CHICAGO—Updated data from an ongoing, multicenter, phase II randomized trial of oral sapacitabine indicate that the drug is active in older patients with myelodysplastic syndromes (MDS) refractory to front-line hypomethylating agents.
"MDS patients have a poor outcome after treatment failures with front-line therapies,” said lead investigator Hagop Kantarjian, MD, the University of Texas MD Anderson Cancer Center, Houston. “Effective therapies are urgently needed for these patients."
Median survival for patients with intermediate-2 or high-risk MDS following treatment failures of hypomethylating agents such as azacitidine (Vidaza) and/or decitabine (Dacogen) is 4.3 to 5.6 months, noted Dr. Kantarjian. Median overall survival to date for patients treated with sapacitabine is 252 days, or approximately 8.4 months.
The study included 63 patients aged 60 years or older with MDS of intermediate-2 (52 patients) or high-risk (11 patients) classification by the International Prognostic Scoring System (IPSS) who were randomized to receive sapacitabine every 4 weeks on one of three dosing schedules: 200 mg twice daily for 7 days (Arm G), 300 mg once daily for 7 days (Arm H), or 100 mg once daily for 5 days per week for 2 weeks (Arm I). The primary efficacy endpoint of the study is 1-year survival with the objective of identifying a dosing schedule that produces a better 1-year survival rate in the event that all three dosing schedules are active. All patients in the study progressed after receiving azacitidine, decitabine, or both agents.
Median overall survival was reported as 240 days (approximately 8 months) for Arm G, 290 days (approximately 10 months) for Arm H, and 153 days (approximately 5 months) for Arm I. Complete remissions (CRs) and major hematologic improvement (HI) in platelet counts or neutrophils, secondary efficacy endpoints in the study, were observed on all three dosing schedules: 1 CR and 3 HIs in Arm G, 1 CR and 2 HIs in Arm H, and 2 CRs and 1 HI in Arm I. The 30-day mortality from all causes is 5%. Forty-one percent of all patients received four or more cycles. More than 34% of the patients are still alive and longer follow-up is needed to assess 1-year survival and overall survival, said Dr. Kantarjian.
Three deaths occurred within 30 days of randomization and one death was considered to be related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, anemia, neutropenia, and thrombocytopenia, most of which were mild to moderate.
"Sapacitabine may emerge as the first oral drug that could address the unmet medical needs in both acute myeloid leukemia (AML) and MDS patients," commented Judy H. Chiao, MD, vice president, clinical development and regulatory affairs for Cyclacel, the biopharmaceutical company developing the drug.
Sapacitabine (CYC682), an orally-available nucleoside analogue, acts through a novel DNA single-strand breaking mechanism, leading to production of DNA double strand breaks and/or checkpoint activation. Unrepaired double strand breaks cause cell death. Repair of sapacitabine-induced double strand breaks is dependent on the homologous recombination DNA repair pathway.
Sapacitabine is currently being evaluated in a phase III trial in elderly patients with newly diagnosed AML; in phase II trials in patients with hematologic malignancies, including MDS, cutaneous T-cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma; a phase II trial in patients with non–small-cell lung cancer; a phase I trial in combination with seliciclib in patients with advanced solid tumors; and an investigator-led, phase II/III study comparing sapacitabine to low-dose cytarabine(Drug information on cytarabine) as front-line treatment of elderly patients with AML or high-risk MDS unfit for intensive chemotherapy.
Last year at ASCO data were reported from a pilot phase I/II study that included promising response rates, and low 4-week and 8-week mortality in elderly patients with AML aged 70 years or older receiving sapacitabine alternating with decitabine. The US Food and Drug Administration and the European Medicines Agency have designated sapacitabine as an orphan drug for the treatment of both AML and MDS.
The exact incidence and prevalence of MDS is unknown because it can go undiagnosed; a national survey canvassing both hospitals and office practitioners has not been completed. Some estimates place MDS incidence at 15,000 to 20,000 new cases or more each year in the United States alone. Incidence is believed to be rising with the increasing aging of the US population.