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. The primary objective of the study is to evaluate relapse free survival (RFS) at 24 months in patients receiving oral azacitidine with ivosidenib.
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
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Subjects will be administered treatment over 28-day cycles until progression or another reason (unacceptable toxicity, patient choice to discontinue study treatment, sponsor decision, HSCT at any time, patients who require the use of any of the excluded therapies). The treatment is the association of ivosidenib with oral azacitidine. * The investigational medicinal product is ivosidenib. Two tablets (500 mg) will be administered as a single dose, once daily, during 28 days-cycles until discontinuation. * The auxiliary treatment is oral azacitidine. Oral AZA 300 mg will be given once-daily for 14 days of repeated 28-day treatment cycles. For all patients, oral AZA will be interrupted systematically after day 14 of each 28-days cycle.
CHU Angers
Angers, France
CH côte Basque
Bayonne, France
CHU Besançon
Besançon, France
Hopital d'Instruction des Armées Percy
Clamart, France
CHU Henri Mondor
Créteil, France
CHU Grenoble
Grenoble, France
Chru de Lille - Hopital Claude Huriez
Lille, France
CHU de Limoges
Limoges, France
CHU de Nantes
Nantes, France
CHU de Nîmes - Institut de Cancérologie du Gard
Nîmes, France
...and 10 more locations
RFS 24 months
relapse-free-survival (RFS) at 24 months in patients receiving oral azacitidine with ivosidenib
Time frame: 24 months
RFS 12 months
RFS at 12 months, with the same definition for RFS as for the primary endpoint
Time frame: 12 months
Overall survival
Overall survival defined as the time between inclusion assignment and death from any cause, at 12 and 24 months
Time frame: 24 months
EFS MRD neg
EFS MRD-, defined in patients who were MRD negative at baseline to MRD relapse (by FCM or RT-qPC for NPM1) or death from any cause, whichever occurred first
Time frame: 24 months
TEAEs
Number of participants with Treatment Emergent Adverse Events (TEAEs), according the CTCAE v5.0 classification
Time frame: 24 months
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