An Open-label Phase 3b Study of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy.

Official title

A Single Arm, Open-label Phase 3b Study to Describe the Safety and Tolerability of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy

Overview

The purpose of this study is to learn more about the safety and efficacy of ivosidenib taken with azacitidine to treat adult patients with acute myeloid leukemia (AML) who are presenting a gene mutation called IDH1 (isocitrate dehydrogenase1 mutation-positive \[IDH1m\]) and cannot receive treatment with intensive chemotherapy (IC).

Detailed description

Participants who are eligible and enroll in the study will attend a study visit on the first day of each 28-day cycle. Study visits will consist of a physical exam, blood work, electrocardiogram (ECG) and other assessments. After treatment discontinuation participants will be contacted every 12 weeks through the end of the study (currently planned for 2026) to assess survival. The study drug, Ivosidenib, will be taken once daily throughout the duration of participation in the study, and Azacitidine will only be administered for 7 days at the beginning of each 28 day cycle. If at any point ivosidenib is made available as a medical prescription at the patient's site, the patient will switch to commercial product and will continue to be followed according to the protocol.

Interventions

• Drug Ivosidenib 500mg Oral Tablet
  Provided as tablets, taken orally as two 250mg tablets once daily.
• Drug Azacitidine
  Administered subcutaneously (SC) or intravenously (IV) at a dose of 75mg/m2/day for 7 days, either consecutively on Days 1-7 or discontinuously for Days 1-5 and 8-9 of each cycle. The 7 days of administration will occur at the beginning of every 4 week-long cycle.

Primary outcome measures

• Number of Adverse Events (AEs) [Time frame: up to week 116]
• Number of Serious Adverse Events (SAEs) [Time frame: up to week 116]
• Differentiation Syndrome of Grade 2 or higher [Time frame: up to week 116]
• Number of Adverse Events (AEs) leading to ivosidenib + azacitidine discontinuation [Time frame: up to week 112]
• Number of Adverse Events (AEs) leading to ivosidenib + azacitidine interruption [Time frame: up to week 112]
• Number of Adverse Events (AEs) leading to ivosidenib + azacitidine dose reduction [Time frame: up to week 112]
• Number of Adverse Events (AEs) leading to death [Time frame: up to week 116]
• Number of clinical laboratory anomalies assessed as Adverse Events (AEs) [Time frame: up to week 116]
• Number of patients requiring transfusion (platelet and RBC) and the average number of units transfused [Time frame: up to week 116]
• Rate of infections [Time frame: up to week 116]

Secondary outcome measures (11)

• Event-free survival (EFS) [Time frame: up to week 116]
• Proportion of patients who achieve a complete remission (CR) [Time frame: up to week 116]
• Proportion of patients who achieve complete remission plus complete remission with partial hematologic recovery rate (CR + CRh) [Time frame: up to week 116]
• Proportion of patients who achieve complete remission plus complete remission with incomplete hematologic recovery rate (CR + CRi) [Time frame: up to week 116]
• Duration of response (DOR) [Time frame: up to week 116]
• Time to response (TTR) [Time frame: up to week 116]
• Overall survival (OS) [Time frame: until study closure]
• Quality of life (QoL), as measured by Hematologic Malignancy-Patient-Reported Outcome (HM-PRO) [Time frame: up to week 116]
• Quality of life (QoL), as measured by Family Reported Outcome Measure (FROM-16), for caregivers and/or family [Time frame: up to week 116]
• Health economic measures, as assessed by the 5-level EuroQol 5-Dimensions (EQ-5D-5L) [Time frame: up to week 116]
• Average proportion of days at home [Time frame: up to week 116]

Eligibility criteria

Inclusion criteria

• Has untreated Acute Myeloid Leukemia (AML)
• Have a documented IDH1 R132 gene-mutated disease
• Have at least one of the following making yourself ineligible for intensive chemotherapy (IC): 75 years or older, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2, or any comorbidity that the investigator judges to be incompatible with IC including but not limited to severe cardiac or pulmonary disorder, creatinine clearance less than 45 mL/minute, or bilirubin greater than 1.5 times the upper limit of normal
• Has adequate hepatic (liver) and renal (kidney) function
• Female participants of reproductive potential must have a negative blood pregnancy test and must use effective contraception during treatment and for at least 6 months following treatment
• Fertile male participants with female partners of reproductive potential must use effective contraception during treatment and for at least 3 months following treatment

Exclusion criteria

• Has received any prior treatment for AML, with the exception of hydroxyurea or leukapheresis for white blood cell count control
• Has received prior treatment with an IDH1 inhibitor
• Is a woman who is pregnant or breastfeeding
• Has an active, uncontrolled, systemic fungal, bacterial, or viral infection (including human immunodeficiency virus \[HIV\], active hepatitis B (HBV), or hepatitis C virus \[HCV\]) without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
• Has had significant active cardiac disease within 6 months prior to the start of study treatment, including Class III or IV congestive heart failure, myocardial infarction (heart attack), unstable angina (chest pain), and/or stroke
• Has dysphagia (difficulty swallowing), short-gut syndrome, gastroparesis (stomach paralysis), or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs
• Has uncontrolled hypertension (high blood pressure)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 5 centers

• Institut Paoli Calmettes — Marseille
• CHU CAEN - Hôpital de la Côte de Nacre — Caen
• CHU de Toulouse pt — Toulouse
• CHU Rennes - Hopital Pontchaillou — Rennes
• CHU Angers - Hôpital Hôtel Dieu — Angers

Italy · 4 centers

• IRCCS Istituto Scientifico Romagnolo Per Lo Studio Dei Tumori "Dino Amadori" - IRST — Meldola
• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civ — Brescia
• IRCCS Ospedale Policlinico San Martino — Genova
• Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia — Perugia

Netherlands · 4 centers

• Meander Medisch Centrum — Amersfoort
• Amsterdam UMC — Amsterdam
• Rijnstate — Arnhem
• Universitair Medisch Centrum Groningen — Groningen

Austria · 2 centers

• AKH - Medizinische Universität Wien — Vienna
• Klinikum Wels-Grieskirchen GmbH — Wels

Publications

• Vyas P, Salek S, Vives S, Recher C, Dohner H, Venditti A, Derrien H, Chatin S, De La Bigne AM, Pelouchova J, Hills R, Nier S. ALIDHE phase 3b study design: ivosidenib + azacitidine in adults with newly diagnosed IDH1 mutant acute myeloid leukemia. Future Oncol. 2025 Dec;21(29):3721-3729. doi: 10.1080/14796694.2025.2567838. Epub 2025 Nov 15. PMID 41241779

Identifiers

NCT: NCT05907057 · DIM-95031-006 · 2022-501709-11

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