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.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72838
Title:
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:
Ranson, Malcolm R; Middleton, Mark R; Bridgewater, John; Lee, Siow Ming; Dawson, Martin J; Jowle, Debra; Halbert, G; Waller, Sue; McGrath, Helen; Gumbrell, Lindsey; McElhinney, R Stanley; Donnelly, Dorothy J; McMurry, T Brian H; Margison, Geoffrey P
Abstract:
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 > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =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.
Affiliation:
Department of Medical Oncology, University of Manchester, UK.
Citation:
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. 2006, 12 (5):1577-84 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
1-Mar-2006
URI:
http://hdl.handle.net/10541/72838
DOI:
10.1158/1078-0432.CCR-05-2198
PubMed ID:
16533784
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorMiddleton, Mark R-
dc.contributor.authorBridgewater, John-
dc.contributor.authorLee, Siow Ming-
dc.contributor.authorDawson, Martin J-
dc.contributor.authorJowle, Debra-
dc.contributor.authorHalbert, G-
dc.contributor.authorWaller, Sue-
dc.contributor.authorMcGrath, Helen-
dc.contributor.authorGumbrell, Lindsey-
dc.contributor.authorMcElhinney, R Stanley-
dc.contributor.authorDonnelly, Dorothy J-
dc.contributor.authorMcMurry, T Brian H-
dc.contributor.authorMargison, Geoffrey P-
dc.date.accessioned2009-07-07T15:44:22Z-
dc.date.available2009-07-07T15:44:22Z-
dc.date.issued2006-03-01-
dc.identifier.citationLomeguatrib, 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. 2006, 12 (5):1577-84 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid16533784-
dc.identifier.doi10.1158/1078-0432.CCR-05-2198-
dc.identifier.urihttp://hdl.handle.net/10541/72838-
dc.description.abstractPURPOSE: 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 > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =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.en
dc.language.isoenen
dc.subjectCanceren
dc.subjectCancer Metastasisen
dc.subject.meshAdenosine Triphosphatases-
dc.subject.meshAdolescent-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshDacarbazine-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshFemale-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshNeoplasm Metastasis-
dc.subject.meshNeoplasms-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshSafety-
dc.titleLomeguatrib, 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.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, University of Manchester, UK.en
dc.identifier.journalClinical Cancer Researchen

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