Myelodysplastic syndrome (MDS) are clonal hematopoietic stem cell disorders characterized by
ineffective hematopoiesis leading to blood cytopenia, especially anemia, and often evolving
to Acute myeloblastic Leukemia (AML). Main prognostic factors of MDS, for progression to AML
and survival, include the number and importance of cytopenias, percent marrow blasts and bone
marrow cytogenetic abnormalities. These factors are combined in an International Prognostic
Scoring System (IPSS) that distinguishes 4 subgroups with significantly different risk of
progression to AML and survival (low, intermediate 1 (int 1), intermediate 2 (int 2), high).
Low and int 1 subgroups are often grouped together as "favorable " or low risk MDS, and int 2
and high subgroups are " unfavorable " or high risk MDS.
On the other hand, only 50 to 60% of the patients respond to Azacitidine, and most responders
relapse within 12 to 15 months resulting in a median survival of only about 6 months in these
patients,. As a result there is a need for new therapies in patients who fail to respond to
azacitidine or decitabine and for whom there is currently no establish treatment.
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert
isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including
low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic chol-
angiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a
gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess
of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes
with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high
levels of D-2HG inhibit alpha-ketoglutarate-dependent dioxygenases, including histone and DNA
demethylases, leading to histone and DNA hypermethylation and finally a block in cell
preclinical studies have demonstrated that inhibition of IDH1/2-mutant enzymes decreases
intracellular D-2-hydroxyglutarate (D-2HG) levels, reverses epigenetic dysregulation, and
releases the differentiation block.
AG-120, a selective inhibitor of the IDH1 mutant enzyme Overall, in myeloid malignancies,
AG120 have been mainly used in generally heavily pretreated AML, with about 40% of responses
in patients with the respective IDH 1 mutation, and a median response duration exceeding 1
year when CR or PR was achieved.
Based on these results, we hypothesize that the IDH1 inhibitor (AG 120) may be an effective
therapeutic option in patient with IDH1 mutation-positive myelodysplastic syndrome This is an
open-label, single-arm multicenter, phase II study
The efficacy of AG 120 will be studied in 3 different groups of MDS patients with IDH-1
- Cohort A: Higher risk MDS without response (Complete response (CR), Partial Response
(PR) ,stable disease with HI) after at least 6 cycles of azacitidine or relapse after a
- Cohort B: Untreated higher risk MDS without life threatening cytopenias (ie Absolute
neutrophil count (ANC )< 500/mm3 or any recent infection, platelets below 30,000/mm3 or
any bleeding symptom). Azacitidine will be added after 3 cycles of AG 120 in the absence
of significant IWG 2006 criteria response
- Cohort C: Lower risk MDS with anemia resistant to erythropoietic stimulating agents
(primary or secondary resistance)
- Patients must meet all of the following criteria to participate in the study:
- 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;
- 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 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
- A patient meeting any of the following criteria is not eligible to participate in the
- 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
- No affiliation to a health insurance system.