Acute Myeloid Leukemia Clinical Trial
Official title:
A Phase 1B Study of KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Acute Myeloid Leukemia
This phase Ib trial studies the side effects and best dose of navtemadlin when given together with decitabine and venetoclax in treating patients with acute myeloid leukemia that has come back after a period of improvement (recurrent), does not respond to treatment (refractory), or is newly diagnosed. Navtemadlin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as decitabine, 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. Giving navtemadlin, decitabine, and venetoclax together may work better than decitabine alone in treating patients with acute myeloid leukemia.
PRIMARY OBJECTIVE: I. To evaluate the toxicities of navtemadlin (KRT-232 [AMG-232]) in combination with decitabine (20 mg/m^2 for 10 days), and venetoclax, and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG-232) in combination with a standard dose of decitabine and venetoclax. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetic (PK) profiles of KRT-232 (AMG-232), venetoclax, and decitabine when used in combination. II. To evaluate p53 signaling induced by KRT-232 (AMG-232), venetoclax, and decitabine as measured by MIC-1 induction. III. To correlate KRT-232 (AMG-232), venetoclax and decitabine exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling). EXPLORATORY OBJECTIVES: I. To evaluate the response rate (RR) and progression free survival (PFS) of KRT-232 (AMG-232), venetoclax, and decitabine in acute myeloid leukemia (AML). II. To evaluate potential predictive biomarkers of response to KRT-232 (AMG-232), venetoclax, and decitabine in AML. III. To evaluate the pharmacodynamic (PD) effects of KRT-232 (AMG-232), venetoclax and decitabine in AML blasts. IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships. OUTLINE: This is a dose-escalation study of navtemadlin. Patients receive decitabine intravenously (IV) over 1 hour on days 1-10, navtemadlin orally (PO) once daily (QD) on days 1-7, and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 4 cycles in patients with evidence of persistent AML. Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5, navtemadlin PO QD on days 1-7, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy, and blood sample collection throughout the trial. After completion of study treatment, patients are followed up for 30 days. ;
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