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A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in Combination with Azacitidine for the Treatment of TP53 Mutant Myeloid Neoplasms
The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.
Primary Objective (Phase1b): 1. To determine the safe and recommended Phase 2 dose (RP2D) of APR-246 in combination with azacitidine as determined by dose-limiting toxicities (DLTs). Primary Objective (Phase 2): 2. To determine the proportion of patients with TP53 mutant myeloid neoplasms alive at 8 months. Secondary Objectives: 3. To determine overall best response rates as measured by the international working group criteria (IWG 2006). 4. To determine if mutant TP53 variant allele frequency (VAF) or p53 protein expression predicts response to APR-246 with azacitidine. 5. To determine if p53 protein expression correlates with TP53 VAF. 6. To determine if APR-246 with azacitidine treatment leads to mutant TP53 clonal suppression. 7. To determine if TP53 clonal suppression correlates with outcomes. 8. To determine if APR-246 treatment upregulates p53 target genes. 9. To determine if APR-246 induces reactive oxygen species (ROS) production. 10. To determine the rate and time to acute myeloid leukemia (AML) transformation. 11. To determine the median overall survival (OS). 12. To determine the duration of response. 13. To determine whether recurrent genetic mutations are predictive of response.