A Phase 1B/2A study of weekly decitabine and venetoclax treatment as maintenance therapy in high-risk myeloid malignancy patients post allogeneic stem cell transplantation

Abstract Study Rationale. 40% of AML patients and 30% of MDS patients have relapse of disease after allogeniec hematopoietic stem cell translplant (alloSCT), which is associated with poor outcomes. Maintenance therapy strategies with low-intensity chemotherapy in the post alloSCT setting have thus far shown mixed results. A standard of care maintenance therapy for AML and MDS in the post alloSCT setting remains an unmet clinical need. Previous post alloSCT maintenance trials of hypomethylating agents with and without venetoclax have utilized doses and schedules similar to those used in the up-front treatment of these diseases and often result in adverse events, with patients missing doses or stopping therapy. We and others have found the pharmacologically optimized combination of weekly low dose weekly decitabine and venetoclax (DEC/VEN) to be efficacious with regard to control of AML and MDS with minimal hematologic toxicities. These results support the clinical investigation of weekly DEC/VEN in the post alloSCT setting for patients with AML and MDS at high risk of relapse. Design. This is an open-label, single-arm phase 1B/2A study (NCT06129734). The primary objective is to evaluate the safety and feasibility of weekly DEC/VEN as maintenance therapy for patients with AML and MDS in the post alloSCT setting. The secondary objective is to assess the efficacy of weekly DEC/VEN as post alloSCT maintenance in patients with AML and MDS by comparing rates of one-year relapse free survival in the study cohort to historical controls. Exploratory endpoints will include analyses of the pharmacodynamic effects of low dose DEC on DNMT1 protein levels in marrow and blood, of the effect of DEC/VEN on the integrated stress response (via measurement of MCL1 and BCL2 levels in marrow and blood), and on the effect of DEC/VEN on immune reconstitution post alloSCT. Eligible patients are adults (≥18 years) with adverse risk AML as defined by CIBMTR DRI or ELN 2022 criteria or high risk MDS as defined by CIBMTR DRI or IPSS-M, who have undergone alloSCT and have <5% bone marrow blasts pre-transplant (and no circulating blasts pre-transplant). Patients must have successful engraftment by day +50 post alloSCT to initiate maintenance study treatment, which may be started at any point between day +30 and day +100 post alloSCT. Patients with grade 2 or higher GVHD or active infections are not eligible for study enrollment. Patients on this trial will be treated with weekly DEC/VEN: decitabine 5 mg/m2 SC followed by a weekly dose of venetoclax 400mg PO (dose reduced for concurrent azole therapies) taken 6 hours after the decitabine. Patients will receive treatment until either one year of therapy, relapse, or recurrent DLT despite dose reduction as per protocol. The 1B portion of the study will be a safety lead-in which will enroll 9 patients. As long as no more than 2 patients experience an SAE in the 1B portion of the study, an additional 11 patients will be enrolled in the phase 2A portion of the trial, for a total of 20 patients. Using Bayesian toxicity monitoring with maximum DLT probability of 0.15, prior distribution (0.5, 0.5), maximum patients 20, minimum number of patients before stopping 6, cohort size 5, and posterior probability 0.8, the study will be paused for review if 2, 3, 4, 5 or more patients experience DLTs out of 6, 11, 16, and 20 patients, respectively. Feasibility is defined as ≥80% of patients receiving ≥80% of planned DEC/VEN doses, excluding patients withdrawn from the study because of relapse. The RFS will be estimated by Kaplan-Meier method. This trial is being open at both clinical sites of the Case Comprehensive Cancer Center, ie University Hospitals and the Cleveland Clinic. It is currently enrolling at University Hospitals and is expected to begin enrolling at the Cleveland Clinic by November 2025. The study is supported by an ASCO Conquer Cancer Young Investigator Award, a VeloSano pilot research grant, and a Case Comprehensive Cancer Center Early Phase Clinical Trial Research Support grant.