Background and Significance: Effective treatment for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) remains an unmet need, with dismal survival outcomes and few novel agents to overcome chemotherapy-resistant disease. Epigenetic modification may mediate chemotherapy-resistant disease through the silencing of tumor suppressor genes, and these alterations can be reversed with epigenetic-modifying agents, such as DNA methyltransferase inhibitors (azacitidine and decitabine) and histone deacetylase inhibitors (vorinostat). Therefore, in T2016-003 (NCT02412475), we previously combined decitabine and vorinostat with fludarabine, cytarabine, and G-CSF (FLAG) for pediatric patients with R/R AML. We found that this regimen was well tolerated and effective, with a complete response rate of 54% and a high percentage of responders achieving measurable residual disease (MRD) negativity and proceeding to allogeneic stem cell transplantation. However, in contrast to patients with known epigenetic alterations (including KMT2A, CEBPA, IDH1/2, and NUP98 mutations) who had promising responses on this trial, patients without epigenetic lesions had inferior outcomes. We identified non-responders as being enriched with anti-apoptotic genes, providing rationale for potential susceptibility to the apoptotic-promoting BCL-2 inhibitor, venetoclax (Ven). This study investigates the safety, tolerability, and preliminary efficacy of Ven in combination with 5-azacitidine, vorinostat, and FLAG.

Study Design and Methods: This is a single-arm, multicenter, phase 1 investigator-initiated dose-escalation study (NCT05317403). Eligible patients are aged 1-25 years with AML in >/= 1st relapse, refractory to 2 or more previous induction attempts, or therapy-related AML (t-AML). Patients must be fit for standard intensive chemotherapy, and enrollment must occur at 1 of 2 treating institutions (Children's Wisconsin and Children's Minnesota). Trial expansion to additional sites in the Midwestern United States is planned to improve trial accrual and access for patients. Patients with Down syndrome and R/R AML are eligible and are included as an exploratory analysis in a separate stratum.

Ven is administered daily on days 1-14 at 2 dose levels (DL1: 240mg/m2/dose, DL2: 360mg/m2/dose) with a one-day ramp-up dose. Dose escalation decisions are guided by standard 3+3 dose escalation Phase 1 design. If a provisional recommended phase 2 dose (RP2D) is established, accrual can continue until a maximum of 16 DLT- and response evaluable patients are enrolled to evaluate secondary endpoints of response and pharmacodynamic analyses. 5-Azacitidine (75mg/m2 IV daily) and vorinostat (180mg/m2 PO daily) are given days 1-5. G-CSF starts on day 5 until neutrophil recovery. Fludarabine (30mg/m2 IV daily) and cytarabine (2 gm/m2 IV daily) are given days 6-10. Patients receiving concomitant strong CYP3A inhibitors will have Ven dosing reduced per protocol. Response is assessed by end-of-cycle bone marrow. A second cycle is allowed if patients achieve a complete/partial response or have stable disease after cycle 1. The primary endpoint for dose escalation is the occurrence of a dose-limiting toxicity (DLT) during cycle 1. Secondary endpoints include response rates as measured by morphology and flow cytometry, and to determine the event-free and overall survival at one year. Exploratory endpoints include correlative biology studies, including epigenetic profiling and BH3 testing, patient-reported outcomes, and evaluation of safety in patients with Down syndrome.

This trial is actively accruing at Children's Wisconsin and Children's Minnesota with a planned enrollment of 16 patients. To date, 8 patients have enrolled, with enrollment expected to continue through the end of 2026. ClinicalTrials.gov Identifier: NCT05317403. This study may identify a novel strategy to decrease chemotherapy resistance and improve outcomes in R/R pediatric and young adult AML.

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2025
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