ALL-132: Ponatinib Versus Imatinib with Reduced-Intensity Chemotherapy in Patients with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia: (ALL): PhALLCON Study

Abstract

<h3>Context:</h3> Ponatinib (PON) is active against native <i>BCR-ABL1</i> and all identified single-resistance mutations, including T315I. In the PACE study, heavily pretreated patients with Ph+ ALL treated with PON had nondurable responses because of new compound mutations (Cortes 2013, 2018). Sequential use of tyrosine kinase inhibitors (TKIs) can select for T315I and compound <i>BCR-ABL1</i> mutants. Use of first-line PON in Ph+ ALL may decrease likelihood of these mutations. A Phase 2 study of PON with chemotherapy in newly diagnosed Ph+ ALL reported improved long-term outcomes (5-year event-free survival, 67%; overall survival, 71%) versus a second-generation TKI (Sasaki 2016). <h3>Objective:</h3> Compare efficacy and safety of first-line PON versus imatinib with reduced-intensity chemotherapy in patients with newly diagnosed Ph+ or <i>BCR-ABL1–</i>positive ALL (p190/p210 transcript type). <h3>Methods:</h3> PhALLCON (NCT03589326) is a Phase 3, open-label, parallel-assignment, randomized study. Patients remain on treatment until they complete study, relapse from complete remission (CR), have progressive disease, have unacceptable toxicity, withdraw consent, proceed to hematopoietic stem cell transplant (HSCT), or sponsor terminates study. The study started August 2018 and will be conducted in up to 35 countries. Currently, 115 sites are active globally. Accrual is ongoing, with 134 patients enrolled. The trial will enroll ≈230–320 patients (≥18 years) with ECOG performance status ≤2. Patients will be randomized 2:1 to PON 30 mg/d or imatinib 600 mg/d orally, with reduced-intensity chemotherapy in induction (Cycles 1–3), consolidation (Cycles 4–9), and maintenance (Cycles 10–20). Primary endpoint is measurable residual disease (MRD)-negative (<i>BCR-ABL1/ABL1</i> ≤0.01%) CR at end of induction (≈3 months). The key secondary endpoint is event-free survival, defined as dates of randomization until death (any cause), failure to achieve MRD-negative CR by end of induction, or relapse from CR. Other secondary endpoints include CR/incomplete blood count recovery rates, molecular response rates, MRD-negative CR duration, primary induction failure, overall response rate, CR duration, time to treatment failure, MR4.5 duration after induction, overall survival, and safety, including arterial occlusive/venous thromboembolic events. Other analyses include a subgroup analysis of patients with/without HSCT and an exploratory analysis by mutation status. PhALLCON is sponsored by Takeda Development Center Americas, Inc.