Phase II Multicenter Study of Ivosidenib in IDH1-Mutated Myelodysplastic Syndrome Patients
- Trial ID
- 2024-515352-20-00
- Protocol
- IDIOME Study
Trial statistics
Objectives
The primary objective of this study is to evaluate the **response rate** (complete response, partial response, and stable disease with hematologic improvement according to IWG 2006 criteria) following the administration of AG-120 in patients with **myelodysplastic syndrome** with IDH1 mutation. This is assessed separately for Cohorts A and B. For Cohort C, the primary focus is on determining the safety and tolerability of AG-120, utilizing CTCAE version 5 for the evaluation of non-hematological toxicities. The clinical relevance of these objectives lies in the potential to improve treatment outcomes and safety profiles for patients with this specific genetic mutation.
Secondary objectives include:
- Determining the response rate (complete response, partial response, and stable disease with hematologic improvement) of AG-120 in patients with IDH1 mutation in Cohort C.
- Assessing the response duration, time to International Prognostic Scoring System (IPSS) progression, and loss of red blood cell transfusion independence in responders.
- Evaluating the rate and interval to acute myeloid leukemia (AML) evolution.
- Determining overall survival.
- Identifying prognostic factors of response, including IPSS-R, IPSS-R karyotype, and somatic mutations.
- Assessing the evolution of IDH1 variant allele frequency (VAF) during therapy.
- Evaluating the safety of the treatment.
Participants
The clinical trial involves participants diagnosed with **myelodysplastic syndrome with IDH1 mutated**. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of screening. Participants are required to have normal renal and liver function, as well as an adequate cardiac ejection fraction. The trial includes individuals who are not known to be refractory to platelet transfusions and who can adhere to the study's visit schedule and protocol requirements. The trial population was selected based on the presence of an IDH1 mutation in either blood or marrow prior to the start of therapy. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and both genders are represented. Participants must have the ability to understand and voluntarily sign the consent form. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **ivosidenib** in patients with **myelodysplastic syndrome** with an IDH1 mutation. This is a single-arm, phase II, multicenter study. The trial employs a non-randomized, open-label design, focusing on the response rate and safety profile of the investigational product. The study is expected to span from April 2019 to August 2026, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and the presence of an IDH1 mutation. Following the screening, eligible participants will commence treatment and attend regular follow-up visits to monitor response and safety. These visits will include assessments at 3 and 6 months to evaluate hematological response, as well as ongoing safety evaluations using CTCAE version 5 for non-hematological toxicities. The end-of-study visit will conclude the participant's involvement, assessing overall outcomes and any long-term effects.
The expected length of participant involvement is up to 24 months, contingent upon individual response and tolerability. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The primary endpoints focus on overall hematological response, while secondary endpoints include response duration, time to progression, and overall survival. The study aims to provide valuable insights into the treatment of myelodysplastic syndrome with IDH1 mutations, contributing to the understanding of prognostic factors and therapeutic outcomes.
Treatment
The clinical trial involves the administration of **Azacitidine**, a **powder for suspension for injection**. The pharmaceutical form is specifically designed for subcutaneous injection. The active substance, azacitidine, is a chemical compound with a concentration of 25 mg/ml. The maximum daily dose is 75 mg/m², and the treatment period is set for a maximum of 24 weeks. The product is manufactured by Thornton & Ross Ltd and is authorized under the marketing authorization number PL 00240/0584. The administration schedule requires careful monitoring to ensure participant compliance with the dosing regimen.
Another treatment used in the study is **Ivosidenib**, marketed as AG-120/S95031, which is provided in the form of a **250 mg film-coated tablet**. This medication is administered orally, with a maximum daily dose of 500 mg. The treatment duration is also capped at 24 weeks. Ivosidenib is a chemical substance developed by the Institut de Recherches Internationales Servier (I.R.I.S) and holds the orphan drug designation EU/3/16/1802. The study aims to evaluate the response rate and safety profile of Ivosidenib in patients with IDH1 mutated Myelodysplastic Syndrome, with compliance monitored through regular assessments.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of overall hematological response at 3 and 6 months for Cohorts A and B. This includes complete response (CR), partial response (PR), and stable disease with hematologic improvement (HI) according to the International Working Group (IWG) 2006 criteria. For Cohort C, the primary focus will be on safety assessments. Secondary endpoints include response duration and time to response, time to progression according to the International Prognostic Scoring System (IPSS) and Revised IPSS (R-IPSS), rate and time to acute myeloid leukemia (AML) evolution, overall survival, cytogenetic and molecular response, and prognostic factors of response, including IPSS-R, IPSS-karyotype, and somatic mutations. Additionally, the evolution of **IDH1** variant allele frequency (VAF) on therapy and adverse events and toxicity, as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5, will be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Myelodysplastic syndrome according to WHO classification including non-proliferative AML up to 29% of BM blast: Belonging to one of the following categories : • higher risk (IPSS high or int 2 ) MDS without response to azacitidine (CR,PR, stable disease with HI) after at least 6 cycles , or relapsing after a response but without overt progression (defined by at least doubling of marrow blasts, compared to pre azacitidine bone marrow, or AML progression beyond 30% blasts) • Untreated higher risk MDS (IPSS int-2, high) without life threatening cytopenia including ANC <500/mm3 or any recent severe infections and /or platelets below 30,000/mm3 or any bleeding symptom • lower risk MDS with resistance or loss of response to a previous treatment with epoetin alpha/ beta (≥60000 U/w) or Darbopoetin (≥250 ug/w) given for at least 12 weeks and RBC transfusion requirement at least 2 U/8 weeks in the previous 16 weeks
- Presence of IDH1 mutation in either blood or marrow prior to start of therapy
- Normal renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance (Modification of diet in renal disease) creatinine clearance ≥ 50 mL/min
- Normal liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal
- Adequate cardiac ejection fraction (>40%);
- Patient is not known to be refractory to platelet transfusions;
- Patient must understand and voluntarily sign consent form
- Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
- ECOG performance status 0-2 at the time of screening
- Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 3 months (females and males) following the last dose of AG-120. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices.
- Male patients must : -Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment. -Agree to learn about the procedures for preservation of sperm before starting treatment
Exclusion Criteria
- Severe infection or any other uncontrolled severe condition
- Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months
- Less than 14 days since prior treatment with growth factors (EPO, G-CSF)
- Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicity from any previous therapy.
- Subject has a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study
- Subject is taking known strong cytochrome P450 (CYP) 3A4 inducers or inhibitors or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing
- Subject is taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to administration of study treatment
- Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast
- Patient already enrolled in another therapeutic trial of an investigational drug
- Known HIV infection or active hepatitis B or C
- Women who are or could become pregnant or who are currently breastfeeding
- Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
- Patient eligible for allogeneic stem cell transplantation
- Known allergies to AG-120 or any of its excipients
- The study does not provide for the inclusion of persons referred to in Articles L. 1121-5 to L. 1121-9 and L. 1122-1-2 of the Public Health Code (e.g. minors, protected adults, etc.)
- Subjects with a known medical history of progressive multifocal leukoencephalopathy (PML) should be excluded from the study
- No affiliation to a health insurance system.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 09 Apr 2019 | 48 |
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 |
|---|---|---|---|---|---|---|
Azacitidine 25 mg/ml powder for suspension for injection | Other | POWDER FOR SUSPENSION FOR INJECTION | SUBCUTANEOUS INJECTION | 75 | 24 | PRD10214373 |
AG-120/S95031 250mg film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 500 | 24 | PRD10101805 |