HOVON 150 AML: A phase 3, multicenter, double-blind, randomized, placebo-controlled study of ivosidenib or enasidenib in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome with excess blasts-2, with an IDH1 or IDH2 mutation, respectively, eligible for intensive chemotherapy.
- Trial ID
- 2022-502832-37-00
- Protocol
- HO150
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **event-free survival** (EFS) between ivosidenib/enasidenib and placebo in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed **acute myeloid leukemia** (AML) or **myelodysplastic syndrome** with excess blasts-2 (MDS-EB2), with an IDH1 or IDH2 mutation, who are eligible for intensive chemotherapy. This objective is clinically relevant as it aims to determine the efficacy of ivosidenib/enasidenib in prolonging the period during which patients remain free from disease-related events, which is crucial for improving long-term outcomes in these patient populations.
Secondary objectives include: - Determining if treatment with ivosidenib/enasidenib, as compared to placebo, prolongs overall survival (OS). - Comparing relapse-free survival (RFS), cumulative incidence of relapse (CIR), and cumulative incidence of death (CID) after complete remission (CR) or CR with incomplete hematologic recovery (CRi) between treatment groups. - Evaluating minimal residual disease (MRD) status at several time points and the CRMRD− rate between treatment groups. - Assessing the safety and tolerability of treatment by comparing the frequency and severity of adverse events according to CTCAE. - Comparing complete remission (CR/CRi) rates between treatment groups. - Assessing the time to hematopoietic recovery after each chemotherapy treatment cycle. - Determining quality of life (QoL) during maintenance treatment with ivosidenib/enasidenib versus placebo.
Participants
The clinical trial involves a total of **119 participants** diagnosed with **acute myeloid leukemia (AML)** or **myelodysplastic syndrome (MDS-EB2)**, specifically those with an IDH1 or IDH2 mutation. The study population includes both male and female subjects aged **18 years and older**, who are eligible for intensive chemotherapy. Participants were selected based on their newly diagnosed condition, with the requirement of a documented IDH1 or IDH2 gene mutation. The trial does not include a vulnerable population. Participants must have an **ECOG/WHO performance status** of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Adequate hepatic and renal function is required, as evidenced by specific laboratory criteria. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree not to participate in another interventional study while on treatment. The trial does not provide information on specific lifestyle habits or additional demographic details beyond age and gender.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of **ivosidenib** or **enasidenib** in combination with induction, consolidation, and maintenance therapy in patients with newly diagnosed **acute myeloid leukemia** (AML) or **myelodysplastic syndrome** (MDS) with excess blasts-2, possessing an IDH1 or IDH2 mutation. The primary objective is to compare event-free survival between the treatment and placebo groups. The trial is expected to run from March 15, 2019, to March 15, 2033, with a total duration of approximately 14 years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific genetic mutations. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The study includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.
The expected length of participant involvement varies, with the maximum treatment period for **enasidenib** being 1529 days and for **ivosidenib** being 1742 days. Participants may be withdrawn from the study early due to reasons such as adverse events, withdrawal of consent, or failure to adhere to study protocols. The study aims to ensure rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and scientific integrity.
Treatment
The clinical trial involves the administration of **Enasidenib Mesilate**, a film-coated tablet, as an experimental medication. Enasidenib Mesilate is chemically derived and is provided by Bristol-Myers Squibb International Corporation. The active substance, **Enasidenib Mesilate**, is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 152,900 mg over a treatment period of 1,529 days. This medication is used in combination with induction therapy, consolidation therapy, and maintenance therapy in patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB2) with an IDH2 mutation.
Another experimental medication used in the trial is **AG-120/S95031**, a 250 mg film-coated tablet containing the active substance **Ivosidenib**. This medication is provided by the Institut de Recherches Internationales Servier (I.R.I.S) and is also of chemical origin. Ivosidenib is administered orally, with a maximum daily dose of 250 mg and a total maximum dose of 871,000 mg over a treatment period of 1,742 days. It is used in combination with induction therapy, consolidation therapy, and maintenance therapy in patients with newly diagnosed AML or MDS-EB2 with an IDH1 mutation.
The trial includes the use of **Ivosidenib-matched placebo tablets** as a non-experimental treatment. These tablets are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The placebo is administered orally, matching the form and appearance of the Ivosidenib tablets.
Additionally, the trial utilizes a combination of excipients, including **Lactose monohydrate, microcrystalline cellulose, CrosCarmellose Sodium, Magnesium stearate, and Opadry II Yellow**. These substances are used in the formulation of the placebo tablets to ensure they are indistinguishable from the active medication tablets in terms of appearance and administration.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **event-free survival (EFS)**. EFS is defined as the time from randomization to the occurrence of any of the following events: failure to achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after remission induction, death after achieving CR or CRi, or relapse after achieving CR or CRi. Patients who achieve CR/CRi and are not known to have relapsed or died will be censored at the date of the last clinical assessment.
