An Open-Label, Single-Arm, Phase 1/2 Study Evaluating the Safety and Efficacy of Ponatinib for the Treatment of Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors in Pediatric Participants
Overview
- Phase
- Phase 1
- Intervention
- Ponatinib
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Incyte Biosciences International Sàrl
- Enrollment
- 70
- Locations
- 48
- Primary Endpoint
- Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)
- Status
- Recruiting
- Last Updated
- 16 days ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 to < 18 years with advanced leukemias, lymphomas, and solid tumors.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed diagnosis of the following malignancies:
- •\- Phase 1: CP-CML, BP-CML, AP-CML ALL. AML. Other leukemias. Lymphoma. Any other tumors, including tumors of the CNS, for which standard therapy is not available or is not indicated.
- •\- Phase 2, Group A with CP-CML: CP-CML at the time of study entry and must be resistant to or intolerant of at least 1 prior BCR-ABL-targeted TKI therapy or be in "warning" response status or have the T315I kinase domain mutation.
- •Must have 1 bone marrow aspirate with documentation of BCR-ABL translocation by conventional cytogenetics, metaphase FISH, or q-PCR performed within 42 days before the first dose of ponatinib.
- •\- Phase 2, Group B with other leukemias or solid tumors: ALL. AML. Other leukemias. Lymphoma. Any other tumors, including tumors of the CNS, with mutations of RET, FLT3, KIT, FGFR, PDGFR, TIE2, VEGFR, or any other mutations where ponatinib may have biological activity (eg, EPH receptors and SRC families of kinases) as assessed on fresh or archived tumor tissue.
- •Participants with solid tumors or with lymphoma must have measurable disease by CT or MRI based on RECIST v1.1 or the Lugano lymphoma guidelines as determined by site radiology.
- •Prior therapies as follows:
- •\- Phase 1: Participants with CML who are resistant to or intolerant of (as defined Appendix F) to at least 1 prior BCR-ABL-targeted TKI therapy.
- •Participants with ALL who have progressed on or after all available or indicated therapies, which may have included 1 prior BCR-ABL-targeted TKI therapy.
- •Participants with AML or other leukemias who have progressed on or after at least 1 prior induction attempt (for France only) or for whom no effective standard therapy is available or indicated (other countries).
Exclusion Criteria
- Not provided
Arms & Interventions
Ponatinib
Phase 1: Ponatinib administered according to age-based cohort doses and formulations to determine the maximum tolerated dose and recommended Phase 2 dose. Phase 2: Ponatinib administered at the recommended Phase 2 dose.
Intervention: Ponatinib
Outcomes
Primary Outcomes
Phase 2: Efficacy of ponatinib assessed by major cytogenetic response (MCyR) in participants with chronic-phase chronic myeloid leukemia (CP-CML)
Time Frame: 12 months
Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) as assessed by conventional cytogenetics or fluorescence in situ hybridization (FISH).
Phase 2: Efficacy of ponatinib assessed by CR in participants with lymphoma
Time Frame: 6 months
According to Lugano criteria based on computed tomography (CT) or magnetic resonance imaging (MRI) (or positron emission tomography \[PET\]).
Phase 1: Number of dose-limiting toxicities
Time Frame: 28 days
Defined as the occurrence of any protocol-defined toxicities occurring after dosing and up to and including Day 28, except those toxicities with a clear alternative explanation.
Phase 2: Efficacy of ponatinib assessed by major hematologic response (MaHR) or major molecular response (MMR) in participants with BCR-ABL-positive leukemias
Time Frame: 3 months
Assessed by polymerase chain reaction (PCR).
Phase 2: Efficacy of ponatinib assessed by complete response (CR) in participants with leukemias other than BCR-ABL-positive leukemias to determine the efficacy of ponatinib
Time Frame: 6 months
Phase 2: Efficacy of ponatinib assessed by incomplete complete response (iCR) in participants with leukemias other than BCR-ABL-positive leukemias
Time Frame: 6 months
Assessed by conventional cytogenetics, FISH, or PCR.
Phase 2: Efficacy of ponatinib assessed by overall response rate in participants with solid tumors
Time Frame: 6 months
Defined as the percentage of participants having CR or PR, as determined by investigator assessment of radiographic disease per tumors per RANO for central nervous system (CNS) tumors or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for other solid tumors based on CT or MRI (or PET).
Secondary Outcomes
- Phase 2: Anticancer activity of ponatinib assessed by MaHR or MMR in participants with BCR-ABL-positive leukemias (AP-CML, BP-CML or Ph+ALL)(3 months)
- Phase 2: Anticancer activity of ponatinib assessed by CRi in participants with leukemias other than BCR-ABL-positive leukemias.(6 months)
- Phase 1: t½ of ponatinib(6 months)
- Phase 1: Vz/F of ponatinib(6 months)
- Phase 1 and Phase 2: Duration of response (DOR) in participants with CP-CML(6 months)
- Phase 1: CR in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML.(6 months)
- Phase 1: CR in participants with lymphoma(6 months)
- Phase 1: Overall response rate in participants with solid tumors(6 months)
- Phase 1: Tmax of ponatinib(6 months)
- Phase 1: MCyR in participants with BCR-ABL-positive leukemias(3 months)
- Phase 1 and Phase 2: CCyR in participants with CP-CML(12 months)
- Phase 2: Anticancer activity of ponatinib assessed by overall response rate in participants with solid tumors(6 months)
- Phase 2: PFS in participants with solid tumors(6 months)
- Phase 1: CLss/F of ponatinib(6 months)
- Phase 1: MMR in participants with BCR-ABL-positive leukemias(3 months)
- Phase 1 and Phase 2: Complete hematologic response (CHR) in participants with CP-CML(6 months)
- Phase 1 and Phase 2: MMR in participants with CP-CML(12 months)
- Phase 1 and Phase 2: Time to response (TTR) in participants with CP-CML(6 months)
- Phase 1 and Phase 2: Overall survival (OS) in participants with CP-CML(6 months)
- Phase 1: CRi in participants with leukemias other than BCR-ABL-positive leukemia or CP-CML(6 months)
- Phase 2: OS in participants with solid tumors(6 months)
- Phase 1: Number of treatment-emergent adverse events(6 months)
- Phase 1: AUCss,0-24 of ponatinib(6 months)
- Phase 1 and Phase 2: Progression-free survival (PFS) in participants with CP-CML(6 months)
- Phase 2: Anticancer activity of ponatinib assessed by CR in participants with leukemias other than BCR-ABL-positive leukemias(6 months)
- Phase 2: Anticancer activity of ponatinib assessed by CR in participants with lymphoma(6 months)
- Phase 2: DOR in participants with solid tumors(6 months)
- Phase 2: Number of treatment-emergent adverse events(6 months)
- Phase 2: Clearance of pediatric-friendly formulation of ponatinib(6 months)
- Phase 2: Volume of distribution of pediatric-friendly formulation of ponatinib(6 months)
- Phase 2: AUC of pediatric-friendly formulation of ponatinib(6 months)