Evaluation of Ivosidenib and Azacitidine With or Without Venetoclax in IDH1-Mutated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy
- Trial ID
- 2024-512753-24-00
- Protocol
- HOVON 173 AML
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether treatment with **venetoclax**, in combination with **ivosidenib** and **azacitidine**, prolongs event-free survival (EFS) in adult patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. This is clinically relevant as prolonging EFS can potentially improve patient outcomes by delaying disease progression and reducing the need for more aggressive treatments.
Secondary objectives include assessing the impact of the treatment combination on various clinical outcomes in the same patient population. These objectives are:
- To determine if the treatment prolongs overall survival (OS).
- To evaluate the increase in the combined rate of complete remission (CR) and CR with partial hematologic recovery (CRh).
- To assess the increase in the rate of CR.
- To evaluate the impact on the combined rate of CR and CR with incomplete hematologic recovery (CRi).
- To assess the increase in the rate of CR, CR/CRh, and CR/CRi without measurable residual disease (MRD).
- To determine if the treatment shortens the time to response (CR, CR/CRh, or CR/CRi).
- To assess the prolongation of the duration of response (DoR).
- To evaluate improvements in transfusion independence rate (platelets and RBC).
- To evaluate the pharmacokinetics of ivosidenib and venetoclax.
- To assess the impact on quality of life using EORTC QLQ-C30 and EQ-5D-5L.
- To evaluate the impact on cumulative incidence of relapse (CIR) and death (CID).
- To assess EFS, OS, DoR, and rates of CR, CR/CRh, and CR/CRi by prognostic variables.
- To evaluate EFS, OS, rates of CR, CR/CRh, CR/CRi, CRMRD-, CR/CRhMRD-, CR/CRiMRD-, time to response, DoR, CIR, CID in patients with IDH1-mutated MDS/AML.
- To evaluate transfusion independence rate and safety objectives in patients with IDH1-mutated MDS/AML.
- To evaluate the pharmacodynamic effect of ivosidenib.
- To assess the safety of the treatment by evaluating the incidence and severity of adverse events (AEs) according to CTCAE version 5.0.
- To assess time to hematopoietic recovery after each treatment cycle.
- To evaluate the number of patients requiring blood transfusions and the need for hospitalization.
Participants
The clinical trial involves a total of **96 participants** diagnosed with **Acute Myeloid Leukemia (AML)**, specifically those with an IDH1 mutation. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants are selected based on their ineligibility for intensive chemotherapy, which may be due to age (≥ 75 years) or specific comorbidities in younger patients (18-74 years), such as cardiac issues, reduced lung function, or moderate hepatic impairment. All participants must have a projected life expectancy of at least 12 weeks and meet specific renal and hepatic function criteria. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to reproductive health guidelines during and after the study. The trial does not include vulnerable populations, ensuring a focus on adult patients with the specified medical condition and genetic mutation.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of adding **venetoclax** to a treatment regimen of **ivosidenib** and **azacitidine** in adult patients with newly diagnosed IDH1-mutated **Acute Myeloid Leukemia (AML)** who are ineligible for intensive chemotherapy. This is a randomized, double-blind, controlled trial with a primary objective to assess whether the combination therapy prolongs event-free survival (EFS). The trial is expected to commence recruitment on April 15, 2025, and conclude by October 15, 2032, with a maximum treatment period of 88 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic mutation status, and overall health. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes, including EFS and overall survival (OS). The expected length of participant involvement is up to 88 weeks, with conditions for early termination including treatment failure, unacceptable toxicity, or withdrawal of consent.
The trial will include primary and secondary endpoints, with the primary endpoint being EFS, measured from randomization to treatment failure, hematologic relapse, or death. Secondary endpoints include OS, rates of complete remission (CR), and quality of life assessments. The study will employ a double-blind design, ensuring that neither participants nor investigators know the treatment assignments, which include active drugs and matching placebos. This methodology aims to minimize bias and provide robust data on the efficacy and safety of the treatment regimen.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Venclyxto** (venetoclax), which is provided in three different dosages: 10 mg, 50 mg, and 100 mg film-coated tablets. Venetoclax is a chemical substance with the active ingredient identified as venetoclax, also known by synonyms such as ABT-199 and GDC-0199. The tablets are administered orally, with a maximum daily dose of 400 mg and a total maximum dose of 316,300 mg over a treatment period of up to 88 days. The tablets are over-encapsuled and re-packaged for the trial. The manufacturer of Venclyxto is AbbVie Deutschland GmbH & Co. KG.
In addition to Venclyxto, the trial includes the administration of **Ivosidenib**, marketed as AG-120/S95031, in the form of 250 mg film-coated tablets. Ivosidenib is a chemical substance with the active ingredient identified as ivosidenib. The tablets are administered orally, with a maximum daily dose of 500 mg and a total maximum dose of 1,232,000 mg over a treatment period of up to 88 days. The manufacturer of Ivosidenib is Institut de Recherches Internationales Servier (I.R.I.S).
Another experimental medication used in the trial is **Azacitidine**, provided as a powder for suspension for injection. Azacitidine is administered subcutaneously, with a maximum daily dose of 75 mg/m² and a total maximum dose of 46,200 mg/m² over a treatment period of up to 88 days. Azacitidine is a chemical substance with the active ingredient identified as azacitidine.
