ALL-049 A Phase 1/2 Study to Evaluate Ponatinib With Chemotherapy in Pediatric Patients With Relapsed/Resistant/Intolerant Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or With T315I Mutation.

OBJECTIVES: Ponatinib, a potent third-generation tyrosine kinase inhibitor (TKI), is approved for adults with chronic/accelerated/blast-phase chronic myeloid leukemia or Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) whose disease is resistant/intolerant to other TKIs or has the T315I mutation. This study in pediatric patients with relapsed/resistant/intolerant Ph+ ALL or those with the T315I mutation aims to establish the recommended Phase 2 dose (RP2D) of ponatinib and assess the pharmacokinetics, safety, and efficacy of ponatinib in combination with chemotherapy.

METHODS: This Phase 1/2, single-arm, open-label, multicenter study is enrolling patients age ≥1-21 years with Ph+ ALL, Ph+ mixed-phenotype acute leukemia, or Ph-like ALL (United States only) who have a targetable kinase-activating lesion and whose disease has relapsed or is resistant/intolerant to ≥1 prior therapy with a second-generation BCR::ABL1-targeted TKI or has a BCR::ABL1 T315I mutation. Phase 1 uses a rolling 6 design; the first cohort will include up to 12 patients (≥30 kg and able to swallow tablets) for dose confirmation. Another cohort of 6 patients will be enrolled to assess the age-appropriate mini-tablet formulation at the RP2D. Phase 2 will enroll ≈68 patients, including those enrolled in Phase 1 at the RP2D. Patients must have an age-appropriate (Lansky or Karnofsky) Performance Scale score of ≥50%. In Phase 1, the primary endpoint is the RP2D of ponatinib in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR::ABL1 domain mutations before and after ponatinib treatment. In Phase 2, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints include the proportion of patients in continued CR or who achieve CR at the end of consolidation, event-free survival (EFS), progression-free survival, and overall survival.

CONCLUSIONS: The study is currently open and enrolling patients and includes ≈70 study sites in ≈16 countries.