Venetoclax Added to 3+7 and Midostaurin Induction in FLT3-Mutated Acute Myeloid Leukemia Eligible for Intensive Chemotherapy

The primary objectives are to identify the maximum tolerated schedule of venetoclax in combination with standard 3+7 and midostaurin induction, and to define the recommended phase 2 schedule. The study also evaluates the proportion of participants achieving complete remission or complete remission with incomplete hematologic recovery without measurable residual disease after induction, as measured by multiparameter flow cytometry according to European Leukemia Net 2022 criteria. These objectives are clinically relevant for establishing a tolerable regimen and assessing early depth of response in FLT3-mutated acute myeloid leukemia. Secondary objectives include describing the incidence of dose-limiting toxicities, serious adverse events, and adverse events leading to treatment discontinuation during induction, consolidation, and maintenance; estimating pharmacokinetics of venetoclax, midostaurin, and midostaurin metabolites across treatment phases; and evaluating safety and tolerability of the combination regimens in induction, consolidation, and maintenance. Additional secondary outcomes assess response categories and measurable residual disease status at multiple post-treatment time points by multiparameter flow cytometry, NPM1 RT-qPCR in the co-mutated subgroup, and FLT3 next-generation sequencing in the FLT3-ITD subgroup. The study also estimates overall survival, event-free survival, relapse-free survival, cumulative incidence of relapse, including analyses that count measurable residual disease relapse as an event, and the proportion of eligible participants proceeding to hematopoietic stem cell transplantation in remission states.

The sponsor did not provide the number of participants. The trial population consisted of male and female patients aged 18 to 70 years with newly diagnosed acute myeloid leukemia and a documented FLT3 gene mutation. Participants were required to be eligible for intensive chemotherapy, have an ECOG performance status of 0 to 2, and have adequate hepatic and renal function. The population was selected from patients who met these disease-specific and clinical eligibility requirements and who provided written informed consent. Relevant lifestyle-related requirements included contraception for participants of reproductive potential, avoidance of sperm donation for male participants, avoidance of ova donation for female participants, and no breastfeeding during the study and for specified periods after the final study drug administration.

This is a Phase 1/2 integrated clinical trial in newly diagnosed Acute Myeloid Leukemia with FLT3 mutation, evaluating the addition of oral venetoclax to standard 3+7 and midostaurin induction treatment. The study aims to identify the maximum tolerated schedule and the recommended phase 2 schedule, and to assess remission outcomes and safety. The trial duration is planned from June 2026 to December 2030. Participant involvement begins with a screening visit to confirm eligibility criteria, including disease characteristics, performance status, and organ function. After enrollment, induction treatment is administered with scheduled follow-up assessments to evaluate dose-limiting toxicities, adverse events, pharmacokinetics, hematologic recovery, and response, including minimal residual disease assessment as soon as possible after recovery or up to day 56. Additional follow-up visits are planned after consolidation, transplant when applicable, and during maintenance to monitor response and safety. An end-of-study visit is performed at the end of protocol-defined treatment and follow-up. Participation is expected to continue for the full study period applicable to the assigned treatment phase. Early termination may occur because of treatment discontinuation, unacceptable toxicity, serious adverse events, disease progression or non-evaluable response, withdrawal of consent, or failure to meet protocol requirements.

The investigational treatment consisted of venetoclax, administered as a film-coated tablet by oral use. The study evaluated the addition of venetoclax to standard induction therapy with 3+7 and midostaurin in participants with FLT3-mutated acute myeloid leukemia eligible for intensive chemotherapy. The trial aimed to identify the maximum tolerated schedule of venetoclax in combination with 3+7 plus midostaurin during induction and to define the recommended phase 2 schedule.

Venetoclax was listed as the test product in the study. No dose, dosing unit, or frequency of administration was specified in the source data. No non-experimental comparator, placebo, or additional study treatment was described in the source data beyond standard 3+7 and midostaurin induction treatment. No information was provided on dosing schedule details or compliance monitoring.

Efficacy will be assessed by the proportion of participants achieving CR/CRi without MRD after induction chemotherapy with the RP2S, measured by multiparameter flow cytometry according to European Leukemia Net 2022. This assessment will be performed as soon as possible after hematological recovery or up to day 56. Additional efficacy evaluations will include the proportions of participants with CR, CRi, CRh, MLFS, PR, no response, and non-evaluable response after induction chemotherapy with the RP2S, according to ELN 2022.

Further efficacy assessments will be based on the proportion of participants with CR/CRi without MRD and CR/CRi/CRh without MRD after induction, consolidation 1, consolidation 2, consolidation 3, HSCT, and maintenance 3, 6, 9, and 12, measured by multiparameter flow cytometry according to ELN 2022 with a sensitivity at 10-4 or limit of detection. In the co-mutated NPM1 subgroup, MRD will also be measured by RT-qPCR on NPM1, and in the FLT3-ITD subgroup by NGS on FLT3. Efficacy analyses also include overall survival, event-free survival, relapse-free survival, and cumulative incidence of relapse, each defined according to ELN 2022, as well as the proportion of participants with HSCT performed in eligible patients in specified response categories.