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. These results were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

Early results from the phase 1 clinical trial of the drug 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. These results were presented by Daniel Pollyea, MD, clinical director of leukemia services and assistant professor of medicine at the University of Colorado in Boulder.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation. Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of Phase I studies are to determine safety and tolerability,” said Pollyea.

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The first clinical trial of AG-120 in hematologic cancers started in March 2014 and, as of the data cut-off date of October 17, 2014, 17 patients with relapsed and/or refractory AML had been enrolled into 1 of 4 dose groups with four or five patients in each, 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. Patients had received a median of two prior treatments.

In the first four groups of patients treated in the trial with AG-120, 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 researchers are continuing to increase the dose; the maximum tolerated dose has not been reached yet.

“These data suggest that using AG-120 to inhibit the IDH1 mutation has the potential to stop the production of 2HG, and encourage cancerous cells to become mature, functioning blood cells. These findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” said Pollyea.

The phase 1 trial is continuing, and now enrolling patients with difficult-to-treat AML whose cancers have failed to respond to previous treatment and/or have relapsed, or who are older than 60 years with untreated AML or myelodysplastic syndromes. All harbor the IDH1 mutation. The prognosis for these cancers is poor: overall, only 25% of patients with AML will live for 5 years; but among patients older than 60 years, who tend to respond less well to treatments, only approximately 12% are alive after 5 years.