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: 42 patients were enrolled, 22 chemo-naive and 20 with prior chemo. In the chemo-naive cohort there were 1 CR, 4 SD, 13 PD, and 4 non-evaluable (NE) patients; the median time to progression (TTP) was 80d and the median survival (MS) was 211d. In the prior chemo cohort there were no objective responses, 3 SD, 15 PD, and 2 NE patients; the median TTP was 40d and the MS was 120d. The NE patients had clinical disease progression. AGT was effectively depleted from PBMC in the 15 patients tested (p<0.001). Grade 3/4 toxicities included thrombocytopenia (n=24), neutropenia (19), anemia (10), lymphopenia (7), fever (2), fatigue (2), hyponatremia (2), neuropathy (1), vomiting (1), decreased DLCO (1), and death (1). Toxicities were similar in the two cohorts. Conclusions: O6BG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppression was seen and the clinical response rate was not greater than what is expected with BCNU alone. Although this regimen should not be explored further, administration of O6BG with other alkylating agents with greater single agent activity should be considered. No significant financial relationships to disclose.