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Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.
The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.
The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.
They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.
“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.
Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.
The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m2 to 125 mg/m2.
The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).
The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.
Safety and efficacy
The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).
The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).
There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m2 daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with AML.
Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2. So the team recommended this as the phase 2 dose.
A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.
Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.
