Trial in Progress: The Phase 3, Randomized, Double-Blind, Placebo-Controlled QuANTUM-Wild Study of Quizartinib in Combination With Chemotherapy and as Single-Agent Maintenance in Newly Diagnosed, FLT3-ITD–Negative Acute Myeloid Leukemia

BACKGROUND: Quizartinib (Quiz) is an oral, selective, type-II inhibitor of FMS-like tyrosine kinase 3 (FLT3), with potent binding affinity against wild-type (wt) FLT3, FLT3 internal tandem duplications (FLT3-ITDs), and several FLT3 variants with point mutations within the kinase domain. Quiz is approved in combination with chemotherapy for the treatment of FLT3-ITD–positive newly diagnosed (ND) acute myeloid leukemia (AML) based on results from the phase 3, randomized, placebo (PBO)-controlled QuANTUM-First trial (NCT02668653).

In normal human hematopoiesis, FLT3 expression is restricted to immature hematopoietic progenitors. Binding of the FLT3 ligand is followed by a conformational change, homodimerization, and subsequent activation of multiple downstream signaling pathways. FLT3 mutations 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 mutations, potentially contributing to the survival and proliferation of leukemic cells.

The clinical utility of Quiz in patients (pts) with FLT3-ITD–negative (FLT3-ITDneg) AML is supported by evidence from preclinical models and clinical trials. In a phase 1 trial, Quiz demonstrated activity as a single-agent in pts with FLT3-mutated or FLT3-wt relapsed/refractory AML; ex vivo plasma inhibitory assays showed robust suppression of FLT3 phosphorylation with Quiz in cells expressing wt FLT3. Preliminary results from the phase 2, PBO-controlled QUIWI trial that included 273 pts from the PETHEMA group showed that the addition of Quiz 60 mg/day (d) to induction and consolidation chemotherapy, followed by up to 12 months of single-agent Quiz maintenance for pts achieving complete remission (CR) or CR with incomplete count recovery (CRi), was associated with significantly prolonged overall survival (OS) in pts aged 18–70 years (y) with ND, FLT3-ITDneg AML.

QuANTUM-Wild is a global, double-blind, randomized, PBO-controlled, phase 3 confirmatory trial assessing the addition of Quiz to standard intensive induction and consolidation, followed by single-agent Quiz maintenance in pts with ND, FLT3-ITDneg AML (EU CT number, 2023-507936-20-00).

METHODS: Eligible pts are aged 18–70 y, have < 5% FLT3-ITD mutant-to-total variant allele frequency by central assessment using a validated assay, and are fit for standard intensive chemotherapy. The study consists of 3 treatment phases: induction, consolidation, and maintenance. Eligible pts are randomized 2:2:1 to receive Quiz or PBO in 3 treatment arms: Arm A) Quiz in all phases, ie, in combination with chemotherapy during induction and consolidation, and as monotherapy maintenance; Arm B) PBO during all phases; or Arm C) Quiz during induction and consolidation, then PBO during maintenance. The inclusion of Arm C allows for a PBO-controlled assessment of Quiz efficacy as monotherapy maintenance without re-randomization.

The induction phase involves the standard "7+3" regimen with cytarabine on d1–7 and an anthracycline on d1–3, then Quiz or PBO from d8–21; a second induction is allowed if bone marrow blast count is ≥ 5% after first induction. Pts who achieve CR/CRi enter the consolidation phase and receive high-dose cytarabine (HiDAC) + Quiz or PBO for 1─4 cycles, or for 1 cycle followed by allogeneic hematopoietic stem cell transplant (allo-HSCT) at investigator discretion. After consolidation with HiDAC ± allo-HSCT, eligible pts will enter the maintenance phase and receive Quiz or PBO in continuous 28d cycles for up to 36 cycles. Quiz is administered orally at 60 mg/d in all phases; pts receiving concomitant strong CYP3A inhibitors will have the study drug reduced to 30 mg.

The primary endpoint is OS, and secondary endpoints include event-free survival (EFS), relapse-free survival (RFS), CR rate and duration, rate of CR with measurable residual disease (MRD) negativity, and safety. MRD will be assessed by FLT3-ITD in all pts, and by NPM1 and CBF if these mutations are present at screening. The planned sample size is ~700 pts, with ~280 pts each in Arm A and Arm B, and ~140 pts in Arm C. The study is powered for the primary analysis of OS between Arm A and Arm B; Arm C is included for descriptive purposes only. Enrollment is expected to continue through 2028.