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

• Published in: British journal of cancer Vol. 105; no. 6; pp. 773 - 777
• Main Authors: Tawbi, H A, Villaruz, L, Tarhini, A, Moschos, S, Sulecki, M, Viverette, F, Shipe-Spotloe, J, Radkowski, R, Kirkwood, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2011; Nature Publishing Group
• Subjects: 631/92/436/108; 692/699/67/1059/2326; 692/699/67/1813/1634; 692/700/565/1436/1437; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical Study; Dacarbazine - administration & dosage; Dermatology; Drug Administration Schedule; Drug Resistance; Epidemiology; Female; Humans; Male; Medical sciences; Melanoma - drug therapy; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors; Oncology; Purines - administration & dosage; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; chemotherapy resistance; melanoma; MGMT pseudosubstrate; lomeguatrib; DNA repair; Antineoplastic agent; Solid tumor; Dacarbazine; Cancerology; Malignant melanoma; Advanced stage; Human; Drug combination; Lomeguatrib; Enzyme; Transferases; Enzyme inhibitor; Malignant tumor; Resistance; Methylated-DNA-protein-cysteine S-methyltransferase; Alkylating agent; Chemotherapy; Treatment; Methyltransferases; DNA; Phase I trial; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.285

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 mg m −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.