Date: 2016-11-18
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of resultsat the Society for Neuro-Oncology (SNO) Annual Meeting in Scottsdale
Company: Agios Pharmaceuticals (USA -MA)
Product: AG-120 - isocitrate dehydrogenase 1 (IDH1)-mutant inhibitor
Action
mechanism: protein inhibitor. AG-120 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: isocitrate dehydrogenase-1 (IDH1) mutant positive glioma and chondrosarcoma
Therapeutic area: Cancer - Oncology
Country: France, USA
Trial
details: The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four arms of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or at Investigator discretion. (NCT02073994)
Latest
news: * On November 18, 2016, Agios Pharmaceuticals announced the first data from the dose expansion cohorts of the Phase 1 study evaluating single agent AG-120 in isocitrate dehydrogenase-1 (IDH1) mutant positive glioma and chondrosarcoma. The glioma data were presented at the Society for Neuro-Oncology (SNO) Annual Meeting in Scottsdale, AZ and the chondrosarcoma data were presented last week at the annual meeting of the Connective Tissue Oncology Society (CTOS) in Lisbon, Portugal .
"Glioma and chondrosarcomas are extremely difficult-to-treat diseases where patients are in need of new therapies," said Chris Bowden , M.D., chief medical officer at Agios. "These Phase 1 dose expansion data are encouraging, as they continue to demonstrate a well-tolerated safety profile for AG-120 at a fixed daily dose of 500 mg. The prolonged stable disease in both patient populations is encouraging in light of AG-120's unique differentiation mechanism of action. In addition, our initial experience utilizing centralized volumetric assessments in patients with glioma has been informative, and along with our ongoing AG-881 Phase 1 trial, will help determine the next steps in clinical development."
"In glioma, AG-120 has the potential to help a large number of patients with IDH1 mutations," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center , an investigator for the study. "The SNO presentation is the first look at data for AG-120 in a defined cohort of glioma patients where we evaluated the potential for volumetric analyses to improve our understanding of the response patterns beyond the conventional bi-dimensional methods. This methodology could be instrumental in developing more effective, targeted therapies for patients with this disease."
The Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, intrahepatic cholangiocarcinoma (IHCC) and chondrosarcomas that harbor an IDH1 mutation. The dose-escalation phase was followed by four expansion cohorts in the following patient groups.
As of the August 1, 2016 data cut off, 66 patients have been treated with single agent AG-120, and 28 patients (42%) remain on treatment. Data reported are from 20 patients who received AG-120 administered from 200 mg to 1200 mg total daily doses in the dose-escalation phase. Forty-six patients who received 500 mg daily doses of AG-120 administered in two expansion cohorts, including 24 patients enrolled in a cohort with non-enhancing glioma and 22 glioma patients with enhancing disease enrolled in a basket cohort.
The median age of these patients is 41 (ranging from 21-71). The median number of prior therapies was two (ranging from one to six) and included temozolomide (71%). Seventy-four percent of patients received radiotherapy.
A safety analysis conducted for all 66 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in glioma patients.
No dose limiting toxicities have been observed.
The majority of adverse events reported by investigators were mild to moderate, with the most common being headache, nausea, diarrhea and vomiting.
There were 11 patients with serious adverse events (SAE) and none of them were drug-related.
Efficacy data from 65 response-evaluable patients as of the data cut-off showed:
Two patients had a minor response according to the Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG).
Forty-one (63%) patients had stable disease, including 27 with non-enhancing disease; the median treatment duration for non-enhancing glioma was 8.1 months (ranging from 1.4 - 17.8 months).
Volumetric analysis conducted centrally demonstrated stabilization or a decrease in tumor growth rate compared to the pretreatment rate in 64% (n=14 of 22) of glioma patients with non-enhancing disease receiving AG-120 and requires further development as a response evaluation tool.
Chondrosarcoma Expansion Data Presented at CTOS Annual Meeting
Agios also analyzed data from 21 chondrosarcoma patients as of September 23, 2016 in the dose escalation (n=12) and expansion cohorts (n=9) and 7 remain on treatment.
Doses received were 100 mg twice daily, and 300, 400, 500, 600, 800, 900 and 1200 mg once a day. Expansion cohort patients received 500 mg once a day. Median treatment duration was 2.6 months (ranging from 0.0-24.4 months).
Prior therapy included surgery (57%), radiotherapy (33%) and chemotherapy (24%). The median number of prior systemic therapies was one (ranging from one to five).
No dose-limiting toxicities were reported; the majority of adverse events reported by investigators were mild to moderate, with the most common being diarrhea, nausea, decreased appetite, QT prolongation and fatigue.
Most SAEs were considered unrelated to treatment with one case of hypophosphatemia (low phosphorous blood level) considered to be possibly related to treatment.
Of 20 response-evaluable patients, 11 (55%) experienced stable disease as their best response; the 3-month progression-free survival rate was 58%.
Baseline plasma levels of the oncometabolite D-2-hydroxyglutarate (2-HG) were elevated above the healthy volunteer range. Treatment with AG-120 resulted in significant reduction of plasma 2-HG compared to baseline. Up to 99.7% tissue 2-HG reduction was documented in paired biopsies obtained from 3 patients treated with AG-120. Together these data indicate the on-target pharmacodynamic effects of AG-120.
