Clolar (clofarabine)

Clolar (clofarabine) is an anti-neoplastic purine nucleoside analog used to treat lymphoblastic leukemia . The drug acts as an anti-metabolite, interfering with DNA replication. In addition, the drug appears to disrupt the integrity of the mitochondrial membrane, releasing pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, activating pathways of programmed cell death. In these ways Clolar exerts a cytotoxic effect on both rapidly dividing and quiescent cancer cells.

Clolar is specifically indicated to treat acute lymphoblastic leukemia (ALL) in pediatric patients ages 1-21, whose disease has relapsed or beecome refractory after at least two prior treatment regimens.

Clolar is administered as an intravenously, with a recommended dosage of 52 mg/m2 via 2-hour infusion dialy for 5 days, with cycle repeats every 2-6 weeks once organ function has returned to baseline.

FDA approval of Clolar was based on a pair of clinical trials, involving a total of 66 pediatric ALL patients. The first was a open-label, dose-escalation, noncomparative study, which enrolled a total of 17 pediatric ALL patients . Subjects received escalating doses of the drug ranging from 11.25 mg/m2 to 70 mg/m2, daily for 5 days. 9 of the 17 received the recommended dose of 52 mg/m2. Among all patients 2 complete and 2 patial responses were observed. Dose limiting toxicities, including reversible hyperbilirubinemia and elevated transaminase levels and skin rash, were observed at 70 mg/m2, leading to the choice of 52 mg/m2 as the optimum dose.

The second study was a single arm, open label study which enrolled 49 pediatric ALL patients. Subjects in this study received up to sequential cycles at the recommended dose (52 mg/m2 x 5 days), with no dose escalation. Efficacy was observed in the trial's primary endpoint, the overall rate of response. Specifically, there were 6 completer responses (CR; 12.2%), 4 complete responses which did not also demonstrate platelet recovery (CRp; 8.2%), and 5 partial responses (PR; 10.2%), for a total response rate of 30.6%. Among the 9 responding patients who did not undergo bone marrow transplant following treatment, response durations were as follows: 43, 50, 82, 93+ and 160+ days for CR subjects, 32 days for one CRp subject, and 7, 16, and 21 days for PR subjects.

Adverse events associated with the use of Clolar may include (but are not limited to) the following:

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• Febrile neutropenia
• Systemic Inflammatory Response Syndrome (SIRS)
• Vomiting
• Nausea
• Diarrhea
• Pyrexia
• Rigors
• Abdominal Pain
• Fatigue
• Tachycardia
• Anorexia Additionally, animal models have demostrated teratogenic potential in pregnant women. Human embryo toxicity has not been investigated, but the likelyhood of risk to the fetus is very high, and pregnancy should be avoided while receiving Clolar.

Clolar disrupts DNA synthesis and causes fatal replication errors through the disruption of several intracellular syntetic pathways. Specifically, the drug depletes deoxynucleotide triphosphate pools through the inhibition of ribonucleotide reductase, and causes termination of DNA chain elongation through incorporation into the DNA strand and competitive inhibition of DNA polymerases. Furthermore, the drug has been shown to disrupt mitochondrial membrane intergrity, possibly through disruption of mitochondrial DNA synthesis. Disruption of mitochondrial integrity leads to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, which activate programmed cell death pathways.

Bonate PL, Craig A, Gaynon P, Gandhi V, Jeha S, Kadota R, Lam GN, Plunkett W, Razzouk B, Rytting M, Steinherz P, Weitman S. Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia. Journal of Clinical Pharmacology. 2004 Nov;44(11):1309-22.

Szafraniec SI, Stachnik KJ, Skierski JS. New nucleoside analogs in the treatment of solid tumors. Acta Poloniae Pharmaceutica. 2004 Jul-Aug;61(4):297-305.

Yamauchi T, Nowak BJ, Keating MJ, Plunkett W. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clinical Cancer Research. 2001 Nov;7(11):3580-9.

For additional information regarding Clolar or acute lymphoblastic leukemia, please visit the Genzyme Oncology web page.