Trial in progress: Phase I trial to evaluate safety of oral azacytidine in combination with pomalidomide as maintenance therapy in AML

Abstract Background and Significance: Despite achieving complete remission with induction therapy, approximately 60% of adults with acute myeloid leukemia (AML) relapse within two years (Jain H, JCO Glob Oncol 2025). This demands the need for maintenance strategies that are safe, effective, and feasible. Oral azacitidine has demonstrated improved relapse-free and overall survival in older, transplant-ineligible patients, establishing a role in AML maintenance (Hunault-Berger M Blood Cancer J. 2017). In resource-limited settings, delivery of high-dose cytarabine or allogeneic transplant is frequently compromised due to multidrug-resistant infections, poor performance status (PS), and lack of donors. At our center, less than 5% of eligible patients undergo stem cell transplant. Immunomodulation is a promising strategy in AML, targeting persistent Treg-mediated immunosuppression and impaired T-effector function that contribute to relapse despite chemotherapy. Pomalidomide, a potent immunomodulatory drug, enhances T-cell activation and suppresses Tregs via cereblon-mediated degradation of Ikaros (IKZF1) and Aiolos (IKZF3) (Zeidner JF, Leukemia. 2020). This trial tests the hypothesis that combining oral azacitidine with pomalidomide in the post-remission setting can safely enhance immune-mediated disease control in AML. Study design and Methods: This is an ongoing single-center, Phase I study (CTRI/2023/09/057552) at Tata Memorial Hospital, Mumbai. The study aims to determine the maximum tolerated dose (MTD) and safety profile of pomalidomide in combination with oral azacytidine in AML patients in first complete remission (CR/CRi). A priming cycle of oral azacytidine (300 mg, days 1–14 of a 28-day cycle) is administered before introducing pomalidomide. The dose escalation follows a rolling six design across six cohorts, where pomalidomide is given at escalating doses (2–4 mg) and durations (10 to 14 days), with azacytidine fixed at 300 mg. Two de-escalation cohorts with reduced azacytidine (200 mg) are predefined in case of dose limiting toxicities. Patients receive up to 2 years of therapy. Adult patients, aged ≥18 years, with confirmed AML in complete remission following induction therapy (up to 2 cycles allowed) are eligible for the study. Participants must have adequate hematologic recovery, ECOG PS 0–2, with no prior exposure to azacytidine or venetoclax. Key exclusion criteria include planned allogeneic stem cell transplantation, diagnosis of acute promyelocytic leukemia, significant cardiac disease, uncontrolled infections, severe hepatic or renal dysfunction, and pregnancy or lactation. The primary objective is to determine the MTD for the combination of oral azacytidine and pomalidomide. Secondary objectives include evaluating the safety profile of the combination, relapse-free survival, overall survival, and minimal residual disease status at 12 months. The study also includes exploratory objectives to identify predictive biomarkers through immunophenotyping, NK-cell functional assays, and analysis of gene expression in bone marrow and peripheral blood. During this trial, we encountered few challenges; reluctance among patients to enrol, primarily due to the requirement for monthly in-person visits. To address this, the protocol was amended to allow alternate monthly teleconsultations, with patients advised to consult local oncologist in case of toxicity. Furthermore, increasing frontline use of hypomethylating agents and venetoclax in patients unfit for intensive therapy, resulted in a proportion of otherwise eligible patients' ineligible, affecting accrual rate. Progress: This single-center study started accrual on February 26, 2024, at Tata Memorial Hospital, India. The planned sample size is 40 adult patients with AML. To date, six participants have been enrolled in Cohorts 1 and 2 each and three participants in Cohort 3. Participants are enrolled sequentially into each cohort to ensure safety. Dose escalation is ongoing as per protocol.