Venetoclax in Combination With Ivosidenib and Azacitidine for Newly Diagnosed IDH1-Mutated AML (IDH1-AML-2024)

A Multicenter, Single-Arm 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.

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 preliminarily evaluate the long-term efficacy of this combination in adult AML.

Study Overview

• Status: Recruiting
• Conditions: AML; Treatment; IDH1 Mutation
• Intervention / Treatment: Drug: Ivosidenib, Venetoclax, Azacitidine

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hui Wei, MD; Phone Number: 13132507161; Email: weihui@ihcams.ac.cn

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300020
      • Recruiting
      • Blood Diseases Hospital
      • Contact: hui wei, MD; Phone Number: 86-13132507161; Email: weihui@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients who meet AML according to WHO (2022) or AML and MDS/AML defined by ICC standards with IDH1 mutations detected by PCR or second-generation sequencing.
2. Age ≥14 years old, male or female.
3. The physical status assessment (ECOG-PS) of the Eastern Oncology Collaboration group was 0-2 points.

4. Fulfill the requirements of the following laboratory tests (performed within 7 days prior to treatment) :

   1. Total bilirubin ≤ 1.5 times the upper limit of normal value (same age);
   2. AST and ALT≤ 2.5 times the upper limit of normal value (same age);
   3. Blood creatinine < 2 times the upper limit of normal (same age);
   4. Myocardial enzymes < 2 times the upper limit of normal (same age);
   5. Left ventricular ejection fraction >50% by measure of echocardiogram (ECHO) Informed consent must be signed before the commencement of all specific study procedures, and is signed by the patient himself or his immediate family. Considering the patient's condition, if the patient's signature is not conducive to the treatment of the condition, the informed consent shall be signed by the legal guardian or the patient's immediate family.

Exclusion Criteria:

Subjects who meet any of the following criteria are excluded from the study:

1. Acute promyelocytic leukemia with PML-RARA fusion gene
2. Acute myeloid leukemia with RUNX1-RUNX1T1 or CBFB-MYH11 fusion gene
3. Acute myeloid leukemia with BCR-ABL fusion gene
4. Treated patients (but can receive hydroxyurea or cytarabine to lower tumor burden).
5. Concurrent malignant tumors of other organs (those requiring treatment).

6. Active heart disease, defined as one or more of the following:

   1. A history of uncontrolled or symptomatic angina;
   2. Myocardial infarction less than 6 months after enrollment;
   3. Have a history of arrhythmia requiring drug treatment or severe clinical symptoms;
   4. Uncontrolled or symptomatic congestive heart failure (> NYHA level 2);
7. Serious infectious diseases (uncured tuberculosis, pulmonary aspergillosis).
8. Those who were not considered suitable for inclusion by the researchers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Venetoclax、Ivosidenib and Azacitidine; Induction regimen includes venetoclax, ivosidenib and azacitidine followed by consolidation therapy with intermediate dose of cytarabine.

Drug: Ivosidenib, Venetoclax, Azacitidine; Induction therapy：Ivosidenib 500mg d1-28 Venetoclax 100mg d1，200mg d2，400mg d3, 800mg d4-14 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRc rate	The ratio of patients achieved CR/CRh/CRi.	Efficacy was assessed at least 2 weeks after completion of the first course of induction therapy.
CRc MRD negtive rate by flow cytometry	The CRc MRD negtive rate was detected by flow cytometry after induction, consolidation and maintenance therapy.	Efficacy was assessed at least 2 weeks after completion of the first course of induction therapy.
CRc MRD negtive rate by PCR	The CRc MRD negtive rate was detected by PCR after induction, consolidation and maintenance therapy.	Efficacy was assessed at least 2 weeks after completion of the first course of induction therapy.
The maximum tolerated dose of ivosidenib and venetoclax combined with intensive chemotherapy	To determine the maximum tolerated dose of ivosidenib and venetoclax combined with intensive chemotherapy	up to 3 months after enrollment of the first participants

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	The interval from the date of enrollment to the date of failed to achieve complete remission, the date of relapse, or the date of death, whichever occurred first.	up to 2 years after the date of the last enrolled participants
30-day mortality	Percentage of patients who died within 30 days from enrollment	Within 30 days of the date of the last enrolled participants
60-day mortality	Percentage of patients who died within 60 days from enrollment	Within 60 days of the date of the last enrolled participants
overall survival	The interval from the date of enrollment to the date of death or the date of last follow-up, whichever occurred first.	up to 2 years after the date of the last enrolled participants
Relapse free survival	The interval from CR to the date of relapse, or the date of death, or the date of last follow-up, whichever occurred first.	up to 2 years after the date of the last enrolled participants

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Hui Wei, MD, Blood Diseases Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2025
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: September 19, 2024
• First Submitted That Met QC Criteria: September 22, 2024
• First Posted (Actual): September 25, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 10, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax; ivosidenib
• Other Study ID Numbers: IIT2024067

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No