Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia

This phase Ib/II trial studies the side effects and best dose of venetoclax in combination with quizartinib and how well they work in treating patients with acute myeloid leukemia that has come back or does not respond to treatment, and who are FLT3-mutation positive. Venetoclax and quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the combination of venetoclax with quizartinib in FLT3-internal tandem duplication (ITD) mutated patients with relapsed/refractory acute myeloid leukemia (AML). (Phase Ib) II. To determine the composite complete remission (CR) (CRc) rate including CR + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) SECONDARY OBJECTIVES: I. To determine the composite CRc rate including CR + CRp + CRi within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) II. To determine the overall response rate (ORR) including CRc + partial remission (PR) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) III. To determine the duration of response (DOR), progression free survival, event-free survival (EFS), overall survival (OS), and number of patients bridged to hematopoietic stem cell transplant (HSCT) and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) IV. To characterize the pharmacokinetic (PK) profiles of combination therapy of venetoclax and quizartinib in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) V. To determine the ORR within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase II) VI. To determine the DOR, progression-free survival (PFS), EFS, OS, and number of patients bridged to HSCT and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) VII. To determine the safety and tolerability of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) EXPLORATORY OBJECTIVES: I. To investigate possible relationships between baseline next generation gene sequencing and clinical response to the combination. II. To investigate quantitative changes of FLT3-ITD allelic burden with time and the extent of pharmacodynamics biomarker (such as phosphorylated \[p\]-FLT3, p-ribosomal protein S6 kinase beta-1 \[p70S6K\], pERK, pSTAT) inhibition, and the induction of apoptosis in the bone marrow and peripheral blasts in patients treated with the combination. III. To investigate possible relationships between baseline gene expression signatures, Bcl-2 family messenger ribonucleic acid (mRNA) and protein levels of AML blasts and/or stem cell sub-population, BH3 profiling of Bcl-2 family member dependency and ex vivo functional screen and clinical response to the combination. IV. To analyze immune modulation including alterations in total and percent of CD3+ T-cells, total and percent of various T-cell subsets (CD4-effector, CD4-regs, CD8 cytotoxic T-cells), and total and percent of T-cell/T-cell subsets expressing specific checkpoint receptors/ligands with the combination. V. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into molecular and immune factors that may influence response to venetoclax and/or quizartinib (where response is defined broadly to include efficacy, tolerability or safety). OUTLINE: This is a phase Ib dose-escalation study of quizartinib, followed by a phase II study. Patients receive quizartinib orally (PO) once daily (QD) on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician. After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.