45 mg once daily p.o., which will be gradually decreased to 30 mg and 15 mg according to the predefined criteria based on responsiveness to treatment and AEs in the course of the treatment.; Other Names: Iclusig

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dynamics of BCR-ABL1 gene expression by qRT-PCR	To explore the dynamics of BCR-ABL1 kinetics by Ponatinib	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Type and frequency of novel genetic variations (mutations, gene expressions, CNV, INDEL, etc.)	To explore the dynamics of various genetic variations in Ponatinib failed patients	24 months
Cobll1/GCA/novel gene network identification: functional tests using Western blot/Knock-down assay	To identify novel genetic networks in Ponatinib failed patients	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and severity of skin rash, fever, hypertension, pancreatitis and vascular events as common adverse events and Frequency and severity of rare adverse events	To explore the dynamics of adverse events according to dose changes up to 24 months	24 months

Collaborators and Investigators

• Sponsor: Dong-Wook Kim
• Collaborators: Takeda; Ulsan National Institute of Science and Technology
• Investigators: Principal Investigator: Dong-Wook Kim, MD, PhD, Eulji University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): August 31, 2024
• Study Completion (Actual): September 25, 2024

Study Registration Dates

• First Submitted: April 18, 2025
• First Submitted That Met QC Criteria: April 18, 2025
• First Posted (Actual): April 25, 2025

Study Record Updates

• Last Update Posted (Actual): April 25, 2025
• Last Update Submitted That Met QC Criteria: April 18, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: tyrosine kinase inhibitor; next generation sequencing; resistance; intolerance; ponatinib; genetic variation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Ponatinib
• Other Study ID Numbers: KC20MISI0507

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes