PRIMARY OBJECTIVE:~I. To determine the maximum tolerated dose (MTD) of tomivosertib in combination with azacitidine and venetoclax (dose limiting toxicities [DLTs] to be evaluated by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 criteria).~SECONDARY OBJECTIVES:~I. To assess the adverse event profile of tomivosertib, azacitidine, and venetoclax.~II. To estimate the rate of complete remission (CR). III. To estimate the rate of overall response. IV. To estimate the duration of response (DOR). V. To estimate progression free survival (PFS). VI. To estimate overall survival (OS). VII. To assess the outcomes for patients who undergo allogeneic hematopoietic stem cell transplant (HSCT).~EXPLORATORY OBJECTIVES:~I. To measure eIF4E phosphorylation before treatment and correlate with treatment response.~II. To measure MCL1 expression before and after treatment and correlate with treatment response.~III. To assess the steady-state pharmacokinetics of tomivosertib when it is combined with azacitidine, and venetoclax.~OUTLINE: This is a dose finding study of tomivosertib followed by a dose expansion study.~Patients receive tomivosertib orally (PO), azacitidine subcutaneously (SC) or intravenously (IV), and venetoclax PO while on study. Patients undergo bone marrow biopsy and/or aspirate throughout the study and blood sample collection at baseline and on study.
This phase I/Ib trial tests the safety, side effects, and best dose of tomivosertib in combination with the standard treatment of azacitidine and venetoclax for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable for intensive chemotherapy. Tomivosertib may stop the growth of cancer cells and may kill them 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 them, 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. Giving tomivosertib with azacitide and venetoclax may kill more cancer cells in patients with newly diagnosed AML who are not suitable for intensive chemotherapy.