SAN DIEGO – Five of seven evaluable patients with advanced hematologic malignancies demonstrated complete remission or complete remission with partial platelet count recovery after treatment with AG-221, an oral first-in-class drug that exploits cancer metabolism, according to preliminary findings from a phase I trial.
"This data is kind of unheard of," Dr. Eytan M. Stein said during a press briefing at the annual meeting of the American Association for Cancer Research. "It’s early clinical data – we’ll have to see what happens to the other patients who are on study – but I would say that this is an extremely exciting result."
Dr. Eytan M. Stein
A novel agent being developed by Cambridge, Mass.–based Agios Pharmaceuticals, AG-221 acts by interfering with cancer metabolism to halt tumor growth. It is an oral inhibitor of the isocitrate dehydrogenase-2 (IDH2) protein and is administered once or twice daily in a 28-day cycle.
IDH2 mutations are found in 10%-15% of acute myelogenous leukemias (AML), 5% of myelodysplastic syndromes/multiple primary neoplasms (MDS/MPN), and 25% of angioimmunoblastic non-Hodgkin lymphomas.
Mutations in the genes for the metabolic enzyme are thought to be the drivers of distinct subsets of AML, by allowing increased production of 2-hydroxyglutarate, an oncometabolite. Researchers hypothesized that blocking production of the enzyme may lead to clinical benefit in patients with these mutations.
In September 2013, Dr. Stein and his associates conducted a single-arm, phase I, open-label study of AG-221 as single-agent therapy with continuous oral daily dosing in 28-day cycles. Patients received the drug at a dose of 30 mg b.i.d., 50 mg b.i.d., 75 mg b.i.d., or 100 mg b.i.d. The median age of the population was 62.5 years, and participants included those with relapsed or refractory AML and MDS, or patients over age 60 who were unable to be treated with conventional therapy because of comorbid medical conditions.
"They had to be IDH2 mutation positive to get into the trial," Dr. Stein explained. "The key objectives were to assess the safety and tolerability; determine maximum tolerated dose and recommended phase II dose; determine dose-limiting toxicity, pharmacokinetics, and pharmacodynamics; and characterize differentiation effect and clinical activity."
As of March 20, 2014, there were 22 patients enrolled and 16 patients remain on study. Dr. Stein reported that there have been two possible treatment-related serious adverse events to date: one grade 2 hyperleukocytosis and differentiation syndrome, and one case of grade 3 confusion in the setting of respiratory failure in a patient with sepsis. There have been four deaths within 30 days of study drug termination, all stemming from complications of disease-related sepsis. "This is not unusual for patients with refractory AML, who are often very ill," Dr. Stein said.
The researchers observed a greater than 90% plasma 2-hydroxyglutarate reduction after multiple doses, providing proof of concept for the drug mechanism. In the 30-mg b.i.d. cohort, there was one complete remission and one complete remission with incomplete platelet recovery. In the 50-mg b.i.d. cohort, there were two complete remissions and one complete remission with an incomplete platelet count recovery, one partial remission, and one patient with progressive disease.
"Overall, this shows that out of the seven patients who were evaluable for efficacy, five of the patients achieved complete remission or complete remission with partial platelet count recovery," Dr. Stein said. "What that means is that there is no more leukemia in the bone marrow; their platelet count just has not risen to above 100,000/mcL."
Preliminary analysis of pharmacokinetics at the 30- and 50-mg dose levels showed a mean plasma half-life of greater than 40 hours. Moving forward, dose escalation will continue, he said, as the maximum tolerated dose has not yet been realized. Expansion cohorts are scheduled to begin in late 2014.
"These data provide early validation of mutant IDH-2 as a therapeutic target in AML and MDS," Dr. Stein said. "We’re going to be further characterizing the safety, pharmacokinetics/pharmacodynamics, and response rate of AG-221 in AML. Down the road, we’re hoping to evaluate this agent in combinations and in earlier lines to treatment. We’re also going to be exploring the activity of AG-221 in other IDH2-mutation-positive hematologic malignancies and solid tumors."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, said that she was impressed by the study’s findings in the context of refractory AML. "To be able to get responses with a drug that’s not nearly as toxic as chemotherapy, that is much more tolerable than chemotherapy, is exciting," she said.