Evaluation of Ponatinib in Pediatric Patients with Recurrent or Refractory Leukemias, Lymphomas, and Solid Tumors: A Phase 1/2 Open-Label Study

The primary objective of this study is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral ponatinib administered once daily in pediatric participants with selected advanced hematologic malignancies or solid tumors. This is clinically relevant as it aims to establish a safe and effective dosage for children, which is crucial for optimizing therapeutic outcomes and minimizing adverse effects.

Secondary objectives include: - Phase 1 Dose Escalation: To examine the safety and tolerability of ponatinib in pediatric participants with selected advanced hematologic malignancies or solid tumors, and to evaluate preliminary anticancer activity. - Phase 2 Expansion Group A (Chronic Phase Chronic Myeloid Leukemia, CP-CML): To determine the antileukemia activity of ponatinib in participants with CP-CML and to assess cytogenetic and molecular response. - Group B (Other Tumors): To determine the anticancer activity of ponatinib in pediatric participants with selected advanced hematologic malignancies or solid tumors. - Evaluation of prior therapies: Participants with CML who are resistant or intolerant to at least one prior BCR-ABL–targeted TKI therapy, and participants with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or other leukemias who have progressed on or after available therapies. This includes participants with solid tumors or lymphomas who have progressed despite standard therapy or for whom no effective standard therapy is available.

The clinical trial involves a total of 10 participants diagnosed with recurrent or refractory leukemias, lymphomas, and solid tumors. The study population includes both male and female pediatric participants aged 1 to less than 18 years. Participants were selected based on their diagnosis of advanced hematologic malignancies or solid tumors, with a focus on those who are resistant or intolerant to prior therapies. The trial includes individuals with a Karnofsky performance status of at least 40% for those aged 16 and older, or a Lansky Play Scale of at least 40% for those under 16. Participants must have recovered from any non-hematologic toxicities to less than Grade 2, except for alopecia, as per the NCI CTCAE v5.0. The trial population is considered vulnerable, and participants must have a parent or legal guardian able to provide informed consent. Both male and female participants are required to take appropriate precautions to avoid pregnancy or fathering children during and after the study period. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed as an open-label, single-arm, Phase 1/2 study to evaluate the safety and efficacy of ponatinib in pediatric participants with recurrent or refractory leukemias, lymphomas, and solid tumors. The trial is structured into two phases: Phase 1 involves dose escalation to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral ponatinib administered once daily (QD). Phase 2 is an expansion phase divided into two groups: Group A focuses on chronic phase chronic myeloid leukemia (CP-CML) participants who are resistant or intolerant to at least one prior BCR-ABL–targeted tyrosine kinase inhibitor (TKI) therapy or have the T315I mutation, while Group B includes participants with other selected advanced hematologic malignancies or solid tumors.

The trial is expected to last until May 2025, with recruitment having started in December 2019. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histologically or cytologically confirmed diagnoses and prior therapy history. Follow-up visits will be conducted to monitor safety, efficacy, and pharmacokinetics, with assessments including determination of dose-limiting toxicities (DLTs) during the first 28 days of treatment in Phase 1, and various efficacy endpoints such as major cytogenetic response (MCyR) and overall response rate (ORR) in Phase 2. The end-of-study visit will conclude the participant's involvement, which is anticipated to last until the study's completion or until early termination criteria are met.

Participant involvement is expected to last for the duration of the trial unless early termination is warranted. Conditions for early termination include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. The trial's methodology ensures rigorous monitoring and assessment to maintain participant safety and data integrity throughout the study.

The clinical trial involves the administration of Ponatinib, a kinase inhibitor, in various pharmaceutical forms. The primary experimental medication is Iclusig, available in film-coated tablets of 15 mg, 30 mg, and 45 mg dosages. These tablets are administered orally. The active substance in Iclusig is Ponatinib, a chemical compound also known by synonyms such as AP-24534 and Benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-. The medication is produced by Incyte Biosciences Distribution B.V. and is authorized for use in the European Union. The administration frequency is once daily (QD), and the trial aims to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) in pediatric participants with selected advanced hematologic malignancies or solid tumors.

In addition to the film-coated tablets, Ponatinib is also available in capsule form and as mini-tabs in capsules, both of which are administered orally. These formulations are specifically designed for pediatric use and are produced by Incyte Biosciences International Sàrl. The trial includes a phase 1 dose escalation to establish the MTD and/or RP2D, followed by a phase 2 expansion to evaluate efficacy in pediatric participants with chronic phase chronic myeloid leukemia (CP-CML) resistant or intolerant to prior BCR-ABL–targeted TKI therapy or with the T315I mutation, as well as in those with other selected advanced hematologic malignancies or solid tumors.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure accurate assessment of the medication's safety and efficacy. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The labels of the medications have been adapted to fit the clinical purpose, ensuring clarity and compliance with trial protocols.

The efficacy of ponatinib in the clinical trial will be assessed through a series of primary and secondary endpoints. For Phase 1, the primary endpoint involves the determination of dose-limiting toxicities (DLTs) during the first 28 days of treatment. In Phase 2, Group A (chronic phase chronic myeloid leukemia, CP-CML), the primary endpoint is the major cytogenetic response (MCyR), defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) by 12 months, assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH). For Group B (other tumors), the primary endpoints include major hematologic response (MaHR) or major molecular response (MMR) for BCR-ABL–positive leukemias, complete remission (CR) or CR with incomplete hematologic recovery (CRi) for other leukemias, and CR for lymphoma according to the Lugano criteria. For solid tumors, the overall response rate (ORR) is defined as the percentage of participants achieving CR or partial response (PR) as determined by investigator assessment using RECIST v1.1 or RANO criteria based on CT or MRI.

Secondary endpoints for Phase 1 include the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), changes in vital signs, clinical evaluations, and clinical laboratory blood samples, as well as pharmacokinetic parameters such as Tmax, AUCss,0-24, t½, CLss/F, and Vz/F. In Phase 2, Group A, secondary endpoints include complete hematologic response (CHR) at 6 months, CCyR and MMR at 12 months, time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). For Group B, secondary endpoints for hematologic malignancies include MaHR or MMR by 3 months for BCR-ABL–positive leukemias, CR or CRi for other leukemias, and CR for lymphoma. For solid tumors, secondary endpoints include ORR, OS, DOR, and PFS. These efficacy parameters will be measured and analyzed using validated scales and laboratory tests at specified timepoints throughout the trial.