Overview

This is a single-center, open-label, exploratory study evaluating ifupinostat hydrochloride (BEBT-908) in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with MEF2D rearrangement. The study will include patients with relapsed or refractory disease and patients who are in morphologic remission but still have measurable residual disease (MRD).

The main purpose of the study is to evaluate the preliminary anti-leukemia activity of BEBT-908 in patients with relapsed or refractory disease and its ability to reduce or eliminate residual leukemia in patients with MRD-positive disease. The study will also assess the depth and duration of response, survival outcomes, subsequent treatment such as stem cell transplantation or CAR-T therapy, and the safety and tolerability of BEBT-908.

Approximately 10 to 15 participants aged 14 to 75 years are planned to be enrolled. All participants will receive BEBT-908 by intravenous infusion at 18.5 mg/m² on Days 1, 3, 5, 8, 10, and 12 of each 21-day cycle for up to two cycles. Bone marrow morphology, flow cytometry MRD, and MEF2D fusion transcript levels will be evaluated during the study to assess treatment response.

Eligibility

Inclusion Criteria:

1. Voluntary participation in the study and provision of written informed consent. For participants aged 14-17 years, written informed consent must be provided by a legal guardian, together with the participant's assent or confirmation as required by the ethics committee.
2. Age ≥14 years and ≤75 years at the time of informed consent, regardless of sex.
3. Diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on morphology, immunophenotyping, and clinical assessment.
4. Prior clinical testing suggesting MEF2D rearrangement, with confirmation of the MEF2D rearrangement and its specific fusion partner during screening by RNA sequencing or a targeted RNA fusion panel.
5. Meets either of the following baseline disease-status criteria:
   1. Relapsed/refractory disease: relapse, refractory disease, or disease progression after at least one line of systemic anti-leukemia therapy, with evaluable bone marrow and ≥5% blasts/lymphoblasts at screening; or
   2. Morphologic remission with MRD positivity: achievement of CR, CRh, or CRi after at least one course of standard induction or salvage therapy, with flow cytometry MRD ≥0.01% and/or MEF2D fusion transcript/ABL1 ≥0.1% at screening.
6. Bone marrow morphology, flow cytometry MRD, and quantitative RT-qPCR for the MEF2D fusion transcript are all performed during screening and meet the applicable baseline stratification and enrollment requirements. Participants in MLFS are not eligible through the MRD-positive pathway.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
8. Estimated life expectancy \>12 weeks.
9. Peripheral blood white blood cell count \<25 × 10\^9/L before the first dose of ifupinostat hydrochloride; cytoreduction during screening is permitted to achieve this threshold.
10. Adequate organ function:
    • ALT and AST ≤2.5 × ULN; values up to ≤5 × ULN may be permitted when abnormalities are attributable to leukemic hepatic involvement, prior therapy, or another controllable cause, at the investigator's discretion;
    • Total bilirubin ≤1.5 × ULN; ≤3 × ULN is permitted for Gilbert syndrome;
    • Creatinine clearance ≥50 mL/min;
    • Left ventricular ejection fraction (LVEF) ≥45%.
11. No active central nervous system leukemia on cerebrospinal fluid examination during screening.
12. Prior therapy meets the protocol-specified washout requirements, and acute non-hematologic toxicities have recovered to CTCAE Grade 0-1, baseline, or a clinically stable level. Reductions in ANC, hemoglobin, or platelet count attributable to leukemia or prior therapy are not exclusionary.
13. Participants of childbearing potential agree to use effective contraception during study treatment and for the protocol-specified period after the last dose.

Exclusion Criteria:

1. Isolated extramedullary relapse, or active extramedullary leukemia without bone marrow disease meeting one of the protocol-defined enrollment pathways.
2. Active central nervous system leukemia.
3. Failure to confirm MEF2D rearrangement during screening.
4. White blood cell count ≥25 × 10\^9/L before the first dose despite cytoreduction, or an unacceptable risk of leukostasis, tumor lysis syndrome, severe infection, severe bleeding, or other acute complications as judged by the investigator.
5. Inadequate washout from prior therapy:
   • Chemotherapy, radiotherapy, immunotherapy, or other clearly anti-leukemia treatment within 14 days;
   • Small-molecule investigational or targeted therapy within 14 days or 5 half-lives, whichever is shorter;
   • Large-molecule therapy within 28 days or 5 half-lives, whichever is shorter;
   • CAR-T therapy or autologous transplantation within 60 days with ongoing active CRS, ICANS, or uncontrolled toxicity;
   • Allogeneic transplantation within 100 days, or active graft-versus-host disease or ongoing systemic immunosuppressive therapy.
6. Uncontrolled active infection, active invasive fungal infection, active tuberculosis, sepsis, or septic shock.
7. Uncontrolled HBV, HCV, or HIV infection; active syphilis; or active EBV- or CMV-related organ disease.
8. Screening QTcF \>450 ms in males or \>470 ms in females; congenital long QT syndrome; clinically significant arrhythmia; or requirement for continued use of an irreplaceable medication known to prolong the QT interval.
9. Uncontrolled or clinically significant cardiovascular disease, including recent myocardial infarction, unstable angina, severe heart failure, or severe arrhythmia.
10. Pregnancy or breastfeeding.
11. Known hypersensitivity to ifupinostat or any component of the formulation.
12. Inability to avoid strong CYP3A4 inducers, or requirement for long-term use of strong CYP3A4 inhibitors or QT-prolonging drugs that cannot be safely managed.
13. Another malignancy that may interfere with assessment of efficacy or safety in this study, except for malignancies considered cured and at low risk of recurrence at the investigator's discretion.
14. Psychiatric, cognitive, or compliance-related problems that prevent adequate understanding of or adherence to study requirements.
15. Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.