Study Evaluating 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.

According to data from the Institut de Veille Sanitaire, the frequency of Acute Myeloid Leukemia (AML) is about 3 cases per 100,000 inhabitants, a frequency which increases with age to reach 20 / 100,000 at 70 years. AML is characterized by recurrent molecular and cytogenetic abnormalities. Among mutations arising with age, those of IDH1 (isocitrate dehydrogenase 1) and IDH2 ((isocitrate dehydrogenase 2) are considered as early molecular events driving AML transformation, characterized by a DNA hypermethylation signature. Somatic mutations in the gene encoding IDH1 occur in 6 to 16% of patients with AML.

In intensively treated (ICT) patients, IDH1 mutations are associated with a poorer outcome in patients treated with ICy34, even in case of favorable-ELN risk. Hematopoietic stem cell transplantation (HSCT) for IDH1mut patients in CR1 after ICT drastically improves OS (HR, 0.48; P = .048). However, in real life settings, and more specifically in elderly patients, only 40% of patients with HSCT indication are effectively transplanted.

For patients who are not candidates for HSCT, effective AML maintenance therapies are needed that can reduce the risk of relapse and prolong overall survival without causing undue adverse effects or compromising health-related quality of life. Indeed, relapse rates after IC without HSCT remain high with limited therapeutic options in this setting. There is a clear unmet medical need to improve the outcome of patients treated with IC who are not candidate for HSCT.

Oral azacitidine is approved as maintenance therapy in adult AML patients who achieve CR or CR without blood count recovery (CRi), following induction therapy and are not eligible for allo-HCT. Nevertheless, according to results of the pivotal QUAZAR-AML-001 placebo-controlled trial, estimated 5-year overall survival reached only 26% in the oral azacitidine arm versus 20% in the placebo arm.

Ivosidenib, a first-in-class, oral, potent, targeted small-molecule inhibitor of mutant IDH1, has shown clinical activity as a single agent in studies involving patients with hematologic and solid-tumors. In a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated relapsed or refractory AML, the rate of CR or CRi was 30,4%.

For newly diagnosed patients with IDH1 mutation, results from a randomized study (AGILE trial) indicate that the IDH1 inhibitor ivosidenib plus azacitidine improves event-free survival (EFS) (hazard ratio, 0.33; 95% CI, 0.16-0.69), clinical response (CR/CRh, 52.8 vs 17.6%), and median OS (29.3 vs 7.9 months) compared with azacitidine plus placebo.

After remission post-induction and consolidation, maintenance therapy by an ivosidenib and oral azacitidine combination is susceptible to improve the prevention of AML relapse, which remains a major issue in the study population. We assume that the combination of ivosidenib with oral azacitidine will not be less well tolerated than in combination with the subcutaneous form, therapeutic regimen authorized until progression or toxicity. Ivosidenib and Onureg®, being already authorized treatments, it has been decided to use the classic administration schedules and dosages in combination

Inclusion criteria

• Male or female ≥ 55 years of age at the time of signing informed consent
• 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, appendix 2), within 17 weeks prior to enrollment.
• Received at least 2 consolidations :

• with intermediate dose of cytarabine (IDAC)
• 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 (appendix 1)
• 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:

• 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)
• 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.
• 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

Exclusion criteria

• 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
• Prior BM or hematopoietic stem cell transplantation
• CR/CRi following treatment with hypomethylating agents
• Proven central nervous system leukemia
• Candidate for Allo-HSCT at screening
• 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)
• 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 discussed with coordinating investigator.

• Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment)
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
• 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
• Other comorbidity that the physician judges to be incompatible with the study design
• 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)
• 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
• Subject with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
• 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.
• 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.