Phase II Multicenter Study of Enasidenib Mesilate in IDH2-Mutated Myelodysplastic Syndrome Patients
- Trial ID
- 2024-513858-29-01
- Protocol
- AG221CLMDSGFM13217
Trial statistics
Objectives
The primary objective of this study is to evaluate the **response rate** of the administration of AG-221, also known as Enasidenib Mesilate, in patients with **myelodysplastic syndrome** with an IDH2 mutation. This is assessed in Cohorts A and B by determining the complete response (CR), partial response (PR), and stable disease with hematologic improvement (HI) according to the IWG 2006 criteria. For Cohort C, the primary objective is to assess the safety and tolerability of AG-221, 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.
The secondary objectives include: - Determining the response rate (CR+PR+ stable disease with HI according to IWG 2006 criteria) of AG-221 in patients with IDH2 mutation in Cohort C. - Evaluating the response duration, time to IPSS progression, and loss of RBC transfusion independence in responders. - Assessing the rate and interval to acute myeloid leukemia (AML) evolution. - Determining overall survival. - Identifying prognostic and predictive factors of response, including IPSS-R, IPSS-karyotype, and somatic mutations. - Assessing the evolution of IDH2 variant allele frequency (VAF) on therapy. - Evaluating the safety of the treatment.
Participants
The clinical trial involves participants diagnosed with **myelodysplastic syndrome** with an IDH2 mutation. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a normal renal function and adequate cardiac ejection fraction, with specific criteria for liver function depending on the country of participation. The trial includes individuals with higher risk myelodysplastic syndrome (MDS) who have not responded to azacitidine or have relapsed, as well as those with untreated higher risk MDS without life-threatening cytopenia. Additionally, lower risk MDS patients with resistance or loss of response to previous treatments are included. The trial population was selected based on the presence of the IDH2 mutation in blood or marrow, and participants must not be refractory to platelet transfusions. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **Enasidenib Mesilate** in patients with **myelodysplastic syndrome** with IDH2 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 approximately seven years, with an estimated end date in March 2026. Participants will be involved in the study for a maximum treatment period of 24 months, depending on their response and tolerance to the treatment.
Study visits are structured to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, involves assessing eligibility criteria, obtaining informed consent, and conducting baseline evaluations. Participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will occur at specified intervals throughout the treatment period. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the primary and secondary endpoints.
Participants are expected to adhere to the visit schedule and protocol requirements. The study includes specific conditions that may lead to early termination, such as significant adverse events, disease progression, or withdrawal of consent. The primary endpoint focuses on the overall hematological response at three and six months, while secondary endpoints include response duration, time to progression, and overall survival. The trial aims to provide valuable insights into the therapeutic potential of Enasidenib Mesilate for this patient population.
Treatment
The clinical trial involves the administration of **Enasidenib Mesilate** in two different dosages as the experimental medication. The first formulation is a **film-coated tablet** containing 50 mg of Enasidenib Mesilate. This medication is administered orally, with a maximum daily dose of 50 mg. The treatment period is set for a maximum of 24 weeks. The active substance, Enasidenib Mesilate, is a chemical compound, and the product is identified by the sponsor product code BMS-986361. The pharmaceutical form ensures ease of administration and compliance monitoring is conducted to ensure adherence to the dosing schedule.
The second formulation of the experimental medication is also a **film-coated tablet**, but it contains 100 mg of Enasidenib Mesilate. Similar to the 50 mg formulation, this medication is administered orally, with a maximum daily dose of 100 mg. The treatment duration is also up to 24 weeks. The chemical nature of the active substance remains consistent across both formulations, and the product is similarly identified by the sponsor product code BMS-986361. Compliance monitoring is implemented to ensure participants adhere to the prescribed dosing regimen.
In addition to the experimental treatments, the study includes the use of **Vidaza**, a non-experimental treatment serving as a comparator. Vidaza is provided as a 25 mg/ml **powder for suspension for injection**. The active substance in Vidaza is **Azacitidine**, a chemical compound. The administration route for Vidaza is subcutaneous injection, with a maximum daily dose of 75 mg/m². The treatment period for Vidaza is also set for a maximum of 24 weeks. This comparator treatment is utilized to evaluate the efficacy and safety of the experimental medication in comparison to a standard treatment option.
Efficacy
Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint focuses on the overall hematological response at 3 and 6 months, which includes complete response (CR), partial response (PR), and stable disease with hematologic improvement (HI) according to the International Working Group (IWG) 2006 criteria for cohorts A and B. For cohort C, safety will be the primary endpoint.
Secondary endpoints include response duration and time to response, time to progression according to the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R), 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 IDH2 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 evaluated.
The efficacy parameters will be measured and collected at specified timepoints, including 3 and 6 months for the primary endpoint. The tools and instruments for these assessments include validated scales and laboratory tests to ensure accurate and reliable data collection. The analysis will be conducted in accordance with the predefined criteria to determine the efficacy of the treatment in patients with IDH2 mutated myelodysplastic syndrome.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Myelodysplastic syndrome according to WHO classification including non-proliferative AML up to 29% of BM blast
- Age ≥ 18 years
- Belonging to one of the following categories: 1. higher risk MDS (IPSS int-2, high) 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) 2. 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 and any bleeding symptom 3. 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 IDH2 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) (MDRD) ≥ 50 mL/min
- France: Normal liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal / Germany: Normal liver function, defined by total bilirubin < 2.0 mg/dl (exception permitted in patients with Gilbert’s Syndrome) 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
- Written informed consent
- 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 of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles. • France: 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 120 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices. • Germany: 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 365 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal) - progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system ( IUS) - bilateral tubal occlusion - vasectomised partner -sexual abstinence
- 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
- 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
- France: Known HIV infection or active hepatitis B or C. / Germany: HIV infection or active hepatitis B or C (test prior to inclusion required)
- 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-221 or any of its excipients
- No affiliation to a health insurance system
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 18 Feb 2019 | 63 |
 Germany | Not Recruiting | 18 Feb 2019 | 5 |
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 |
|---|---|---|---|---|---|---|
Enasidenib Mesilate | Test | FILM-COATED TABLET | ORAL USE | 50 | 24 | PRD11286343 |
Enasidenib Mesilate | Test | FILM-COATED TABLET | ORAL USE | 100 | 24 | PRD11286365 |