QuANTUM-Wild: A phase 3, randomized, double-blind, placebo-controlled trial of quizartinib in combination with chemotherapy and as single-agent maintenance in <i>FLT3</i> -ITD–negative acute myeloid leukemia (AML).

Abstract

TPS6580 Background: Quizartinib (Quiz) is an oral, selective, type-II FLT3 inhibitor with potent activity against wild-type (wt) FLT3, FLT3-ITDs, and other kinase domain variants. Quiz is approved for patients (pts) with FLT3 -ITD+ newly diagnosed (ND) AML based on results from the QuANTUM-First trial (NCT02668653). Mutations in the FLT3 gene are observed in ~30% of AML cases, most commonly as ITDs, but they are not the only mechanism affecting FLT3 activation. Elevated expression of the FLT3 receptor is observed in nearly all cases of AML, and high levels of FLT3 gene expression are detected in 70–100% of AML blasts, independent of the presence of FLT3 gene mutations, potentially contributing to leukemic cell survival and proliferation. Evidence from preclinical and clinical studies supports Quiz activity in FLT3 -ITD–negative ( FLT3 -ITDneg) AML. In the phase 2 QUIWI trial, the addition of Quiz to standard chemotherapy and as single-agent maintenance significantly prolonged overall survival (OS) vs placebo (Pbo) in ND FLT3 -ITDneg AML. QuANTUM-Wild is a global, phase 3, double-blind, Pbo-controlled trial evaluating Quiz with standard induction/consolidation chemotherapy and as maintenance in ND FLT3 -ITDneg AML (NCT06578247). Methods: Eligible pts are aged 18–70 years with FLT3 -ITD allelic frequency &lt; 5%. Treatment includes standard induction with cytarabine and an anthracycline plus Quiz/Pbo, followed by up to 4 cycles of consolidation (+/– allo-HSCT) with high-dose cytarabine and Quiz/Pbo, and then single-agent maintenance with Quiz/Pbo in 28d cycles for up to 36 cycles. Pts are randomized 2:2:1 into 3 arms: Arm A (Quiz in all phases), Arm B (Pbo in all phases), or Arm C (Quiz in induction/consolidation and Pbo in maintenance). Quiz is administered at 60 mg/day, reduced to 30 mg if combined with strong CYP3A inhibitors. The primary endpoint is OS, and secondary endpoints include event-free survival (EFS), relapse-free survival (RFS), complete remission (CR) rate and duration, measurable residual disease (by FLT3 -ITD in all pts and by NPM1 and CBF if present), and safety. Planned enrollment is ~700 pts, with 280 each in Arms A and B, and 140 pts in Arm C. The primary OS analysis compares Arms A and B, while Arm C is descriptive. Enrollment is expected to continue through 2028. © American Society of Hematology (2024). Reused with permission. Clinical trial information: 2023-507936-20-00; NCT06578247 .