Secondary efficacy endpoints include **overall survival (OS)**, which is the time from randomization to death from any cause, with patients still alive or lost to follow-up being censored at the last known date of being alive. **Relapse-free survival (RFS)** is measured from the date of achieving CR/CRi until relapse or death from any cause, with patients still in first CR/CRi and alive or lost to follow-up being censored at the last clinical assessment. The **cumulative incidence of relapse (CIR)** and **cumulative incidence of death (CID)** after CR/CRi will also be evaluated, with specific criteria for censoring and competing causes of failure.
Additional secondary endpoints include the **CR without minimal residual disease (CRMRD−) rate** after induction cycle 2, determined by negativity for a genetic marker via RT-qPCR and multi-color flow cytometry. The frequency and severity of adverse events will be assessed according to CTCAE version 5.0. The rates of CR and CRi after induction cycles 1 and 2, as well as the CR+CRi rate after remission induction, will be determined based on the European LeukemiaNet (ELN2017) recommended response criteria. Time to hematopoietic recovery after each chemotherapy cycle, and quality of life assessments using the EQ-5D-5L visual analogue scale (VAS) and EORTC-QLQ-C30 scales, will also be measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years.
- Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a documented IDH1 or IDH2 gene mutation (as determined by the clinical trial assay) at a specific site (IDH1 R132, IDH2 R140, IDH2 R172). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related (in which prior disease should have been documented to have existed for at least 3 months). Patients may have had previous treatment with hypomethylating agents (HMAs) for MDS. HMAs have to be stopped at least four weeks before registration.
- Patients with dual mutant FLT3 and IDH1 or IDH2 mutations may be enrolled only if, for medical or other reasons, treatment with a FLT3 inhibitor is not considered.
- Considered to be eligible for intensive chemotherapy.
- ECOG/WHO performance status ≤ 2.
- Adequate hepatic function as evidenced by: o Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to Gilbert’s disease (e.g. a mutation in UGT1A1) (only for patients in IDH2 cohort), or leukemic involvement of the liver – following written approval by the (Co)Principal Investigator. o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement of the liver, following written approval by the Principal Investigator.
- Adequate renal function as evidenced by creatinine clearance > 40 mL/min based on the Cockroft-Gault formula for glomerular filtration rate (GFR).
- Able to understand and willing to sign an informed consent form (ICF).
- Written informed consent.
- Female patient must either: o Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening) o Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 6 months after the final study drug administration And have a negative urine or serum pregnancy test at screening And, if heterosexually active, agree to consistently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration. * See protocol for details highly effective contraception. o Female patient 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. o Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
- Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
- Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
- Subject agrees not to participate in another interventional study while on treatment.
Exclusion Criteria
- Prior chemotherapy for AML or MDS-EB2 (with the exception of HMA). Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30x109/L).
- Dual IDH1 and IDH2 mutations.
- Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations.
- Blast crisis after chronic myeloid leukemia (CML).
- Known allergy or suspected hypersensitivity to Ivosidenib or Enasidenib and/or any exipients.
- Taking medications with narrow therapeutic windows with potential interaction with investigational medication (see protocol Appendix I), unless the patient can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study.
- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter-sensitive substrate medications (see Appendix J) unless the patient can be transferred to other medications within ≥ 5 half-lives prior to administration of ivosidenib or enasidenib, or unless the medications can be properly monitored during the study.
- Breast feeding at the start of study treatment.
- Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
- Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed: o Basal or squamous cell carcinoma of the skin o Carcinoma in situ of the cervix o Carcinoma in situ of the breast o Incidental histologic finding of prostate cancer
- Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure fraction (LVEF) < 40% by ultrasound or MUGA scan obtained within 28 days prior to the start of study treatment.
- QTc interval using Fridericia's formula (QTcF) ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator.
- Taking medications that are known to prolong the QT interval (see protocol Appendix K), unless deemed critical and without a suitable alternative. In those cases, they may be administered, but with proper monitoring (see section 1.2. Table 13).
- Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
- 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.
- A known medical history of progressive multifocal leukoencephalopathy (PML).
- Immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular coagulation.
- Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 15 Mar 2019 | 6 |
 Belgium | Not Recruiting | 15 Mar 2019 | 42 |
 Estonia | Not Recruiting | 15 Mar 2019 | 2 |
 Finland | Not Recruiting | 15 Mar 2019 | 9 |
 France | Not Recruiting | 15 Mar 2019 | 292 |
 Germany | Not Recruiting | 15 Mar 2019 | 240 |
 Ireland | Not Recruiting | 15 Mar 2019 | 8 |
 Lithuania | Not Recruiting | 15 Mar 2019 | 19 |
 The Netherlands | Not Recruiting | 15 Mar 2019 | — |
 Norway | Not Recruiting | 15 Mar 2019 | 32 |
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 |
|---|---|---|---|---|---|---|
AG-120/S95031 250mg film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 250 | 1742 | PRD10101805 |
Ivosidenib-matched placebo tablets | Placebo | N/A | — | — | — | N/A |
Enasidenib Mesilate | Test | FILM-COATED TABLET | ORAL USE | 100 | 1529 | PRD11286365 |
Lactose monohydrate, microcrystalline cellulose, CrosCarmellose Sodium, Magnesium stearate, Opadry II Yellow | Placebo | N/A | — | — | — | N/A |