Cositecan

This review covers the preclinical and clinical activity of the novel camptothecin analog, karenitecin, in melanoma.

While the camptothecins are widely used antitumor agents that inhibit topoisomerase I, their utility is limited by instability, high interpatient variability and the development of drug resistance. Karenitecin was rationally designed to overcome these limitations. The authors review the data on karenitecin in preclinical models and in clinical trials in melanoma using studies published in Medline and reports presented at AACR and ASCO.

Karenitecin shows activity in melanoma, both as a single agent and in combination. In adverse prognostic factor melanoma, karenitecin showed prolonged disease stabilization in 34% of patients. Because preclinical studies suggested a synergistic interaction between karenitecin and HDAC inhibitors, a schedule-specific combination Phase I-II trial of valproic acid and karenitecin was carried out in heavily pretreated melanoma patients which showed a benefit rate in 47% patients with acceptable toxicity. The treatment for melanoma is in rapid transition and genomic profiling is now an integral part, and hence the optimal use of karenitecin in melanoma should be re-evaluated with regard to specific mutational status.

Purpose: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma.Experimental Design: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function.Results: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was ∼200 μg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose.Conclusion: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.