Ivosidenib and Azacitidine With or Without Venetoclax in Adult Patients With Newly Diagnosed IDH1-Mutated AML or MDS/AML Considered Ineligible for Intensive Chemotherapy

ConditionAcute Myeloid Leukemia

Trial statusRecruiting

Trial phasePhase 3

Trial typeInterventional

Biological sexAll

Age18+

SponsorStichting Hemato-Oncologie voor Volwassenen Nederland

About this trial

The standard treatment for patients with acute myeloid leukemia (AML) with an abnormality in the IDH1 gene, who are not eligible for intensive chemotherapy, is a combination of ivosidenib and azacitidine. In this study it is investigated whether adding venetoclax to the standard treatment can improve the outcome of the treatment of this specific form of AML. The safety is investigated and how well it works. In order to properly assess the value of venetoclax, the effect of venetoclax is compared with the effect of a placebo. A placebo is a product without an active ingredient, a 'fake medicinal product'.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification (Appendix A). Patients with AML with both IDH1 and IDH2 mutation are eligible as well. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173/AMLSG 3423/ACT-HOV-AML-001) and EVOLVE-2 (HO177/AMLSG 35-24/ACT-HOV-AML-002are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173)

Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories.

Age ≥ 18 years, no upper age limit.

older than or equal to 75 years of age ineligible for intensive chemotherapy per physician's discretion (with an ECOG performance status 0-2; Appendix C).

Disqualifiers

Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.

Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.

AML with BCR-ABL1; or myeloid blast crisis of CML

Severe cardiac arrhythmias

Trial design

Design model

Single group

Treatments tested in this trial

Venetoclax 400
Drug
day 1-28 per cycle
Placebo
Drug
day 1-28 per cycle

Treatment groups

227 Participants

are divided into 2 treatment groups

Group A: Placebo comparator: Venetoclax-placeboPlacebo comparator 1 intervention

Group B: Experimental: VenetoclaxExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

Event-free survival (EFS) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy

Event-free survival (EFS) in patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy, measured from the date of randomization to the date of treatment failure, hematologic relapse from CR/CRh or death from any cause, whichever occurs first. Treatment failure is defined as lack of obtaining either CR or CRh by week 24. Patients evaluable for response but not achieving CR or CRh by week 24 will be considered a treatment failure at day 1 post randomization to avoid ambiguities of variable or prolonged periods without response. Patients who die before week 24 without response assessments will also be considered treatment failures at day 1 post randomization. Patients who are alive but not evaluable for response will be censored at day 1 post randomization. Patients who achieved CR or CRh by week 24 and are not known to have morphologic relapse or died will be censored at the date of the last clinical assessment.

Time frame