A study to evaluate the safety and efficacy of oral decitabine plus ivosidenib in newly diagnosed adult patients with acute myeloid leukemia older than 60 years and/or inelegible for standard induction chemotherapy

Prior treatment

• Prior therapy for AML (except hydroxiurea)

Other illness

• Subject has history of myeloproliferative neoplasm [MPN] with BCR-ABL1 translocation and AML with BCR-ABL1 translocation
• Subject is known to be positive for HIV (HIV testing is not required)
• Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required)
• Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients that in the opinion of the investigator would adversely affect his/her participating in this study
• Any severe uncontrolled systemic infection
• Subject has a history of other malignancies within 1 year prior to study entry which is not controlled and/or requiring active therapy which may compromise the administration of IVO and oral decitabine

Lab values

• Inadequate liver function as demonstrated by AST or ALT > 5.0 × ULN, or bilirubin > 2.5 × ULN (unless considered to be due to leukemic disease)
• Subject has a white blood cell count > 30 × 109/L that is not controlled using hydrea or 1 gr/sqm/day per 1 day of cytarabine
• Patient has a heart rate-corrected QT interval using Fridericia’s method QT for corrected heart rate (QTcF) ≥450 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (e.g., hypokalemia, family history of long QT interval syndrome). Patients with prolonged QTcF interval in the setting of bundle branch block may participate in the trial
• Creatinine clearance <25 mL/min (calculated by the Cockcroft-Gault formula)

Other

• Contraindications for IVO or oral decitabine according to the SmPC
• Genetic diagnosis of acute promyelocytic leukemia

• Morphological diagnosis of AML (WHO criteria 2022)
• Female subjects must be either postmenopausal OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control. Female subjects of childbearing potential must have negative results for pregnancy test performed
• Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception
• Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures
• Newly diagnosed AML
• IDH1 R132 mutations (centrally assessed by PCR and NGS). A patient will be allowed to be included with local result after approval of the medical monitor
• Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2 if ≥ 60 years of age, or 0 to 3 if ≥ 18 to 60 years
• Age ≥ 18 years with comorbidities contraindicating intensive chemotherapy; or age ≥ 60 years
• Patients <70 years, with favorable risk AML according to ELN will be included only if they are not candidates to standard treatment with intensive chemotherapy
• Adequate renal function as demonstrated by a creatinine clearance ≥ 25 mL/min (calculated by the Cockcroft Gault formula)
• Adequate liver function as demonstrated by: aspartate aminotransferase (AST) ≤ 5.0 × ULN, alanine aminotransferase (ALT) ≤ 5.0 × ULN, bilirubin ≤ 2.5 × ULN (unless considered to be due to leukemic disease)
• Subject has a white blood cell count < 30 × 109/L (Hydroxyurea is permitted to meet this criterion)