An Open-label, Dose-Escalation and Dose-Expansion Study of GB3226 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Inclusion Criteria

• •Eligible participants are males and female aged 18 years or older at screening with relapsed or refractory acute myeloid leukemia Diagnosis
• •1. Patients in Phase 1 must have active acute myeloid leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines, Version 3.2024).
• •2. Phase 2 patients must have documented active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the NCCN Guidelines for Acute Myeloid Leukemia (Version 3.2024) and may have specific genetic profiles.
• •For Phase 2, if inclusion is restricted to specific genetic subtypes, mutational status will be assessed locally for initial eligibility determination and confirmed by central laboratory testing. Patients with mutational status not confirmed centrally, or with final pathology or flow cytometry reports indicating \<5% bone marrow blasts, will be replaced to ensure adequate enrolment for the primary efficacy analyses.
• •Disease Status
• •3. Recurrent or refractory AML, as defined by standardized criteria (for example, European LeukemiaNet criteria (Döhner 2022); International Working Group criteria (Cheson 2003)) after standard of care therapy, including but not limited to one or two cycles of intensive chemotherapy, or venetoclax combinations. Patients with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment (including allogeneic HSCT) are eligible. Refractory or relapsed leukemia is defined by presence of ≥5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. Patients who, upon central review, have \<5% blasts in the bone marrow at baseline may be replaced to ensure enough patients for the efficacy analyses.
• •In addition, all patients must have:
• •5. Male or female patients aged ≥18 years of age
• •6. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2
• •7. Adequate cardiac function defined as ejection fraction (EF) of ≥45% by echocardiogram or multigated acquisition (MUGA) scan.
• •Prior Therapy:
• •8. Prior treatment-related toxicities must have resolved to ≤Grade 1 before enrolment, except for ≤Grade 2 neuropathy or alopecia.
• •9. Radiation therapy: ≥60 days since TBI, craniospinal, or ≥50% pelvic radiation; ≥14 days since local palliative (small port) radiation.
• •10. Stem cell infusion: ≥90 days since HSCT and ≥4 weeks since DLI.
• •11. Immunotherapy: ≥28 days since prior immunotherapy (including tumor vaccines) and ≥21 days since CAR T-cell or other modified T/NK cell therapy.
• •12. Antileukemia therapy: ≥14 days or 5 half-lives (whichever is shorter) since last antileukemia therapy (e.g. small molecule, cytotoxic, or myelosuppressive therapy), unless otherwise specified. Hydroxyurea for cytoreduction can be initiated without restriction related to timing of study entry. Hydroxyurea can be continued concomitantly with GB3226. Please also refer to Appendix 6 that includes treatment options for the treatment of Differentiation Syndrome.
• •Patients may receive intrathecal chemotherapy at the time of diagnostic lumbar puncture at least 24 hours prior to the start of GB3226 and may continue prophylactic intrathecal chemotherapy beginning in Cycle 2 at the treating physician's discretion.
• •13. Hematopoietic growth factors: ≥7 days since short-acting and ≥14 days since long-acting growth factor therapy.
• •14. Biologics: ≥90 days or 5 half-lives (whichever is shorter) since antineoplastic biologic therapy.
• •15. Steroids: ≥7 days since systemic glucocorticoids, except for physiologic doses (≤10 mg prednisone daily) or if used as cytoreductive therapy.
• •16. Adequate liver and kidney function i.e., i) Estimated glomerular filtration rate (GFR) based on local institutional practice (e.g., Cockcroft-Gault formula) ≥ 60 mL/min/1.73m2 ii) Adequate liver function defined as: Total bilirubin \<1.5 times the upper limit of normal (ULN) or normal conjugated bilirubin, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<3 times ULN (unless attributed to leukemic involvement).
• •Contraception
• •17. Female of childbearing potential: willing to use a highly effective method of contraception or double barrier method from the time of enrolment through 180 days following the last study drug dose.
• •18. childbearing potential males with female partners of agrees to use barrier contraception from the time of enrolment through 90 days following the last study drug dose.
• •Informed Consent
• •19. Patient is able and willing to provide written informed consent and able to follow study instructions.
• •* Any concurrent systemic treatment to prevent GVHD.
• •20. The following Exclusions apply related to concomitant use of CYP3A4 inhibitors or inducers:
• •Phase 1:
• •Cohort A: Arm E: Concurrent use of weak, moderate, and strong inhibitors or inducers of CYP3A4, which should be discontinued at least 7 days prior to enrolment.
• •Cohort B: Concurrent use of weak, moderate and strong CYP3A4 inhibitors/inducers (except for systemic itraconazole, ketoconazole, posaconazole, or voriconazole, which should have been started at least 7 days prior to enrolment). Other weak, moderate or strong inhibitors or inducers of CYP3A4 should be discontinued at least 7 days prior to enrolment Cohort C: Concurrent use of weak, moderate, and strong inhibitors or inducers of CYP3A4, except for isovuconazole or fluconazole, which should have been started at least 7 days prior to enrolment. All other CYP3A4 inhibitors should be discontinued at least 7 days prior to enrolment.
• •Phase 2:
• •Patients who will not be receiving GB3226 in combination with a CYP3A4 inhibitor antifungal must discontinue all CYP3A4 inhibitors at least 7 days prior to the first dose of GB3226. These patients will receive the GB3226 RP2D established for administration without a CYP3A4 inhibitor as determined in the Phase 1 part of the study.
• •Patients who will be receiving GB3226 in combination with a CYP3A4 inhibitor antifungal must have initiated the antifungal treatment at least 24 hours prior to enrolment. These patients will receive the GB3226 RP2D established for co-administration with a CYP3A4 inhibitor as determined in the Phase 1 part of the study.
• •Note: The RP2D for GB3226 for patients on a CYP3A4 inhibitor versus patients who are not on a CYP3A4 inhibitor may be different.