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    A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer.

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    Authors
    Sabharwal, A
    Corrie, P G
    Midgley, R S
    Palmer, C
    Brady, J
    Mortimer, P
    Watson, A J
    Margison, Geoffrey P
    Middleton, M R
    Affiliation
    Department of Medical Oncology, Churchill Hospital, University of Oxford, Oxford, UK.
    Issue Date
    2010-10
    
    Metadata
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    Abstract
    BACKGROUND: Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment. PATIENTS AND METHODS: Patients with metastatic colorectal cancer received lomeguatrib (10-80 mg PO) on days 1-5 with irinotecan (250-350 mg/m(2) IV) on day 4 of a 21-day cycle. RESULTS: Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m(2) irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease. CONCLUSION: This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.
    Citation
    A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer. 2010, 66 (5):829-35 Cancer Chemother Pharmacol
    Journal
    Cancer Chemotherapy and Pharmacology
    URI
    http://hdl.handle.net/10541/112846
    DOI
    10.1007/s00280-009-1225-0
    PubMed ID
    20039040
    Type
    Article
    Language
    en
    ISSN
    1432-0843
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00280-009-1225-0
    Scopus Count
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