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dc.contributor.authorSabharwal, A
dc.contributor.authorCorrie, P G
dc.contributor.authorMidgley, R S
dc.contributor.authorPalmer, C
dc.contributor.authorBrady, J
dc.contributor.authorMortimer, P
dc.contributor.authorWatson, A J
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorMiddleton, M R
dc.date.accessioned2010-10-12T15:02:28Z
dc.date.available2010-10-12T15:02:28Z
dc.date.issued2010-10
dc.identifier.citationA phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer. 2010, 66 (5):829-35 Cancer Chemother Pharmacolen
dc.identifier.issn1432-0843
dc.identifier.pmid20039040
dc.identifier.doi10.1007/s00280-009-1225-0
dc.identifier.urihttp://hdl.handle.net/10541/112846
dc.description.abstractBACKGROUND: 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.
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subjectCancer Metastasisen
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshCamptothecin
dc.subject.meshColorectal Neoplasms
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshDrug Interactions
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMaximum Tolerated Dose
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasm Metastasis
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshPurines
dc.subject.meshTreatment Outcome
dc.titleA phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, Churchill Hospital, University of Oxford, Oxford, UK.en
dc.identifier.journalCancer Chemotherapy and Pharmacologyen
html.description.abstractBACKGROUND: 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.


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