IDH2 (AG 221) Inhibitor in Patients With IDH2 Mutated Myelodysplastic Syndrome
- Conditions
- Leukemia Acute MyeloidMyelodysplastic Syndromes
- Interventions
- Registration Number
- NCT03744390
- Lead Sponsor
- Groupe Francophone des Myelodysplasies
- Brief Summary
patients with MDS (Myelodysplastic Syndrome) and mutated IDH2 patients will be treated with AG221 (IDH2 inhibitor)
- Detailed Description
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 伪-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic chol-, and hematologic angiosarcomas c 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 antimetabolite, 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 differentiation.
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-221, a selective inhibitor of the IDH2 mutant enzyme Overall, in myeloid malignancies, AG221 have been mainly used in generally heavily pretreated AML, with about 40% of responses in patients with the respective IDH 1 and IDH2 mutations, and a median response duration exceeding 1 year when CR or PR was achieved.
Based on these results, the investigators hypothesize that the IDH2 inhibitor (AG 221) may be an effective therapeutic option in patient with IDH2 mutation-positive myelodysplastic syndrome This is an open-label, single-arm multicenter, phase II study
The efficacy of AG 221 will be studied in 3 different groups of MDS patients with IDH-1 mutation:
* Cohort A:Higher risk MDS (IPSS int-2, high) without response (CR,PR,stable disease with HI) after at least 6 cycles of azacitidine or relapse after a response but without overt progression (defined by at least doubling of marrow blasts, compared to pre azacitidine bone marrow, or by AML progression beyond 30% blasts)
* Cohort B:Untreated higher risk MDS (IPSS int-2, high) without life threatening cytopenias (ie red blood cell (ANC) \< 500/mm3 or any recent severe infection and/or platelets below 30,000/mm3 and any bleeding symptom). Azacitidine will be added after 3 cycles of AG-221 in the absence of response
* Cohort C: Lower risk MDS with anemia resistant to erythropoietic stimulating agents (primary or secondary resistance)
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 68
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description AG-221 AG-221 Subjects enrolled will receive continuous 28-day cycles of AG-221 - 100 mg.
- Primary Outcome Measures
Name Time Method Overall hematological response 6 months Overall hematological response
- Secondary Outcome Measures
Name Time Method Progression IPSS 3 years Progression IPSS
Duration Response 3 years Duration Response
Trial Locations
- Locations (22)
CHU de Bordeaux
馃嚝馃嚪Bordeaux, France
H么pital Henri Mondor
馃嚝馃嚪Cr茅teil, France
H么pital Andr茅 Mignot
馃嚝馃嚪Versailles, Le Chesnay, France
CHU C么te de Nacre/Service d'H茅matologie Clinique
馃嚝馃嚪Caen, France
CH d'Angers/Service des Maladies du sang
馃嚝馃嚪Angers, France
CH de la Cote Basque
馃嚝馃嚪Bayonne, France
centre hospitalier Victor Dupouy
馃嚝馃嚪Argenteuil, France
CH Le Mans/Service d'h茅matologie Oncologie
馃嚝馃嚪Le Mans, France
CHU de Grenoble
馃嚝馃嚪Grenoble, France
CH lyon
馃嚝馃嚪Lyon, France
Institut Paoli Calmettes/Unit茅 d'H茅matologie 3
馃嚝馃嚪Marseille, France
CHU Montpellier St Eloi
馃嚝馃嚪Montpellier, France
GHR Mulhouse Sud-Alsace
馃嚝馃嚪Mulhouse, France
CHU Nantes - H么tel Dieu/Service d'H茅matologie Clinique
馃嚝馃嚪Nantes, France
H么pital Archet 1/Service d'H茅matologie Clinique
馃嚝馃嚪Nice, France
CHU de Nimes
馃嚝馃嚪N卯mes, France
H么pital Saint Louis - Service d'h茅matologie s茅niors
馃嚝馃嚪Paris, France
H么pital saint Antoine
馃嚝馃嚪Paris, France
Centre Henri Becquerel/D茅partement d'H茅matologie
馃嚝馃嚪Rouen, France
Institut de canc茅rologie Lucien Neuwirth Saint priest en Jarez
馃嚝馃嚪Saint-Priest-en-Jarez, France
M茅decine Interne/IUCT Oncopole
馃嚝馃嚪Toulouse, France
CHU de Tours
馃嚝馃嚪Tours, France