Work

Pb1763: 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

Year: 2022

Type: article

Abstract: Background: Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy; current 5-year event-free survival (EFS) and overall survival (OS) for newly diagnosed patients (pts) are 60% and 86%, respectively. Ponatinib (PON) is a potent third-generation TKI active against BCR::ABL1 and all identified single resistance mutations, including the gatekeeper T315I mutation that confers resistance to other TKIs. PON is approved for adults with chronic/accelerated/blast-phase chronic myeloid leukemia or Ph+ ALL whose disease is resistant/intolerant to other TKIs or has the T315I mutation. Aims: This study in pediatric pts with relapsed/resistant Ph+ ALL or with the T315I mutation aims to establish the recommended Phase 2 dose (RP2D) of PON and assess the pharmacokinetics, safety, and efficacy of PON in combination with chemotherapy. Methods: This Phase 1/2, single-arm, open-label, multicenter study will enroll pts aged ≥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 BCR::ABL1–targeted TKI or has a BCR::ABL1 T315I mutation. Phase 1 has a rolling 6 design; the first cohort will include up to 12 pts (≥30 kg and able to swallow tablets) for the dose confirmation. Another cohort of 6 pts will be enrolled to assess the age-appropriate mini-tablet formulation at the RP2D. Phase 2 will enroll ≈68 pts, including those enrolled in Phase 1 at the RP2D. Pts aged >16 years must have a Karnofsky performance status of ≥50%; pts aged ≤16 years must have a Lansky Play Scale score of ≥50%. In Phase 1, the primary endpoint is the RP2D of PON 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 PON treatment. In Phase 2, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints include the proportion of pts in continued CR or who achieve CR at the end of consolidation, EFS, progression-free survival, and OS. Results: The study is currently open and enrolling pts and will include ≈70 study sites in ≈16 countries. Summary/Conclusion: This study will establish the RP2D of PON and assess pharmacokinetics, safety, and efficacy of PON in combination with chemotherapy in pediatric pts with relapsed/resistant Ph+ ALL or with T315I mutation. This abstract is an encore from the Society of Hematologic Oncology 2021 Annual Meeting.

Source: HemaSphere

DOI: 10.1097/01.hs9.0000849908.11106.d2