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
Abstract
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…
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