The trial also includes the use of **placebos** to match the venetoclax tablets in 10 mg, 50 mg, and 100 mg dosages. These placebos are used to maintain blinding in the study and do not contain any active pharmaceutical ingredients. The placebos are administered in the same manner as the corresponding venetoclax tablets.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to assess the efficacy of the combination of venetoclax, ivosidenib, and azacitidine in prolonging event-free survival in adult patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
Efficacy
Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is event-free survival (EFS) in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML). EFS is measured from the date of randomization to the date of treatment failure, hematologic relapse from complete remission (CR) or complete remission with partial hematologic recovery (CRh), or death from any cause, whichever occurs first. Treatment failure is defined as the lack of obtaining either CR or CRh by week 24.
Secondary endpoints include overall survival (OS), which is measured from the date of randomization to the date of death from any cause. The rate of CR/CRh is defined as the proportion of AML patients achieving CR/CRh at any time-point during the treatment period. Additional secondary endpoints include the rate of CR, rate of CR/CRi (complete remission with incomplete hematologic recovery), and rates of CR, CR/CRh, and CR/CRi without measurable residual disease (CRMRD-, CR/CRhMRD-, and CR/CRiMRD-). These are defined as the proportion of AML patients achieving these responses at any time point during protocol treatment.
Other secondary endpoints involve the time to achievement of response, duration of response, rate of transfusion independence, and plasma concentrations of **ivosidenib** and **venetoclax**. Quality of life will be assessed using the EORTC QLC-C30 and EQ-5D-5L forms. Additional measures include cumulative incidence of relapse (CIR), cumulative incidence of death (CID), and various efficacy parameters across different subgroups based on prognostic characteristics and specific AML genotypes.
Data collection will occur at specified time points throughout the trial, with analyses conducted to evaluate the efficacy of the treatment regimen. The trial aims to determine if the combination of **venetoclax**, **ivosidenib**, and **azacitidine** can prolong EFS in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification. Patients with AML with both IDH1 and IDH2 mutation are eligible as well
- Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories.
- Age ≥ 18 years, no upper age limit.
- Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria: ≥ 75 years of age: ineligible for intensive chemotherapy per physician’s discretion (with an ECOG performance status 0-2. 18-74 years: patient is not eligible for standard chemotherapy because any of the following co-morbidities: ECOG performance status 2 or 3; Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina; DLCO ≤ 65% or FEV1 ≤ 65%; Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the Cockcroft Gault formula; Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upper limit of normal (ULN); Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy.
- Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician).
- Patient must have a white cell blood (WBC) count of < 25 x 109/L.
- Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance ≥ 30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
- Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert’s disease, or leukemic involvement ; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement.
- Female patients: must be of nonchildbearing potential or when of childbearing potential must agree to avoid pregnancy during the study and for 6 months after the final study drug administration; must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration; must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
- Men must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration).
- Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
- Able to understand and willing to sign an informed consent form (ICF).
- Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable).
Exclusion Criteria
- 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.
- Significant active cardiac disease within 3 months prior to the start of study treatment, including: New York Heart Association (NYHA) class III or IV congestive heart failure; Myocardial infarction; Unstable angina; Severe cardiac arrhythmias; Congenital long QT syndrome of family member with this condition; QTcF >450 msec on screening electrogram for males and >470 msec on screening electrogram for females (mean of triplicate recordings, calculated using Fridericia’s correction).
- Familial history of sudden death or polymorphic ventricular arrhythmia
- Severe obstructive or restrictive ventilation disorder.
- History of stroke or intracranial hemorrhage within 6 months prior to randomization.
- Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
- Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients with COVID-19 infection can be enrolled, if the patient has no symptoms and was tested negative twice by PCR test prior to inclusion in the trial.
- Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
- Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
- Patient with a currently active second malignancy. However, patients with the following history/concurrent conditions are allowed: Basal or squamous cell carcinoma of the skin; Carcinoma in situ of the cervix; Carcinoma in situ of the breast; Incidental histologic finding of prostate cancer.
- Receipt of live, attenuated vaccine within 30 days prior to the study inclusion.
- Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
- Contraindication to any of the anti-leukemic agents used (as per SmPC)
- Participation in other prospective studies with anti-leukemic and/or investigational agents.
- Patient taking Dabigatran unless they can be transferred to other medications at least 3 days prior to dosing. Patients taking other P-gP transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications.
- Patients taking known strong cytochrome P450 (CYP) 3A4 inducers unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
- The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
- Patient who has once been screened and randomized into this HO173 trial but was considered ineligible cannot re-enter this trial at a later date.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Yet Recruiting | 15 Apr 2025 | 4 |
 Belgium | Recruiting | 15 Apr 2025 | 14 |
 Denmark | Recruiting | 15 Apr 2025 | 7 |
 Estonia | Recruiting | 15 Apr 2025 | 3 |
 Finland | Recruiting | 15 Apr 2025 | 6 |
 France | Recruiting | 15 Apr 2025 | 25 |
 Germany | Recruiting | 15 Apr 2025 | 45 |
 Ireland | Recruiting | 15 Apr 2025 | 6 |
 Italy | Not Yet Recruiting | 15 Apr 2025 | 10 |
 Lithuania | Recruiting | 15 Apr 2025 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venclyxto 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 400 | 88 | PRD6353830 |
Venclyxto 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 400 | 88 | PRD6353822 |
AG-120/S95031 250mg film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 500 | 88 | PRD10101805 |
placebo to match venetoclax 10 mg | Placebo | N/A | — | — | — | N/A |
placebo to match venetoclax 100 mg | Placebo | N/A | — | — | — | N/A |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 400 | 88 | PRD6353838 |
placebo to match venetoclax 50 mg | Placebo | N/A | — | — | — | N/A |
AZACITIDINE | Test | — | SUBCUTANEOUS | 75 | 88 | SUB05624MIG |