Phase 1, open-label, multi-center trial of RPT1G in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic syndromes/neoplasms.

TPS6601 Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in the NAD salvage pathway, regulates cellular energy metabolism and is overexpressed in blood cancers. Because cancer cells depend on elevated NAD-flux, they are highly sensitive to NAMPT inhibition. Since normal cells also require NAD for survival, prior clinical trials of complete NAMPT inhibitors lead to dose-limiting toxicities. We developed RPT1G, a novel hyperbolic inhibitor with an improved therapeutic window that enables therapeutically effective NAD depletion in malignant cells while sparing normal tissues (Crimmins, ASH 2023). A first-in-human, Phase 1, randomized, double-blind, placebo-controlled, SAD and MAD study in healthy volunteers of RPT1G showed that oral administration of RPT1G is safe and well-tolerated with a favorable pharmacokinetics (PK) profile. Target engagement results showed that RPT1G inhibits NAMPT at doses predicted to be therapeutically relevant. Methods: RPT1G is being investigated in a Phase 1, multi-center, open-label clinical trial (NCT07107126) for treatment of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS). It is the first NAMPT hyperbolic inhibitor to be studied for the treatment of R/R-AML and HR-MDS patients. With a standard 3+3 design, this study explores escalating oral doses of RPT1G, given twice daily in 28-day cycles. Other dosing schedules will be studied based on observed PK, PK/pharmacodynamic relationships, safety, and tolerability to identify the maximum tolerated dose or presumptive biologically effective dose and select the recommended phase 2 dose (RP2D). The starting dose of 120 mg BID was active in healthy adults. Primary objectives include: 1) defining safety and tolerability; 2) determining the RP2D, optimal schedule and/or BED. Key secondary objectives include: 1) evaluating PK; 2) assessing preliminary efficacy by European LeukemiaNet 2022, including overall response rate, duration of response, and hematologic improvement, and clinical benefit by transfusion independence and the International Working Group 2023 HR-MDS response criteria. Enrollment criteria: adults ≥ 18 years old, with a histological confirmation of R/R-AML (ELN 2022 criteria) or HR-MDS (International Consortium for MDS 2023 criteria) that have received appropriate standard of care therapy(s) or declined receipt of these. Adequate organ function is required. Exclusion criteria: ongoing AEs from prior therapies; received radiation < 14 days from the first RPT1G dose; known active infections; or have uncontrolled cardiac issues, or other medical comorbidities that preclude safety evaluation. Clinical trial information: NCT07107126 .