Credit: University of Colorado
BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.
Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.
“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,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”
Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.
In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.
The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to
receive AG-120 in 1 of 4 dose groups: 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.
Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.
Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.
“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.
He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.
Eight patients experienced serious adverse events, but these were primarily related to disease progression.
One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.
The maximum-tolerated dose of AG-120 has not been reached.
There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.
Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.
