MILAN – The investigational drug AG-221 induced responses in more than half of patients with advanced IDH2 mutation–positive hematologic cancers, updated phase I data showed.
Among 25 evaluable patients, 14 responded to treatment with AG-221: 6 had complete responses, 2 had complete responses with incomplete platelet count recovery, 1 had a complete response with incomplete hematologic recovery, and 5 had partial responses.
Twelve of 14 responses are ongoing, and five patients with stable disease remain on study.
Responses are seen in acute myelogenous leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia, Dr. Stéphane de Botton said during a late-breaking abstract session at the annual congress of the European Hematology Association.
"Very interestingly, at least in five patients, the duration of the responses has reached greater than 2.5 months," he said.
AG-221 is a first-in-class inhibitor of the isocitrate dehydrogenase–2 (IDH2) protein and was just granted orphan drug status by the Food and Drug Administration for the treatment of acute myelogenous leukemia (AML).
About 15% of patients with AML carry an IDH2 mutation, as do 5% with myelodysplastic syndromes.
An initial report from this phase I, multicenter study showed five of seven patients evaluable at that time had a complete response or platelet count recovery after treatment with AG-221.
Of the 35 patients now enrolled, 27 had relapsed or refractory AML, 4 had myelodysplastic syndromes, 2 had untreated AML, 1 had chronic myelomonocytic leukemia, and 1 had granulocytic sarcoma. Patients’ mean age was 66 years, 31 had IDH2 R140Q mutations, and 4 had IDH2 R172K mutations.
Up to 100% plasma 2-hydroxyglutarate inhibition was seen after multiple doses in R140Q patients and up to 60% plasma 2-HG inhibition, in R172K patients, said Dr. de Botton, head of hematology, Institut Gustave Roussy, Villejuif, France.
Dose escalation has continued with single-agent oral dosing ranging from 30 mg twice daily to 150 mg once daily in 28-day cycles. The results were very similar with 50 mg b.i.d. and 100 mg every day.
AG-221 was also "remarkably well tolerated," with the maximum tolerated dose yet to be reached, he said.
The majority of adverse events are grade 1 and 2, notably edema, leukocytosis, nausea, sepsis, and thrombocytopenia.
Grade 3 or higher events in 18 evaluable patients included 3 cases each of thrombocytopenia and febrile neutropenia, 2 of leukocytosis, and 1 case each of diarrhea and rash, he said.
There have been four possible treatment-related serious adverse events: grade 3 confusion and grade 5 respiratory failure in a patient with severe sepsis, one case of grade 3 leukocytosis along with grade 3 anorexia and grade 1 nausea, one case of grade 3 diarrhea, and one case of grade 3 leukocytosis.
There have been seven deaths within 30 days of study drug termination: five stemming from complications of disease-related sepsis, one from complications of a humeral fracture not related to the study drug, and one from stroke, also unrelated to treatment, Dr. de Botton said.
"AG-221 is safe and well tolerated to date with durable clinical activity," he concluded.
Dr. de Botton reported research funding from Agios Pharmaceuticals, the study sponsor.