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Phase II Trial of the O⁶-Alkylguanine DNA Alkyltransferase Inhibitor O⁶-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma

Authors' Affiliations: ¹ Department of Medicine, University of Chicago, Chicago, Illinois, ² Vanderbilt University, Nashville, Tennessee, and ³ Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Requests for reprints: Thomas F. Gajewski, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4601; Fax: 773-702-3163; E-mail: tgajewsk{at}medicine.bsd.uchicago.edu.

Purpose: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) induces DNA damage via a chloroethyl adduct at the O⁶ position of guanine, which can be repaired by O⁶-alkylguanine DNA alkyltransferase (AGT) expressed in melanoma. We postulated that the addition of O⁶ benzylguanine (O⁶BG), a potent inactivator of AGT, would improve the clinical response to BCNU in melanoma.

Experimental Design: Patients had measurable disease, adequate organ function, and a corrected Diffusing capacity of the lung for carbon monoxide (DLCO) of 70% predicted. They were accrued into two cohorts based on prior chemotherapy. O⁶BG (120 mg/m²) was administered i.v. followed by BCNU (40 mg/m²) on an outpatient basis. Peripheral blood mononuclear cells (PBMC) were collected pre- and 18 hours post-O⁶BG to analyze AGT depletion. Treatment was every 6 weeks, and clinical response was assessed after every two cycles.

Results: Forty-two patients were enrolled, 22 of these patients were chemotherapy-naïve. In the chemotherapy-naïve cohort, there was a patient with a complete response (CR), 4 with stable disease (SD), 13 with progressive disease (PD), and 4 nonevaluable patients; the median time to progression was 80 days and the median survival was 211 days. In the prior-chemotherapy cohort, there were no responses, 3 SD, 15 PD, and 2 nonevaluable patients; median time to progression was 54 days and median survival was 120 days. AGT was depleted from PBMC in the 15 patients tested. Grades 3 to 4 myelosuppression was seen in 57% of patients; toxicities were similar between the two cohorts.

Conclusions: O⁶BG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppression was observed and the clinical outcome was not improved. Alternative mechanisms of resistance to melanoma cell death need to be investigated.

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