Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers

Abstract

This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

Mechanisms of anti-cancer action and pharmacology of clofarabine

“…A wide variability in responses among the patient populations has been observed, indicating the complexity of factors that need to be considered before administering clofarabine [67].…”

New agents in acute myeloid leukemia and other myeloid disorders

“…8 The chloride chain in the adenosine ring provides resistance to deamination by adenosine deaminase; a fluoride in the 2Ј position of the arabinofuranosyl ring hinders phosphorolysis by purine nucleoside phosphorylase. Clofarabine is phosphorylated by dCK to its active metabolite, clofarabine triphosphate, resulting in the inhibition of DNA polymerases and ribonucleotide reductase, enzymes important in nucleoside analog metabolism.…”

“…Clofarabine is phosphorylated by dCK to its active metabolite, clofarabine triphosphate, resulting in the inhibition of DNA polymerases and ribonucleotide reductase, enzymes important in nucleoside analog metabolism. 8 In Phase I studies in patients with acute leukemia, reversible dose-limiting toxicity was hepatic dysfunction, which was observed at the clofarabine dose of 55 mg/m 2 administered intravenously over 1 hour daily for 5 days every 3-6 weeks. The recommended dose for acute leukemia studies in adults was 40 mg/m 2 daily for 5 days.…”

“…The recommended dose for acute leukemia studies in adults was 40 mg/m 2 daily for 5 days. 8 Among 32 patients who were treated for refractory or recurrent acute leukemia, the response rate was 16%, which included 2 CRs and 3 patients who had bone marrow remission without platelet recovery. 8 In the subsequent Phase II study of clofarabine given at a dose of 40 mg/m 2 daily for 5 days, 62 patients with recurrent or refractory acute leukemia, high-risk MDS, or CML in blast phase (CML-BP) were treated.…”

“…8 Among 32 patients who were treated for refractory or recurrent acute leukemia, the response rate was 16%, which included 2 CRs and 3 patients who had bone marrow remission without platelet recovery. 8 In the subsequent Phase II study of clofarabine given at a dose of 40 mg/m 2 daily for 5 days, 62 patients with recurrent or refractory acute leukemia, high-risk MDS, or CML in blast phase (CML-BP) were treated. 9 Seventeen of 31 patients (55%) with AML, 4 of 8 patients (50%) with MDS, and 7 of 11 patients (64%) with CML-BP achieved a CR.…”