Investigating Novel Therapies for the Treatment of Acute Myeloid Leukemia Patients with Rising Measurable Residual Disease and/or Morphological Relapse, ALLG AMLM26 INTERCEPT Trial

Inclusion Criteria

• REGISTRATION TO AMLM26 PLATFORM: Provision of informed consent
• REGISTRATION TO AMLM26 PLATFORM: Acute myeloid leukemia (ambiguous lineage with myeloid overlap is permitted) according to World Health Organization (WHO) or International Consensus Classification (ICC) 2022 criteria
• REGISTRATION TO AMLM26 PLATFORM: Registration on the Australasian Leukaemia and Lymphoma Group (ALLG) National Blood Cancer Registry (NBCR)
• REGISTRATION TO AMLM26 PLATFORM: Age ≥ 18 years
• REGISTRATION TO AMLM26 PLATFORM: Eastern Cooperative Oncology Group (ECOG) 0-2
• REGISTRATION TO AMLM26 PLATFORM: Diagnosis of AML in first or second CR/CR with incomplete count recovery (CRi)/CR with partial hematologic recovery (CRh)
• REGISTRATION TO AMLM26 PLATFORM: Presence of molecular and/or flow cytometric MRD marker(s) which can be tracked as ratified by the AMLM26 Intercept MRD reference committee. For entry into MRD monitoring phase, this marker(s) may or may not be detected at study entry
• GENERAL TREATMENT PHASE: Patient previously registered to AMLM26 INTERCEPT platform
• GENERAL TREATMENT PHASE: White blood cells (WBC) < 25 x 10^9/L (hydroxyurea permitted for WBC control)
• GENERAL TREATMENT PHASE: Presence of molecular MRD marker and/or flow cytometric MRD marker(s) ratified by the AMLM26 Intercept MRD reference committee at the time of screening to commence Intercept treatment
• GENERAL TREATMENT PHASE: For initial therapy on AMLM26 INTERCEPT, the patient must have evidence of either * Morphologic relapse or * CR/CRh/CRi with MRD relapse or * CR/CRh/CRi with flow or molecular MRD persistence in CR1 after at least 2 cycles of intensive chemotherapy
• GENERAL TREATMENT PHASE: For patients on AMLM26 INTERCEPT rotating to other therapies, must have evidence of no morphologic response or suboptimal MRD response (< 1 log reduction in molecular MRD or ≥ 0.1% flow MRD) or morphologic relapse or MRD relapse
• GENERAL TREATMENT PHASE: Patient must have completed consolidation therapy or it is considered unsafe or inappropriate to continue further conventional therapy
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Meets inclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol including: * Master Protocol Inclusion Criteria * The mutation/mutations specified for this treatment arm in Master Protocol
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Meets MRD eligibility for INTERCEPT therapy based on a screening sample taken no more than 42 days prior to cycle 1 of day 1 of treatment on this treatment arm. Eligibility will be confirmed by the MRD review committee
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: ECOG 0-2
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Patients entering this arm post-allogeneic stem cell transplantation will need to have an absolute lymphocyte count of ≥ 0.2 x 10^9/L and no evidence of active acute graft-versus-host disease (GVHD)
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN)
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Alanine aminotransferase (ALT) ≤ 3.0 x ULN
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Agrees to follow the recommended contraception procedures for this treatment domain * Female subjects must be either ** Postmenopausal defined as: *** Age > 55 years with no menses for 12 or more months without an alternative medical cause *** Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level > 40 IU/L OR ** Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR ** Woman of childbearing potential (WOCBP) practicing at least one protocol specified method of birth control starting at study day 1 through at least 180 days after the last dose of study drug * Male subjects who are sexually active, must agree, from study day 1 through at least 180 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug * Females of childbearing potential must have negative results for pregnancy test performed: ** At screening with a serum sample obtained within 7 days prior to the first study drug administration, and ** Subjects with borderline pregnancy tests at screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result * While participating in this research study, female subjects should not become pregnant or breastfeed a baby. Male subjects should not father a baby * Unless postmenopausal or permanently surgically sterile, a woman of childbearing potential must practice at least one of the following methods of birth control, on study day 1 (or earlier) through at least 180 days after the last dose of study drug ** Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 1 month prior to study day 1. Also, subjects must use a barrier method during this study from initial study drug administration to 180 days after the last dose of study drug ** Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 1 month prior to study day 1. Also, subjects must use a barrier method during this study from initial study drug administration to 180 days after the last dose of study drug ** Bilateral tubal occlusion/ligation or bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms success of the procedure ** Vasectomised partner(s), provided the vasectomized partner verbally confirms receipt of medical assessment of the surgical success, vasectomy occurred more than 3 months prior to screening, and is the sole sexual partner of the WOCBP trial participant ** Intrauterine device (IUD) ** Intrauterine hormone-releasing system (IUS) ** True abstinence: Refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable) * Male subjects who are sexually active with a WOCBP, even if the male subject has undergone a successful vasectomy, must agree: ** From study day 1 through at least 180 days after the last dose of study drug to use condoms and his female partner(s) must use at least one of the contraceptive measures (as defined in the protocol for female study subjects of childbearing potential) ** Additionally, male subject agrees not to donate sperm from study day 1 through at least 180 days after the last dose of study drug

