FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia

This is a Phase 1, uncontrolled, single-arm, open-label, nonrandomized, dose escalation, study of Decitabine (DAC)+Venetoclax (VEN)+FHD-286 in participants with newly diagnosed Acute Myeloid Leukemia (AML) classified as adverse risk per the 2022 European Leukemia Net (ELN) criteria or AML that has progressed after one prior line of therapy.

This study evaluates the addition of FHD-286, which has a distinct mechanism of action and clinical activity in AML, to a modification of the current standard of care regimen (DAC/VEN) that has been shown to be more tolerable than and have similar clinical activity as the more intensive regimen evaluated in the VIALE-A study (see References section). Total duration of trial intervention for each participant will vary. Participants are anticipated to remain on treatment for at least 12 weeks (induction period). As long as they are receiving benefit from treatment, participants may remain on treatment until they experience a reason for treatment discontinuation or study withdrawal. Participants may remain on study as long as they are receiving DAC and VEN, even if FHD-286 is on hold or discontinued due to toxicity. After written informed consent is obtained from a participant, they will undergo screening evaluations within 28 days before the first dose of study treatment. Results from assessments conducted within 28 days before the first dose of study treatment may be used to fulfill screening requirements, even if they occurred before written informed consent was obtained. The first 3 to 6 participants will participate in the safety run-in portion of the study. During this portion, if ≥3 of the participants develop AEs meeting the stopping criterion during the DLT evaluation period, the study will be terminated. Thereafter, interim safety analyses will be conducted after the enrollment of every 3 participants. The first 12 weeks of treatment (cycles 1-3) are an induction period intended to produce a relatively rapid reduction in tumor burden, to a level that will permit more functional hematopoiesis, alleviating cytopenias and permitting bone marrow recovery. During the induction period, dose modifications and holds are discouraged, except in the case of severe toxicity from severe, non-hematologic adverse events. Additionally, if treatment-related myelosuppression is suspected, dose holds or reductions may be implemented, upon agreement with the principal investigator (PI). If the participant is receiving clinical benefit (at minimum, stable disease) after 12 weeks of treatment, they will have the option of continuing their treatment regimen during the long-term treatment period. The goal of the long-term treatment period is to continue to provide clinical benefit via disease control and hematopoietic improvement. Each participant may continue treatment until they experience a reason for treatment discontinuation. Upon discontinuation of treatment, each participant will be asked to undergo an end-of-treatment evaluation. Thirty days after discontinuation of study treatment, each participant will be asked to undergo a safety follow-up evaluation. Participants will then be contacted approximately every 2 months for long-term follow-up to assess survival status, receipt and type of subsequent anticancer therapy, and disease status. Dose-limiting toxicities will be assessed during the first cycle (first 28 days) of treatment.