This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. . Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.
Additional locations may be listed on ClinicalTrials.gov for NCT04140487.
Locations matching your search criteria
United States
Texas
Houston
M D Anderson Cancer CenterStatus: Active
Contact: Nicholas Short
Phone: 713-563-4485
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) of the combination of azacitidine, venetoclax and gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML) or high-risk myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). (Phase I)
II. To determine the complete remission/complete remission with incomplete count recovery (CR/CRi) rate of the regimen in patients with newly diagnosed or relapsed/refractory FLT3-mutated AML or CMML or high-risk MDS/MPN and in FLT3 wild type AML. (Phase II)
SECONDARY OBJECTIVES:
I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, overall survival).
II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).
III. To determine the safety of the combination regimen.
EXPLORATORY OBJECTIVES:
I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.
II. To determine the impact of baseline FLT3 allelic ratio on response and survival.
III. To evaluate clonal evolution from diagnosis to relapse using single-cell sequencing.
OUTLINE: This is phase I, dose-escalation study of gilteritinib followed by a phase II study.
Patients are assigned to 1 of 4 arms.
ARM I: Patients with newly diagnosed FLT3-mutated AML receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on days 1-7 of cycle 1 and days 1-5 of subsequent cycles, venetoclax orally (PO) once daily (QD) on days 3-28 of cycle 1 and on days 1-7 of subsequent cycles, and gilteritinib PO QD on days 1-28 of each cycle. Treatment of azacitidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients with relapsed/refractory FLT3-mutated AML or CMML or higher-risk MDS/MPN receive azacitidine SC or IV over 30-60 minutes on days 1-7 of cycle 1 and days 1-5 of subsequent cycles, venetoclax PO QD on days 3-28 of cycle 1 and on days 1-7 of subsequent cycles, and gilteritinib PO QD on days 1-28 of each cycle. Treatment of azacitidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM III: Patients with adverse-risk FLT3 wild type AML who are suitable for allogeneic HSCT receive azacitidine SC or IV over 30-60 minutes on days 1-7 of each cycle, venetoclax PO QD on days 3-28 of cycle 1 and on days 1-7 of subsequent cycles, and gilteritinib PO QD on days 1-14 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
ARM IV: Patients with adverse-risk FLT3 wild type AML who are unsuitable for allogeneic HSCT receive azacitidine SC or IV over 30-60 minutes on days 1-7 of each cycle, venetoclax PO QD on days 3-28 of cycle 1 and on days 1-7 of subsequent cycles, and gilteritinib PO QD on days 1-14 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo blood collection, bone marrow aspirate and biopsy throughout the study and echocardiogram (ECHO) or multigated acquisition scan (MUGA) at baseline.
After completion of study treatment, patients are followed up at 30 days and then every 6 months until death.
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorNicholas Short
