A Phase II Study of Clinical Efficacy of Venetoclax in Combination with Azacitidine in Patients with Therapy Related Myelodysplastic Syndrome (t-MDS)

Background: The occurrence of therapy-related myelodysplastic syndrome (t-MDS) is a well-recognized sequelae of cytotoxic treatments for prior neoplasms, including other hematologic malignancies, sarcomas, and ovarian and testicular cancer. t-MDS accounts for 10% to 20% of newly diagnosed MDS, with a median time to development of 3 to 5 years. The prognosis of t-MDS is often poor, as the genetic abnormalities that characterize multiple subtypes can lead to rapid progression to AML and confer resistance to conventional therapies. In general, treatment with conventional anti-leukemic chemotherapy has uniformly poor outcomes, with median survivals of 8.6 months for t-MDS.In patients with high-risk t-MDS, hypomethylating treatment is associated with objective response rates (ORR) of 38% to 42%, among which only 14%-15% achieve complete remission (CR). Innovative strategies using targeted agents provide a unique opportunity to combat the dismal outcomes experienced by this t-MDS patient population. The combination of azacitidine and venetoclax has been a large area of interest in the clinical research field for the MDS and AML population. Whether the combination of azacitidine and venetoclax can similarly benefit a high-risk t-MDS population has yet to be addressed. We hypothesize that the combination therapy of azacitidine and venetoclax will result in improved outcomes for treatment-naïve t-MDS compared to azacitidine alone.

Study Design and Methods: This is a multi-center, open-label, phase II study of clinical efficacy of venetoclax in combination of azacitidine in patients with treatment-naïve t-MDS (NCT05379166) being led by The Ohio State University Comprehensive Cancer Center with active sub-site University of Texas Southwestern. Our primary endpoint is rate of complete remission.

Up to 53 participants will be enrolled to this study (Figure 1). Patients must be untreated with IPSS intermediate, high, or very high risk. Prior venetoclax is allowed if not utilized for MDS or AML. Prior transplant is allowed if received greater than 2 years prior to initiation of study treatment. Participants will receive the combination of azacitidine and venetoclax according to the recommended dosing parameter determined by Wei et al. Participants will initiate first cycle with Venetoclax 400 mg for Days 1 to 14 and Azacitidine 75 mg/m ² days 1 through 7 of each 28-day treatment cycle. Participants will continue to receive the study combination until disease progression (per 2006 International Working Group [IWG] response criteria for myelodysplasia), unacceptable toxicity, death, or discontinuation of study treatment for any other reason (e.g., withdrawal, start of an off-protocol therapy, or at the discretion of study investigator). This study is active and open accrual and has enrolled 9 patients to date (Table 1).

A sample size of 53 participants will provide 80% power to detect a CR of 30% (desired response rate) vs. 15% (poor response rate) based on Simon's 2-stage minimax design with a 5% false positive rate and accounting 10% over accrual. The trial will stop early after stage 1 if there are ≤3 CRs among 23 evaluable participants. If, after 25 additional participants are evaluated up to 4 cycles, there are ≥12 CRs among a total of 48 evaluable participants, the combination of azacitidine and venetoclax will be considered promising for t-MDS and will warrant further investigation. All eligible patients who receive at least one dose of any study drug will be considered evaluable for the primary endpoint analysis and included in the efficacy-evaluable set.