AZACITIDINE for Myelodysplastic syndrome (IDH1‑mutated)

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years\n- 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 •\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\n- Presence of IDH1 mutation in either blood or marrow prior to start of therapy\n- 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\n- Normal liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal\n- Adequate cardiac ejection fraction (>40%);\n- Patient is not known to be refractory to platelet transfusions;\n- Patient must understand and voluntarily sign consent form\n- Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements\n- ECOG performance status 0-2 at the time of screening\n- 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.\n- 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

• {"criterion_text":"- Severe infection or any other uncontrolled severe condition\n- Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months\n- No affiliation to a health insurance system.\n- Less than 14 days since prior treatment with growth factors (EPO, G-CSF)\n- 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.\n- 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\n- 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\n- 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\n- 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\n- Patient already enrolled in another therapeutic trial of an investigational drug\n- Known HIV infection or active hepatitis B or C\n- Women who are or could become pregnant or who are currently breastfeeding\n- Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form\n- Patient eligible for allogeneic stem cell transplantation\n- Known allergies to AG-120 or any of its excipients\n- 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.)\n- Subjects with a known medical history of progressive multifocal leukoencephalopathy (PML) should be excluded from the study"}

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":"Hematological response defined using IWG 2006 criteria (CR, PR, stable disease with HI). Safety for cohort C assessed using CTCAE version 5 for non-hematological toxicities."}

Secondary endpoints

• {"endpoint_text":"- Response duration and time response\n- Time to IPSS and R-IPSS progression\n- Rate and time to AML evolution\n- Overall survival\n- Cytogenetic and molecular response\n- Prognostic factors of response, including IPSS-R, IPSS-karyotype and somatic mutations\n- Evolution of IDH1 VAF on therapy\n- Adverse events and toxicity as measured by NCI CTCAE 5","definition_or_measurement_approach":"Response duration/time to response (method not further specified); progression by IPSS/R-IPSS; AML evolution rate/time (method not further specified); overall survival measured as time-to-death; cytogenetic and molecular response assessed by cytogenetic and molecular assays; IDH1 VAF evolution measured by allele frequency on therapy; adverse events graded per NCI CTCAE v5."}

France

Earliest CTIS Part Ii Submission Date

16-07-2024

Latest Decision Or Authorization Date

02-08-2024

Processing Time Days

17

Number Of Sites

25

Number Of Participants

48

Primary sponsor

Full Name

Groupe Francophone Des Myelodysplasies

Organisation Type

Patient organisation/association

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"SERVIER (formerly AGIOS)","duties_or_roles":"Source of monetary support","organisation_type":""}