Exclusion Criteria

• REGISTRATION TO AMLM26 PLATFORM: Acute promyelocytic leukemia
• REGISTRATION TO AMLM26 PLATFORM: Morphological relapse at the time of study entry
• GENERAL TREATMENT PHASE: Known active central nervous system (CNS) disease
• GENERAL TREATMENT PHASE: Within 14-days from receipt of prior anti-leukemic therapy (except hydroxyurea or 6-thioguanine)
• GENERAL TREATMENT PHASE: Subject has radiation therapy within 4 weeks prior to the first study dose
• GENERAL TREATMENT PHASE: Patients post-allogeneic cell transplant receiving immunosuppressive drugs for treatment of graft versus host disease (GVHD). Patients requiring calcineurin inhibitors for GVHD should have such drugs ceased for at least 4 weeks to be eligible
• GENERAL TREATMENT PHASE: For initial therapy on AMLM26 INTERCEPT bone marrow blasts > 15% on screening bone marrow
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Presence of any general exclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Prior allogeneic stem cell transplantation within 3 months of post-conditioning or on ≥ 10mg/day prednisolone for graft vs host disease
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Subject is HIV positive
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Patients with ≥ 5% myeloblasts in bone marrow on morphologic assessment
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal) * Acute/chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or resolved HBV infection may participate
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Systemic chronic corticosteroid therapy (≥ 10 mg/day prednisone or equivalent) or any immunosuppressive therapy within 7 days of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: For initial enrollment to INTERCEPT therapy, patients who have received previous TIM3 inhibitor treatment are excluded. This exclusion criteria does not apply to patients crossing-over from MBG453 arm to the combination MBG453 + azacitidine arm, unless MBG453 was ceased due to MBG453-related toxicity
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur should not be excluded
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: History of or current drug-induced interstitial lung disease or pneumonitis grade ≥ 2
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Patients with fully excised basal cell carcinoma (BCC)/squamous cell carcinoma (SCC)/cervical intraepithelial neoplasia (CIN) or other minor malignancy are not excluded
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Use of any live vaccines against infectious diseases (i.e. Influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Impaired cardiac function or clinically significant cardiac disease, including any of the following: * Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] grade ≥ 2) with an left ventricular ejection fraction [LVEF] of < 40%, uncontrolled hypertension or clinically significant arrhythmia * Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry
• AMLM26/T5 MBG453 +/- AZACITIDINE THERAPY-SPECIFIC: Known hypersensitivity to azacitidine or mannitol