OBServatory of Compassionate Use of IVOsidenib in France for Patients With Acute Myeloid Leukemia

Обзор

Mutations in IDH genes are found in numerous cancers and more specifically in acute myeloid leukemia (AML). These mutations target specific amino acids, at positions 140 or 172 of IDH2, and 132 of IDH1. Mutant IDH proteins acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) into D-2 hydroxyglutarate (D-2HG), an oncometabolite which massively accumulates in IDH-mutated cells. At high levels, D-2HG behaves as a competitive inhibitor of αKG and affects the activity of Fe(II)/αKG-dependent dioxygenases. This enzymatic family is involved in a broad spectrum of pathways such as demethylation of histone (JHDM histone demethylases) or DNA (methylcytosine hydroxylases of the TET family). As a result, IDH-mutated cells show altered survival, motility, invasiveness and cell differentiation. In AML, IDH1 mutations might be present in 10-15% at diagnosis Ivosidenib (IVO) a first-in-class, oral, irreversible inhibitor of mutant IDH1 has shown clinical activity as a single agent in studies involving patients with IDH1 mutated relapsed or refractory (R/R) AML and in front line settings. In phase II clinical trials, IVO yielded 30-35% of complete response rates both in frontline and R/R settings, with long lasting responses. Based on these results, the FDA (Food and Drug Agency) gave its approval for newly-diagnosed AML IDH1mut patients who are ≥ 75 years old or who have comorbidities and in R/R. However, European Medicines Agency (EMA)'s did not approved IVO due to lack of evidences to support the application. Agios Netherlands B.V. (the company that previously own the drug before Servier Laboratories) withdrew its EMA application. Nevertheless, IVO has been available in France through a compassionate use program (CUP), since February 2020 for R/R patients and March 2022 for first line treatment. In this multicentric retrospective study, sponsor aim to evaluate the efficacy and safety of Ivo in two cohorts of IDH1mut AML patients treated within the CUP. The first cohort will concern patients treated in first line setting and the second cohort those treated in R/R disease. Results might provide new insights regarding IVO in real life settings and support signs of efficacy. This could provide new data for the haematologist community and for another appliance to grant EMA approval of IVO in the setting of R/R IDH1mut AML.

Первичные конечные точки

• characterize the Overall survival (OS) in the both cohort : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]

Вторичные конечные точки (5)

• characterize the composite response rate (CRc) at any time during follow-up, for the both cohort : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]
• characterize the Event Free Survival (EFS) in both cohorts : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]
• characterize the incidence and relatedness of serious adverse events (SAE), for patients treated by Ivosidenib, for both cohorts : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]
• describe the management of treatment by Ivosidenib in both cohorts : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]
• describe the management of treatment by Ivosidenib in both cohorts : 1st line and Relapsed/Refractory (R/R) [Срок оценки: 6 months]

Критерии участия

Критерии включения

• Patient with IDH1 R132 mutated with newly diagnosed or Relapsed or Refractory (R/R) acute myeloid leukemia
• Patient treated within French compassionate access program that have started the treatment between 01/01/2017 to 01/08/2023
• patient treated by Ivosidenib received either as a monotherapy or in combination with other AML therapy (i.e. azacytidine, venetoclax)
• Patient not included within IDH inhibitor clinical trial.

Критерии исключения

• Patients who expressed their opposition to entered in the study
• Patients who received IVO through a trial

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Франция · 21 центр

• Amiens CHU — Amiens
• Angers CHU — Angers
• Bayonne CH — Bayonne
• Besançon CHU — Besançon
• CHU Estaing — Clermont-Ferrand
• Créteil CHU HENRI MONDOR — Créteil
• DUNKERQUE-Hôpital Alexandra Lepève — Dunkirk
• Grenoble CHU — Grenoble
• … и ещё 13 центров

Идентификаторы

NCT: NCT06377579 · FILObsLAM_IVOOBS

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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