1. ¹CR UK Medical Oncology Unit, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK
2. ²Department of Medical Oncology, University of Manchester, Christie Hospital, Wilmslow Road, Manchester M20 9BX, UK
3. ³Department of Hematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
4. ⁴Royal Adelaide Hospital, Adelaide, South Australia, Australia
5. ⁵Kudos Pharmaceuticals Ltd, 327 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK
6. ⁶CR UK Carcinogenesis Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, UK

Correspondence: Dr MR Middleton, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail: mark.middleton@cancer.org.uk

Received 7 November 2007; Revised 25 March 2008; Accepted 28 March 2008; Published online 13 May 2008.

Abstract

To evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50–200 mg m^-2) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Pharmacokinetics of lomeguatrib and TMZ as well as their pharmacodynamic effects in peripheral blood mononuclear cells (PBMC) were determined. Nineteen patients received 49 cycles of treatments. Despite consistent depletion of O⁶-methylguanine-DNA methyltransferase in PBMC, none of the patients responded to treatment. Three patients had stable disease, one for the duration of the study, and no fall in carcinoembryonic antigen was observed in any patient. Median time to progression was 50 days. The commonest adverse effects were gastrointestinal and haematological and these were comparable to those of TMZ when given alone. This combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated.