Clinical Trials

Date: 2017-06-03

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago

Company: Agios Pharmaceuticals (USA -MA)

Product: AG-120 (ivosidenib)

Action mechanism:

• enzyme inhibitor/isocitrate dehydrogenase inhibitor . AG-120 (ivosidenib) is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH1 (Isocitrate dehydrogenase 1) protein, and is a highly targeted investigational medicine for the treatment of patients with cancers that harbor an IDH1 mutation. Isocitrate dehydrogenase (IDH) 1 and 2 are metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myelogenous leukemia (AML) and glioma, a type of aggressive brain tumor with poor prognosis. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH creates a molecule that alters the cells’ genetic programming, and instead of maturing, the cells remain primitive and proliferate quickly. AG-120 is being developed in collaboration with Celgene.

Disease: cholangiocarcinoma

Therapeutic area: Cancer - Oncology - Rare diseases

Country:

Trial details:

Latest news:

• • On June 3, 2017, Agios Pharmaceuticals presented updated data from the dose-escalation and expansion cohorts of the Phase 1 study evaluating single agent AG-120 (ivosidenib) in isocitrate dehydrogenase-1 (IDH1) mutant positive cholangiocarcinoma at the American Society of Clinical Oncology (ASCO) Annual Meeting being held June 2-6, 2017 in Chicago.
• The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, cholangiocarcinoma and chondrosarcomas with an IDH1 mutation. Enrollment is now complete for the dose-escalation and expansion cohorts. As of March 10, 2017, 73 patients with IDH1 mutant positive cholangiocarcinoma have been treated with single agent AG-120 in the dose escalation (n=24) and expansion cohorts (n=49). Thirteen patients remain on treatment. AG-120 was administered at the following dose levels and schedules in the dose-escalation cohort: 100 mg twice daily, and 300, 400, 500, 800 and 1200 mg once a day over a 28 day cycle length. In the dose expansion cohort, patients received 500 mg once a day, which was the selected dose for the ongoing Phase 3 ClarIDHy trial. Among the Phase 1 cholangiocarcinoma population, the median age is 60 (ranging from 32-81). Sixty-five patients had intrahepatic cholangiocarcinoma and eight had extrahepatic disease. The median number of prior systemic therapies was two (ranging from one to five) and 97% of patients received a prior gemcitabine-based chemotherapy regimen.
• A safety analysis conducted for all 73 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in IDH1 mutant positive cholangiocarcinoma patients. No dose limiting toxicities or treatment-related deaths have been observed. The majority of adverse events  reported were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea and decreased appetite. Four patients experienced drug-related adverse events ? grade 3: two at the 500 mg dose level, fatigue (n=1) and blood alkaline phosphatase increases (n=1) and two at the 1200 mg dose level, fatigue (n=1) and blood phosphorous decreases (n=1). One patient had a dose reduction for a grade 2 adverse event of worsening leg cramps that was considered to be possibly drug-related. Efficacy Data: Efficacy data from all 73 treated patients as of the data cut-off showed:
• Four patients (5%) experienced a confirmed partial response (one at 300 mg QD and three at 500 mg QD). A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
• Forty-one patients (56%) experienced stable disease. Landmark analyses of progression free survival at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3).
• AG-120 treatment inhibited plasma 2-hydroxyglutarate (2-HG) to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies, with 2-HG levels in plasma and tumor biopsies showing a positive correlation. Pathology review of on-study tumor biopsies were conducted in a patient achieving a partial response, which showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of AG-120.

Is general: Yes