IDH1 Inhibitor Demonstrates Anticancer Activity in Advanced Leukemia


Key Points

  • Seven out of 14 evaluable patients with advanced AML responded to AG-120, including four with complete remissions.
  • AG-120 has been well tolerated by patients to date, and the maximum tolerated dose has not yet been reached yet.

A phase I trial of the first drug designed to inhibit the cancer-causing activity of a mutated enzyme known as isocitrate dehydrogenase (IDH) 1, which is involved in cell metabolism, has shown clinical activity in patients with advanced acute myeloid leukemia (AML) with the IDH1 mutation. The findings were reported at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona (Abstract LBA1).

Early results from the phase I clinical trial of AG-120, an oral, selective, and potent inhibitor of the mutated form of the IDH1 enzyme, have shown that the drug was well tolerated with encouraging clinical activity in patients with advanced IDH1 mutation–positive AML, reported Daniel Pollyea, MD, Clinical Director of Leukemia Services and Assistant Professor or Medicine at the University of Colorado.

Mutations in IDH1 lead to a cascade of metabolic events in cells that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which is normally present in cells in low levels. When 2-HG is present in excessive amounts, it prevents them from maturing into normal functioning cells, leading to cancer.

In this ongoing phase I study, AG-120 was able to reduce 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells. IDH1 mutations have been identified in a range of solid tumors, such as chondrosarcoma, cholangiocarcinoma and gliomas, and hematologic cancers, such as AML and myelodysplastic syndromes.

Study Details

The phase I trial is enrolling patients with relapsed or refractory AML and patients over the age of 60 who have untreated AML or myelodysplastic syndromes with IDH1 mutation. The prognosis for these cancers is poor: overall, only 25% of patients diagnosed with AML will live for 5 years, but among patients over the age of 60, who tend to respond less well to treatments, about 12% are alive after 5 years.

As of the data cutoff date of October 17, 2014. 17 patients with relapsed and/or refractory AML had been enrolled into one of four dose groups, with each group receiving the drug in tablet form at different and increasing dose levels: 100 mg twice a day, 300 mg once a day, 500 mg once a day and 800 mg once a day over continuous 28-day cycles. There are between four to five patients in each group. The median number of prior treatments before entering the study was two.

Results from 14 evaluable patients showed seven patients whose cancers responded to the drug, including four complete remissions. Three patients had not reached the time in their treatment for bone marrow assessments in the first 28-day treatment cycle, and so were not evaluable. AG-120 has been well tolerated by patients to date, and the maximum tolerated dose has not yet been reached yet.

“These data suggest that using AG-120 to inhibit the IDH1 mutation has the potential to stop the production of 2-HG and encourage cancerous cells to become mature, functioning blood cells. AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr. Pollyea said.

The study was sponsored by Agios Pharmaceuticals. For full disclosures of the study authors, view the study abstract at

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