The experimental drug AG-120, which inhibits mutant IDH1, showed promising results in a phase I trial in patients with relapsed or refractory acute myeloid leukemia.

An experimental drug that inhibits the action of mutant isocitrate dehydrogenase 1 (IDH1) shows promise for treating patients with acute myeloid leukemia (AML), according to preliminary results from a phase I trial.

In the first human clinical trial of an IDH1-mutant inhibitor, 17 patients with relapsed or refractory AML and IDH1 mutations were enrolled in one of four groups that received AG-120 (Agios Pharmaceuticals; Cambridge, MA) in escalating doses. The trial began in March 2014, and as of October 17, seven patients were responding to treatment, including four who experienced complete remissions; three had not yet been evaluated. The findings were presented at the 26th Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, sponsored by the European Organization for Research and Treatment of Cancer, the NCI, and the American Association for Cancer Research.

“IDH1 appears to be a very viable target,” says lead investigator Daniel Pollyea, MD, clinical director of leukemia services and assistant professor of medicine at the University of Colorado in Denver. “The drug is well tolerated, and it appears to work by inducing differentiation in the leukemia cells, a very promising mechanism of action.”

The mutated form of IDH1 produces the oncometabolite R-2-hydroxy-glutarate (2-HG) that, when present in excessive amounts, alters the epigenetic programming of cells and prevents their maturation. 2-HG is present in trace amounts in normal cells but is overproduced in cancer cells with the IDH1 mutation.

“When present at very high levels, 2-HG inhibits the function of certain enzymes that are necessary for proper cell maturation, which leads to AML,” Pollyea says. “By inhibiting IDH1 mutations, 2-HG levels drop back to normal levels and the blockage in cell maturation is lifted, allowing the leukemia cells to mature, and then die.”

Patients in the study were given either 100 mg of AG-120 twice daily, or 300 mg, 500 mg, or 800 mg once daily, over continuous 28-day cycles. To date, one dose-limiting toxicity has been reported, but the maximum tolerated dose has not been reached.

More than 10% of AML patients have IDH1 mutations, and relatively few, especially those over age 60, survive 5 years following diagnosis. IDH1 mutations have also been detected in solid tumors, such as chondrosarcomas, cholangiocarcinomas, and gliomas, and other hematologic cancers, such as myelodysplastic syndromes.

Considering that some patients in the study experienced complete remission of their cancers, AG-120 may have potential to transform treatment for IDH1 mutant–positive AML, Pollyea says.

“In the phase I study, we had hoped to see a little bit of a signal that there's efficacy,” he remarks. “The fact that there were complete remissions, that there were so many complete remissions, and that the complete remissions were in many cases very rapid, and durable, was all very surprising.”

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