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A phase I clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias.

Author(s): Karp JE, Ricklis RM, Balakrishnan K, Briel J, Greer J, Gore SD, Smith BD, McDevitt MA, Carraway H, Levis MJ, Gandhi V

Affiliation(s): Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, United States.

Publication date & source: 2007-06-11, Blood., [Epub ahead of print]

Clofarabine has shown impressive response rates in patients with acute leukemias. In vitro investigations with clofarabine in combination with cyclophosphamide in primary cells have demonstrated synergistic cytotoxicity and inhibition of DNA repair. Based on these clinical and laboratory observations we designed a mechanism-based combination protocol with clofarabine and cyclophosphamide for patients with relapsed acute leukemias. Eighteen patients were treated with cytoxan (200 mg/m(2)) alone on day 0 and with clofarabine plus cyclophosphamide on day 1. Clinical responses, toxicity, DNA damage measured as H2AX phosphorylation, and accumulation of clofarabine triphosphate (TP) were analyzed. At dose level 1 (20 mg/m(2) clofarabine + cyclophosphamide, 6 patients) and dose level 0 (10 mg/m(2) clofarabine + cyclophosphamide, 12 patients) overall response rates were 50 and 30%, respectively, with responses in 4/6 (67%) patients with refractory acute lymphoblastic leukemia. Dose limiting toxicity occurred at dose level 1 with prolonged marrow aplasia. Four (22%) patients died from prolonged aplasia (1), fungal pneumonia (1), or multiorgan failure (2). In 12 of 13 patient samples, increased DNA damage (gammaH2AX) was observed with clofarabine and cyclophosphamide compared to cyclophosphamide alone. In conclusion, pharmacodynamic endpoints along with clinical results suggest usefulness of this combination strategy while toxicity data suggest reduction in chemotherapeutic intensity. This clinical trial is registered with the National Cancer Institute's PDQ at www.clinicaltrials.gov as #JHOC-J0561.

Page last updated: 2007-08-04

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