ENASIDENIB MESILATE for Myelodysplastic syndrome with IDH2 mutation

Inclusion criteria

• {"criterion_text":"- Myelodysplastic syndrome according to WHO classification including non-proliferative AML up to 29% of BM blast"}
• {"criterion_text":"- Patient must understand and voluntarily sign consent form"}
• {"criterion_text":"- Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements"}
• {"criterion_text":"- ECOG performance status 0-2 at the time of screening"}
• {"criterion_text":"- 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. •\tFrance: 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. •\tGermany: 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) -\tprogestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable) -\tintrauterine device (IUD) -\tintrauterine hormone-releasing system ( IUS) -\tbilateral tubal occlusion -\tvasectomised partner -sexual abstinence"}
• {"criterion_text":"- Male patients must : -\tAgree 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. -\tAgree to learn about the procedures for preservation of sperm before starting treatment"}
• {"criterion_text":"- Age ≥ 18 years"}
• {"criterion_text":"- Belonging to one of the following categories: 1.\thigher 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.\tUntreated 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.\tLower 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"}
• {"criterion_text":"- Presence of IDH2 mutation in either blood or marrow prior to start of therapy"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Adequate cardiac ejection fraction (>40%)"}
• {"criterion_text":"- Patient is not known to be refractory to platelet transfusions"}
• {"criterion_text":"- Written informed consent"}

Exclusion criteria

• {"criterion_text":"- Severe infection or any other uncontrolled severe condition"}
• {"criterion_text":"- Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form"}
• {"criterion_text":"- Patient eligible for allogeneic stem cell transplantation"}
• {"criterion_text":"- Known allergies to AG-221 or any of its excipients"}
• {"criterion_text":"- No affiliation to a health insurance system"}
• {"criterion_text":"- Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months"}
• {"criterion_text":"- Less than 14 days since prior treatment with growth factors (EPO, G-CSF)."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Patient already enrolled in another therapeutic trial of an investigational drug"}
• {"criterion_text":"- France: Known HIV infection or active hepatitis B or C. / Germany: HIV infection or active hepatitis B or C (test prior to inclusion required)"}
• {"criterion_text":"- Women who are or could become pregnant or who are currently breastfeeding"}

Primary endpoints

• {"endpoint_text":"- Overall hematological response at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006) for cohort A and B; SAFETY FOR COHORT C","definition_or_measurement_approach":"Response evaluated using IWG 2006 criteria (CR, PR, stable disease with HI). Safety (cohort C) assessed using CTCAE Version 5 for non-hematological toxicities."}

Secondary endpoints

• {"endpoint_text":"- Response duration and Time response","definition_or_measurement_approach":"Duration of response and time to response (as listed in secondary objectives)."}
• {"endpoint_text":"- Time to IPSS and IPSS-R progression","definition_or_measurement_approach":"Time until progression assessed by IPSS and IPSS-R criteria."}
• {"endpoint_text":"- Rate and time to AML evolution","definition_or_measurement_approach":"Rate and interval to progression to acute myeloid leukemia (AML)."}
• {"endpoint_text":"- Overall survival","definition_or_measurement_approach":"Overall survival (OS) measured from baseline to death."}
• {"endpoint_text":"- Cytogenetic and molecular response","definition_or_measurement_approach":"Assessment of cytogenetic and molecular response (including IDH2 VAF monitoring)."}
• {"endpoint_text":"- Prognostic factors of response, including IPSS-R, IPSS-karyotype and somatic mutations","definition_or_measurement_approach":"Identification of prognostic/predictive factors including IPSS-R, karyotype and somatic mutations."}
• {"endpoint_text":"- Evolution of IDH2 VAF on therapy","definition_or_measurement_approach":"Monitoring IDH2 variant allele frequency (VAF) over the course of therapy."}
• {"endpoint_text":"- Adverse events and toxicity as measured by NCI CTCAE 5","definition_or_measurement_approach":"Adverse events and toxicity graded according to NCI CTCAE version 5."}

France

Earliest CTIS Part Ii Submission Date

04-11-2024

Latest Decision Or Authorization Date

31-12-2024

Processing Time Days

57

Number Of Sites

22

Number Of Participants

63

Germany

Earliest CTIS Part Ii Submission Date

04-11-2024

Latest Decision Or Authorization Date

02-01-2025

Processing Time Days

59

Number Of Sites

1

Number Of Participants

5

Primary sponsor

Full Name

Groupe Francophone Des Myelodysplasies

Organisation Type

Patient organisation/association

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"Celgene/Bristol Myers Squibb (BMS)","duties_or_roles":"Source of monetary support","organisation_type":""}