ENLIGHT-AML - An Open-label, Study of GB3226 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Eligible participants are males and female aged 18 years or older at screening with a diagnosis of relapsed or refractory acute myeloid leukemia Diagnosis

1. Patients 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 2.2025).

   Disease Status
2. 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 two cycles of intensive chemotherapy, or venetoclax combinations or four cycles of lower-intensity chemotherapy. 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.
3. Patients must not be eligible for other therapies known to provide clinical benefit

   In addition, all patients must have:
4. White blood cell (WBC) count below 25,000/μL at the time of enrolment. Patients may receive cytoreduction prior to enrolment per Inclusion Criteria 12 and 15
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: ≥30 days since prior immunotherapy (including tumor vaccines) and CAR T-cell or other modified T/NK cell therapy, allowing for a first response evaluation.

    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 administered in Cycle 1 if warranted.
12. 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)
16. Adequate kidney and liver function as evidenced by GFR ≥ 60 mL/min, total bilirubin ≤ 2 times ULN (unless due to Gilbert's syndrome), ALT/AST ≤ 3 times ULN.

    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. Males with female partners of childbearing potential 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.

Exclusion Criteria

Patients meeting any of the following criteria are NOT eligible for study participation:

Diagnosis

1. Diagnosis of active acute promyelocytic leukemia. (APML).
2. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis.
3. Active CNS disease (cytology, such as any blasts on cytospin, or radiography). Patients who have cleared CNS disease by at least one negative tap prior to dosing may be enrolled, and prophylactic intrathecal chemotherapy may be continued while on trial (see inclusion criteria 12).
4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrolment.
5. Hepatitis B (defined as hepatitis B virus \[HBV\] surface antigen positive and HBV core antibody positive, or positive HBV deoxyribonucleic acid \[DNA\]).
6. Hepatitis C (defined as positive hepatitis C \[HCV\] antibody with reflex to positive HCV ribonucleic acid \[RNA\]).

   NB: Patients with controlled HIV, Hep B and Hep C disease will not be excluded from study enrolment.

   Pregnancy and Breast-Feeding
7. Pregnant or nursing women. Negative serum pregnancy tests are required during Screening and a negative serum or urine pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

   Concurrent Conditions

   Cardiac Disease:
8. Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥III), life-threatening, uncontrolled hypertension or arrhythmia, ischemic or severe valvular heart disease, cerebrovascular accident, or transient ischemic attack.
9. Mean QTcF ≥470 ms on triplicate ECG. Appropriate corrections for patients with bundle branch block and ventricular paced rythms are allowed.

   Gastrointestinal Disease:
10. Any gastrointestinal issue of the upper GI tract likely to affect oral drug absorption or ingestion (e.g., gastric bypass, gastroparesis, etc).
11. Cirrhosis with a Child-Pugh score of B or C.
12. Signs or symptoms of acute or chronic GVHD (Harris 2016, Lee 2015) requiring systemic treatment within 4 weeks of enrolment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrolment. Patients may be on physiological doses of steroids (≤10 mg/day prednisone equivalent).
13. Concurrent malignancy in the previous 2 years, with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the patient is not receiving any systemic therapy or radiation.
14. Concurrent malignancy must be in complete remission (CR) or no evidence of disease (NED) during this timeframe.
15. Pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML).
16. Acute or chronic systemic fungal, bacterial, viral, or other infection which is uncontrolled.
17. Major surgery within 4 weeks prior to the first dose of GB3226.
18. History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients (see formulation details in Investigator Brochure) that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.

    Concomitant Medications and Interventions
19. Any commercially available or investigational antileukemic therapy other than GB3226, with the following exceptions:

    * Short-term administration of corticosteroids and/or hydroxyurea for cytoreduction. For treatment of life-threatening events, alternative cytoreductive agents as judged by the treating physician after consultation with study physician may be applied.
    * Intrathecal chemotherapy for CNS prophylaxis is permitted, at the treating physician's discretion. In the Phase 1a evaluable cohort, CNS prophylaxis may continue starting in C2D1.
    * Receipt of an investigational agent within 30 days of starting GB3226, unless inclusion criteria 10-14, then the longer period may be applied. Patients may continue with noninterventional follow-up from previous clinical studies.
20. The following Exclusions apply related to concomitant use of CYP3A4 inhibitors or inducers:

Phase 1a:

Cohort A: Concurrent use of weak, moderate, and strong inhibitors or inducers of CYP3A4. Patients who were receiving CYP3A4 inhibitors/inducers must have discontinued the medication at least 7 days or 5 half-lives which-ever is longer, for CYP3A4 inhibitors or 14 days or 5 half-lives, which-ever is longer for CYP3A4 inducers prior to enrolment

Cohort B: Concurrent use of 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). Patients who were receiving other CYP3A4 inhibitors/inducers must have discontinued the medication at least 7 days or 5 half-lives which-ever is longer, for CYP3A4 inhibitors or 14 days or 5 half-lives, which-ever is longer for CYP3A4 inducers prior to enrolment

Cohort C: Concurrent use of 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. Patients who were receiving other CYP3A4 inhibitors/inducers must have discontinued the medication at least 7 days or 5 half-lives which-ever is longer, for CYP3A4 inhibitors or 14 days or 5 half-lives, which-ever is longer for CYP3A4 inducers prior to enrolment