Background: Venetoclax (Ven) with azacitidine (Aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory (R/R) setting. However, this regimen requires seven consecutive daily SQ or IV doses of Aza each month. The relative inconvenience of this, and its negative impact on quality of life, may lead to its early discontinuation, possibly decreasing the overall efficacy of this regimen. An all-oral regimen may decrease infusion center visits, and potentially increase the efficacy of the regimen due to improved compliance. CC-486 is the oral formulation of Aza that is currently approved for post-induction chemotherapy maintenance in AML. Methods: This is a single center open label, Ph 1 study investigating CC-486 and Ven in R/R AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Ven was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for the two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with Ven. An expansion cohort is planned for 10 patients treated at the MTD. Results: As of February 1, 2023, 8 patients have been accrued. The average age at the time of enrollment was 64, and median prior treatment regimens was 1 (range 1-3). Four patients had received Ven in prior treatments. In cohort 1, there were no DLT events. There have been no DLT events in 5/6 patients enrolled in cohort 2. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 7, 88%), Gr 3-4 anemia (n = 6, 75%), and Gr 3-4 thrombocytopenia (n = 4, 50%). The most common non-hematologic toxicities were Gr 1-2 nausea (n = 4, 50%), Gr 1-2 fatigue (n = 2, 25%), and Gr 1-2 diarrhea (n = 2, 25%). Best responses were complete remission (CR) (n = 2, 25%), partial remission (PR) (n = 1, 13%), and stable disease (SD) (n = 2, 25%). Three patients proceeded to an allogeneic stem cell transplant. Conclusions: CC-486 and Ven is an all-oral regimen being investigated for the treatment of R/R AML. Our Ph 1 dose escalation thus far has demonstrated a favorable safety profile for this regimen. Full Ph 1 findings and the MTD will be presented at the meeting. Responses have been seen in both dose cohorts, and patients have been bridged to hematopoietic stem cell transplant. Clinical trial information: NCT05287568.

* PD = Progressive disease.