ALL-167: A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Relapsed, Resistant, or Intolerant Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) or Have the T315I Mutation

Abstract

<h3>Context:</h3> Ph+ ALL is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) for newly diagnosed patients of 60% and 86%, respectively. Ponatinib is a third-generation TKI active against <i>BCR-ABL1</i> and all identified single-mutation variants and is the only TKI active against the T315I mutation. Ponatinib has approvals for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia, Ph+ ALL resistant/intolerant to other TKIs, or have the T315I mutation. <h3>Objective:</h3> Determine the recommended phase 2 dose (RP2D) and assess pharmacokinetics, safety, and efficacy of ponatinib in combination with chemotherapy in pediatric patients with relapsed or resistant Ph+ ALL or with the T315I mutation. <h3>Methods:</h3> This phase 1/2, single-arm, open-label, multicenter study will enroll patients into phase 1 with 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 enroll to assess the age-appropriate mini-tablet formulation (AAF) at the RP2D. Phase 2 will enroll ≈68 patients, including those in phase 1, at the RP2D. Patients (aged ≥1–21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with targetable ABL-class kinase-activating lesions must have relapsed or be resistant/intolerant to ≥1 prior therapy with a <i>BCR-ABL1</i>-targeted or ABL-class TKI or have a <i>BCR-ABL1</i> T315I mutation. In phase 1, the primary endpoint is the RP2D of ponatinib with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of <i>BCR-ABL1</i> domain mutations before and after ponatinib treatment. In phase 2, the primary endpoint is 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, proportion with minimal residual disease-negative status <0.01% at the end of each treatment block, proportion who relapsed/progressed, and time-to-event estimates (EFS, progression-free survival, OS). The study will include ≈70 study sites in ≈16 countries; initial sites are open to enrollment. PONATINIB-1501 is sponsored by Takeda Development Center Americas, Inc.