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Lomeguatrib, a Potent Inhibitor of O⁶-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Department of Medical Oncology, University of Manchester; ² Cancer Research UK Clinical and Experimental Pharmacology Group and ³ Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, United Kingdom; ⁴ Department of Oncology, Royal Free and University College Medical School, University College; ⁵ Cancer Research UK Drug Development Office, London, United Kingdom; ⁶ Cancer Research UK Formulation Unit, Strathclyde University, Glasgow, United Kingdom; and ⁷ Chemistry Department, Trinity College, Dublin, Ireland

Requests for reprints: Mark R. Middleton, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. Phone: 44-1865-226185; Fax: 44-1865-226179; E-mail: mark.middleton{at}cancer.org.uk.

Purpose: A major mechanism of resistance to temozolomide involves the DNA repair protein O⁶-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer.

Experimental Design: Lomeguatrib was administered at dose levels of 10 to 40 mg/m² days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m² on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination.

Results: Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of 10 mg/m²/d i.v. or 20 mg/m²/d orally, and tumor biopsies showed 92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m² days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months.

Conclusion: This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.

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