The open-label, multi-center, Phase 2 study randomized 63 patients aged 60 years or older with MDS of intermediate-2 (n=52) or high-risk (n=11) classification by the International Prognostic Scoring System (IPSS) at study entry to receive sapacitabine every 4 weeks on one of 3 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.
About Myelodysplastic Syndromes (MDS)
MDS is a family of clonal myeloid neoplasms, or malignancies of the blood, caused by the failure of blood cells in the bone marrow to develop into mature cells. Patients with MDS typically suffer from bone marrow failure and cytopenias, or reduced counts of platelets, red and white blood cells. The exact incidence and prevalence of MDS are unknown because it can go undiagnosed and 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 each year in the US alone with some authors estimating incidence as high as 46,000. Literature evidence suggests that there is a rising incidence of MDS as the age of the population increases with the majority of patients aged above 60 years.
Median survival for patients with intermediate-2 or high-risk disease, as defined by the International Prognostic Scoring System (IPSS), is 4.3 to 5.6 months.
Patients with high IPSS scores also have a high probability of experiencing transformation of their MDS into AML, an aggressive form of blood cancer with typically poor survival.
Prebet T, Gore S, et al, Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure, Journal of Clinical Oncology 2011, 10.1200/JCO.2011.35.8135.
Jabbour E, Garcia-Manero G, et al, Outcome of Patients With Myelodysplastic Syndrome After Failure of Decitabine Therapy, Cancer 2010, 10.1002/cncr.25247.
Sapacitabine (CYC682), an orally-available nucleoside analogue, is in the SEAMLESS, registration-directed, Phase 3 trial in elderly patients with newly diagnosed acute myeloid leukemia (AML), and in the investigator-led, Phase 2/3 LI-1 Trial in patients aged 60 years or older with previously untreated AML or high risk MDS who are unfit for intensive chemotherapy. Sapacitabine is in Phase 2 trials in patients with hematological malignancies, including myelodysplastic syndromes (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and non-small cell lung cancer (NSCLC), a Phase 1 trial in combination with seliciclib in patients with advanced solid tumors and an investigator-led, Phase 2/3 study comparing sapacitabine to low dose cytarabine as front-line treatment of elderly patients with AML or high risk MDS unfit for intensive chemotherapy. Sapacitabine acts through a novel DNA single-strand breaking mechanism, leading to production of DNA double strand breaks (DSBs) and/or checkpoint activation. Unrepaired DSBs cause cell death. Repair of sapacitabine-induced DSBs is dependent on the homologous recombination DNA repair (HRR) pathway. Both sapacitabine and CNDAC, its major metabolite, have demonstrated potent anti-tumor activity in preclinical studies.