This phase IB/II trial studies the best dose of TP-0903 and how well it works when given alone or with azacitidine in treating patients with FLT3 gene mutated acute myeloid leukemia. TP-0903 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TP-0903 alone or with azacitidine may kill more cancer cells.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
3
Given IV
Given PO
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Maximum tolerated dose of dubermatinib (TP-0903)
Determine a tolerable dose of TP-0903 monotherapy for relapsed/refractory patients with FLT3 AML.
Time frame: Up to 28 days
Composite complete response (CR) rate
Will calculate the composite CR rate (complete remission \[CR\]/complete remission with incomplete count recovery \[CRh) defined according to the 2017 European LeukemiaNet Acute Myeloid Leukemia recommendation.
Time frame: Up to 5 years post registration
Composite CR rate with partial hematologic recovery (CRh) rate
Will calculate the composite CR rate (CR/CRh), defined according to the International Working Group criteria and assessed at the end of induction.
Time frame: through study completion, an average of 1 year
Disease-free survival
Will be summarized by the Kaplan-Meier method to determine disease-free survival for patients achieving complete response CR/CRh in each cohort of the study.
Time frame: From the date of first CR/CRh until the first date of relapse/progression or death from any cause, assessed up to 5 years post registration
The Number of patients who proceed to transplant
The number of patients who got to transplant
Time frame: Up to 5 years post registration
Overall survival
Will be summarized by the Kaplan-Meier method.
Time frame: From the treatment start date until the date of death from any cause or date last known alive, assessed up to 5 years post registration
Maximum grade of each type of adverse event
Will be recorded for each patient and summarized.
Time frame: Up to 5 years post registration
Incidence of treatment-related adverse events
Treatment-related adverse events, defined as possibly, probably or definitely related to study treatment per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be summarized separately.
Time frame: Up to 5 years post registration
Tolerability of TP-0903
Reasons for treatment discontinuation and number of TP-0903 cycles received will be summarized and used to assess tolerability.
Time frame: Up to 5 years post registration
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