Phase II trial of O6-benzylguanine (O6BG) and BCNU in patients with advanced melanoma

Abstract

7524 Background: While alkylating agents such as BCNU are active in melanoma, they give response rates of only 10–15%. BCNU induces DNA damage by formation of a chloroethyl adduct at the O6 position of guanine. This modification can be repaired by alkylguanine DNA alkyltransferase (AGT), and melanoma tumor cells can express high levels of AGT. O6BG is a potent inhibitor of AGT. We hypothesized that addition of O6BG would improve the clinical response to BCNU in patients with advanced melanoma. Methods: Patients had measurable disease, adequate organ function, PS≤ 2, and a corrected DLCO of ≥ 70% predicted. Patients were accrued into 2 cohorts based on whether or not they received prior chemotherapy. O6BG (120 mg/m2) was administered i.v. over 1 hour, followed by BCNU (40 mg/m2) i.v. over 1 hour, as an outpatient. PBMC were collected pre- O6BG and 18 hours later to assess for AGT depletion. Treatment cycles were repeated every 6 weeks and response using RECIST criteria was assessed every 2 cycles. Results:...