NCT06611839

Venetoclax in Combination With Ivosidenib and Azacitidine for Newly Diagnosed IDH1-Mutated AML

A Multicenter, Single-Arm Phase I/II Clinical Study of the Venetoclax, Ivosidenib, and Azacitidine Triple-Drug Regimen in the Treatment of Chemotherapy-eligible Adult Patients With IDH1-Mutated Acute Myeloid Leukemia.

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Sponsor: Institute of Hematology & Blood Diseases Hospital, China · Academic / Other
• Sex: All
• Age: 14 Years
• Healthy volunteers: Not accepted

Summary

Venetoclax can bind to the BCL-2 protein, thereby initiating the apoptosis program and exerting anti-AML effects. The induction regimen combining venetoclax with hypomethylating agents (HMA) significantly improves the remission rate (over 60%) in elderly unfit AML patients and markedly prolongs survival in those achieving complete remission. Isocitrate dehydrogenase (IDH) 1 and 2 are involved in the citric acid cycle. Approximately 20% of AML patients carry IDH1 or IDH2 mutations, which lead to the reduction of α-ketoglutarate to 2-hydroxyglutarate (2-HG). 2-HG can cause histone methylation and inhibit TET2 activity, resulting in DNA hypermethylation, thereby affecting gene expression and cell differentiation. IDH mutations are more common in elderly patients and are often associated with cytogenetic abnormalities; they may also co-occur with FLT3-ITD, NPM1, or DNMT3A mutations. Ivosidenib is an IDH1 inhibitor, and previous studies have confirmed its safety and efficacy in AML treatment. According to adult AML treatment guidelines, IDH-mutated patients eligible for intensive chemotherapy may receive IDH inhibitors during induction therapy. Based on the study by Montesinos et al. on the role of ivosidenib and azacitidine in IDH-mutated AML, for patients ineligible for intensive chemotherapy, a new treatment option has been added: IDH1-mutated AML patients may receive ivosidenib (500 mg, days 1-28) combined with azacitidine (75 mg/m²/day for 7 days) in 28-day cycles, or ivosidenib monotherapy. Recent studies have shown that a triple-drug regimen comprising ivosidenib, venetoclax, and azacitidine demonstrates excellent efficacy and safety. In chemotherapy-ineligible patients, the triple regimen achieved a composite complete remission rate (CRc) of 86% and an overall response rate (ORR) of 92%. At a median follow-up of 27.4 months, the 2-year overall survival (OS) was 72%, and the 2-year event-free survival (EFS) was 72%. Therefore, this study aims to conduct a multicenter, single-arm clinical trial to determine the maximum tolerated dose of the triple-drug regimen (ivosidenib, venetoclax, and azacitidine) and preliminarily evaluate the long-term efficacy of this combination. Additionally, it seeks to elucidate the relationship between measurable residual disease (MRD) levels and the selection of transplantation treatment strategies, providing evidence for MRD-based therapeutic decision-making.

Conditions

• AML
• IDH1 Mutation
• Treatment

Interventions

Type	Name	Description
DRUG	Ivosidenib, Venetoclax, Azacitidine	phase I: Induction therapy：Ivosidenib 、Venetoclax、Azacitidine Dose climbing stage: adopt the 3 + 3 design principle, and the dose level 0,-1and 1 are set as follows dose level 0: Ivosidenib 500mg d1-28 Venetoclax 100mg d-3，200mg d-2，400mg d-1,800mg d1-14 Azacitidine 75mg/m2/d, d1-7 dose level -1:Ivosidenib 500mg d1-28 Venetoclax 100mg d-3，200mg d-2，400mg d-1, 600mg d1-14 Azacitidine 75mg/m2/d, d1-5 dose level 1:Ivosidenib 500mg d1-28 Venetoclax 100mg d-3，200mg d-2，400mg d-1 800mg d1-21 Azacitidine 75mg/m2/d, d1-7 Consolidation therapy intermediate-dose cytarabine regimen ： 3 courses If IDH1 mutant residual disease was positive before consolidation chemotherapy, Ivosidenib was added; Maintenance treatment: Azacitidine、Venetoclax 、Ivosidenib： 6 courses phase II: dose based on phase I results

Timeline

• Start date: 2025-10-17
• Primary completion: 2026-10-01
• Completion: 2028-10-01
• First posted: 2024-09-25
• Last updated: 2026-02-11

Locations

1 site across 1 country: China