Phase I Study of Oral Clofarabine Consolidation in Adults Aged 60 and Older with Acute Myeloid Leukemia,

Less than 16% of adults aged 60 and older diagnosed with acute myeloid leukemia (AML) will remain disease free after cytarabine consolidation. Clofarabine (clo) is a next generation nucleoside analogue whose IV formulation has shown considerable activity in older patients with AML considered unlikely to benefit from conventional therapy. This phase I trial is the first study of an oral formulation of clo for consolidation in patients >= 60 with AML who achieve a remission with cytotoxic induction regimens.

The primary objective was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oral clo on a 21 day dosing schedule for consolidation therapy. For safety reasons, the initial cohort was tested on a 14 day schedule. Tolerability of the regimen was a secondary objective. Six cohorts were tested (1 mg × 14 days, and 1 mg, 2 mg, 3 mg, 4 mg, and 6 mg × 21 days) with oral clo administered once daily for 14 or 21 days of a 28 day cycle, for up to 5 cycles. DLT were assessed during cycle 1 and defined as Grade 4 neutropenia lasting >=14 days or Grade 3–4 neutropenia with infection; Grade 4 thrombocytopenia >= 7 days or Grade 3–4 thrombocytopenia with bleeding; or Grade 3 or 4 non-hematologic toxicities with the exception of drug-related fever, alopecia, anorexia, or adequately treated nausea, vomiting and/or diarrhea.

Twenty patients were enrolled on the dose escalation phase of the study. Seventeen patients completed at least 1 cycle and were thus evaluable for response, while 3 patients were taken off study prior to completion of cycle 1 due to relapse. No DLTs were observed in any cohort. At the 1 mg dose, 3 patients completed all 5 cycles of therapy (2 on the 21 day schedule), 2 patients relapsed after 2 or 3 cycles, (21 day and 14 day schedule, respectively), and 1 patient withdrew after completion of cycle 1 (14 day schedule). At the 2 mg dose, 2 patients completed all 5 cycles and 1 patient relapsed after cycle 1. The 1 mg dose on both dosing schedules and the 2 mg dose were well-tolerated and did not require dose reductions. Of the 3 patients enrolled at the 3 mg dose, one completed 5 cycles with a dose reduction to 2 mg after the first cycle for intermittent grade 4 neutropenia, 1 patient completed 3 cycles with no evidence of disease, then received allogeneic transplant at the discretion of the treating physician, and the final patient completed 3 cycles with persistent grade 2–3 neutropenia and thrombocytopenia and was taken off study for evidence of minimal residual disease. In the 4 mg cohort, 2 patients completed 3 cycles and were subsequently taken off study, one to proceed to allogeneic transplant at the discretion of the treating physician and one for recurrent disease. A third patient completed 2 cycles and has proceeded to allogeneic transplant for recurrent disease. The fourth patient was dose reduced to 3 mg after the first cycle for grade 3 thrombocytopenia, completed a total of 3 cycles, and was subsequently taken off study for persistent cytopenias. One patient received the 6 mg dose and required 2 dose reductions (to 4mg and then 3 mg) for grade 3–4 neutropenia and thrombocytopenia. Therefore, enrollment at the 6 mg dose level was halted. Grade 1–2 non-hematologic toxicities occurring in >=30% of patients were fatigue, diarrhea, nausea, hyperbilirubinemia, elevated AST or ALT, infection, hyperglycemia, electrolyte abnormalities, hypoalbuminemia, dizziness, cough, SOB, and anxiety. Grade 3 non-hematologic toxicities included: fatigue (1), AST elevation (1), hyperglycemia (3), hyperbilirubinemia (1) and anxiety (1). These Grade 3 toxicities were transient and did not require dose reductions. No Grade 4 toxicities occurred.

Oral clo consolidation is a well-tolerated regimen in adults aged 60 or older with acute myeloid leukemia in remission. Although the MTD is undefined as no DLTs occurred in any cohort, Grade 3–4 cytopenias halted enrollment at the 6 mg dose and patients in both the 3 and 4 mg cohorts required dose reductions subsequent to cycle 1 for cytopenias. Future studies investigating clo as a maintenance strategy appear feasible at 3 mg with an option to dose reduce in the setting of prolonged cytopenias.

Off Label Use: Clofarabine is a purine nucleoside inhibitor indicated for the treatment of pediatric patients aged 1 to 21 with relapsed or refractory ALL. Cashen:Genzyme: Membership on an entity's Board of Directors or advisory committees. Uy:Genzyme: Consultancy. Abboud:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.