Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours

BACKGROUND: The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) reverses the O(6)-methylguanine (O(6)-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O(6)-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O(6)-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mgm(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O(6)-meG pseudosubstrates. British Journal of Cancer (2011) 105, 773-777. doi: 10.1038/bjc.2011.285 www.bjcancer.com Published online 2 August 2011 (C) 2011 Cancer Research UK