TP-0903 for the Treatment of FLT3 Mutated Acute Myeloid Leukemia

PRIMARY OBJECTIVES: I. To determine a tolerable dose of dubermatinib (TP-0903) monotherapy for relapsed/refractory patients with FLT3 acute myeloid leukemia (AML). II. To determine the maximum tolerated dose (MTD) of TP-0903 with azacitidine in untreated unfit patients with FLT3 AML. III. To determine the complete remission (CR) or complete remission with partial hematologic recovery (CRh) rate following induction therapy with TP-0903 in relapsed/refractory patients or TP-0903 with azacitidine therapy in untreated unfit patients with FLT3 AML. SECONDARY OBJECTIVES: I. To determine the toxicity profile of TP-0903 as a single agent and in combination with or azacitidine. II. To determine disease-free survival for patients achieving CR/CRh in each cohort. III. To determine overall survival for patients in each cohort. IV. To determine the proportion of patients who go to transplant. EXPLORATORY OBJECTIVES: I. To conduct pharmacokinetic studies of TP-0903 alone and in combination with azacitidine. II. To examine changes in circulating AXL, Gas6, FLT3 ligand, and other cytokines/chemokines by TP-0903. III. To determine the impact of TP-0903 on the inhibition of kinase signaling (AXL, FLT3, STAT5, AURKA), and metabolomics in AML cells. IV. To determine differentially expressed genes in bone marrow stromal cells and AML cells upon TP-0903 treatment. V. To examine sensitivity and resistance patterns associated with TP-0903 by genomic, epigenomic, and transcriptomic profiling. OUTLINE: This is a phase Ib, dose-escalation study of dubermatinib followed by a phase II study. (FLT3 AML WITH RELAPSED/REFRACTORY DISEASE): INDUCTION: Patients receive dubermatinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients with clinical or hematologic response and not transplant eligible may continue dubermatinib until loss of response/clinical benefit. Patients with clinical or hematologic response and transplant eligible may continue dubermatinib until one week prior to admission. After completion of study treatment, patients are followed up followed every 3 months for up to 2 years from registration and then every 6 months for up to 5 years from registration.