Venetoclax and Ivosidenib Combined With Chemotherapy in IDH1 Mutated AML

Phase 1

Not yet recruiting

• Conditions: AML; IDH1 Mutation; Treatment
• Interventions: Drug: Ivosidenib,venetoclax,azacytidine,cytarabine

• Registration Number: NCT06611839
• Lead Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Brief Summary

Leukemia is one of the common malignant tumors threatening human health. Intensive chemotherapy or non-intensive chemotherapy has limited efficacy. There is an urgent need to improve treatment outcomes with more specific, well-designed drugs that target leukemia specifically.

The induction therapy of venetoclax combined with demethylation agents (HAM) significantly improves the response rate in elderly unfit AML patients (more than 60%), and studies are being conducted in venetoclax combination with intensive induction (3 + 7) and consolidation chemotherapy in newly treated AML patients.

Isocitrate dehydrogenase (IDH) 1 and 2 are present in the citric acid cycle. About 20% of AML patients carry IDH1 or IDH2 mutations that result in the reduction of alpha-ketoglutaric acid to 2-hydroxyglutaric acid (2-HG), which methylates intracellular histones and inhibits TET2 activity to hypermethylate DNA, thereby affecting gene expression and cell differentiation. IDH mutations are more common in older patients, are often cytogenetically-related, and can also co-occur with FLT3-ITD, NPM1, or DNMT3A mutations. Ivosidenib is an IDH1 inhibitor, and its safety and efficacy in the treatment of AML have been confirmed in previous studies. Based on the study of Montesinos et al. on the role of ivosidenib and azacitidine in IDH-mutated AML, for patients who cannot tolerate intensive chemotherapy, a new treatment regimen has been added for AML patients with IDH1 mutation: ivosidenib combined with azacitidine can be selected for 1 cycle every 28 days or ivosidenib monotherapy.

Therefore, this study intends to conduct a multi-center, single-arm clinical study to determine the maximum tolerated dose of ivosidenib and venetoclax combined chemotherapy, and the composite complete response rate, the negative conversion rate of MRD measured by flowcytometry and IDH1 mutant.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-19
• Study First Submitted QC: 2024-09-22
• Study First Posted: 2024-09-25
• Study Start: 2024-10-30
• Last Update Submitted: 2024-11-04
• Last Update Posted: 2024-11-05
• Primary Completion: 2026-10-01
• Study Completion: 2028-10-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 29

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Venetoclax and Ivosidenib combined intensive chemotherapy	Ivosidenib,venetoclax,azacytidine,cytarabine	The study was divided into two phases: dose climbing (phase I)and dose extension (phase II).

Primary Outcome Measures

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

Secondary Outcome Measures

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