FILO-AML-01-MIVONU A single arm phase II study investigating the efficacy and safety of the addition of ivosidenib to oral azacitidine (Onureg®) in patients over 55 with Acute Myeloid Leukemia (AML) and IDH1 mutation, in complete remission after intensive chemotherapy. A study of the French AML Intergroup.

Prior treatment

• Prior BM or hematopoietic stem cell transplantation
• CR/CRi following treatment with hypomethylating agents
• Diagnosis of malignant disease within the previous 12 months (excluding MDS or CMML, basal cell carcinoma of the skin without complications, “in- situ” carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure)
• Subject with positive HIV test treated or planned to be treated with drugs with potential drug-drug interactions. HIV testing will be performed at screening, if required per local guidelines or institutional standards.

Other illness

• Subject known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status with undetectable PCR viral load on antivirals (non-exclusionary medications) are not excluded.
• Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment)
• Severe medical or mental condition precluding the administration of protocol treatments
• Persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care
• Any condition causing an inability to swallow tablets or known hypersensitivity to the study medication
• Any condition that would impair absorption of the study medication (i.e. short gut, malabsorption syndrome)

Lab values

• Abnormal cardiac status with any of the following: - Unstable angina ; - Myocardial infarction within the last 6 months ; - Significant cardiac arrhythmia ; - New York Heart Association (NYHA) class 3 or 4 congestive heart failure ; - Congenital long QT syndrome, familial history of sudden death or polymorphic ventricular arrhythmias and QT/QTc interval > 500 msec regardless of the correction method. For subject with 450 ≤ QTc ≤ 500 ms, practitioners should thoroughly reassess the benefit/risk of initiating ivosidenib. In case QTc interval prolongation is between 480 msec and 500 msec, initiation of treatment with ivosidenib should remain exceptional and be accompanied by close monitoring. This issue will be discuss with coordinating investigator.
• Subject with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• Subject requiring treatment with concomitant drugs that are strong inducers/inhibitors of cytochrome P450 (CYP)3A /PGP or dabigatran (PGP substrate) (see appendix 6) or QT-prolongating agent other than 5-HT3 antagonists (see appendix 8) or other forbidden medications listed in section 10.7.

Other

• Acute promyelocytic leukemia (FAB M3) with t(15;17) or its molecular equivalents (PML::RARA)
• AML associated with t(9;22) or molecular evidence of such a translocation
• Proven central nervous system leukemia
• Candidate for Allo-HSCT at screening
• Other comorbidity that the physician judges to be incompatible with the study design

• Male or female ≥ 55 years of age at the time of signing informed consent
• Absence of any psychological, familial, sociological, or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule
• Patient suitable for oral administration of study drug.
• A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented as surgically sterile (at least 1 month prior to Screening); b. WOCBP agrees to follow the contraceptive treatment starting at screening and continued throughout the study period, and for at least 180 days after the final study drug administration; c. WOCBP agrees to perform planned pregnancy tests in the study
• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for one month after the final study drug administration.
• Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration.
• A male subject with a partner(s) of childbearing potential must agree to use contraception starting at screening and continue throughout the study period, for at least 90 days after the final study drug administration.
• A male subject must not donate sperm starting at screening nor throughout the study period and for 90 days after the final study drug administration
• Patient must be affiliated to the French social security (health insurance)
• Signed written informed consent for the study
• Patients with confirmation of newly diagnosed AML by 2022 WHO criteria
• Presence of IDH1 R132 mutation at AML diagnosis
• Achievement CR or CRi following induction therapy by intensive chemotherapy (according to ELN 2022), within 17 weeks prior to enrollment.
• Received at least 2 consolidations : a. with intermediate dose of cytarabine (IDAC); b. or with standard dose cytarabine and idarubicin (5+1)
• Adequate BM function: ANC ≥1 × 109/L and platelet count ≥50 × 109/L at the time of inclusion
• Patients who are not candidate for Allo-HSCT
• Adequate baseline organ function defined by the following criteria: - Estimated Glomerular Filtration Rate (eGFR) ≥ 30 ml/min (using CKD-EPI); - aspartate aminotransferase (AST) ≤ 2.5 × ULN ; - alanine aminotransferase (ALT) ≤ 2.5× ULN ; - bilirubin ≤ 1.5 × ULN
• ECOG < 3