Lomeguatrib, a Potent Inhibitor of O super(6)-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors
PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O super(6)-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 suita...
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| Veröffentlicht in: | Clinical cancer research 2006-03, Vol.12 (5), p.1577-1584 |
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| creator | Ranson, Malcolm Middleton, Mark R Bridgewater, John Lee, Siow Ming Dawson, Martin Jowle, Debra Halbert, Gavin Waller, Sue McGrath, Helen Gumbrell, Lindsey McElhinney, RStanley Donnelly, Dorothy McMurry, TBrian H Margison, Geoffrey P |
| description | PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O super(6)-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/m super(2) 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/m super(2) 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 greater than or equal to 10 mg/m super(2)/d i.v. or greater than or equal to 20 mg/m super(2)/d orally, and tumor biopsies showed greater than or equal to 92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m super(2) 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. |
| format | Article |
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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/m super(2) 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/m super(2) 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 greater than or equal to 10 mg/m super(2)/d i.v. or greater than or equal to 20 mg/m super(2)/d orally, and tumor biopsies showed greater than or equal to 92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m super(2) 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.</description><identifier>ISSN: 1078-0432</identifier><language>eng</language><ispartof>Clinical cancer research, 2006-03, Vol.12 (5), p.1577-1584</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids></links><search><creatorcontrib>Ranson, Malcolm</creatorcontrib><creatorcontrib>Middleton, Mark R</creatorcontrib><creatorcontrib>Bridgewater, John</creatorcontrib><creatorcontrib>Lee, Siow Ming</creatorcontrib><creatorcontrib>Dawson, Martin</creatorcontrib><creatorcontrib>Jowle, Debra</creatorcontrib><creatorcontrib>Halbert, Gavin</creatorcontrib><creatorcontrib>Waller, Sue</creatorcontrib><creatorcontrib>McGrath, Helen</creatorcontrib><creatorcontrib>Gumbrell, Lindsey</creatorcontrib><creatorcontrib>McElhinney, RStanley</creatorcontrib><creatorcontrib>Donnelly, Dorothy</creatorcontrib><creatorcontrib>McMurry, TBrian H</creatorcontrib><creatorcontrib>Margison, Geoffrey P</creatorcontrib><title>Lomeguatrib, a Potent Inhibitor of O super(6)-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors</title><title>Clinical cancer research</title><description>PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O super(6)-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/m super(2) 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/m super(2) 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 greater than or equal to 10 mg/m super(2)/d i.v. or greater than or equal to 20 mg/m super(2)/d orally, and tumor biopsies showed greater than or equal to 92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m super(2) 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.</description><issn>1078-0432</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqNjk9Lw0AQxXNQsP75DnMShQY2adDiLdSKBdFAcy-bZGLG7u7U3U0lflw_iVsjnj093vs9Zt5RNEnE7TwW2Sw9iU6dexMiyRKRTaKvJ9b42ktvqZqChII9Gg8r01FFni1wCy_g-h3aq5vrOFfbQYW6IYPx_XM-Bt5K41q00uEdFF0QWMFatuiH6cFbLWtuBiM11eGJaf7CbbjjqYbSklQ_ZLmXKswhNkAGFqwrMqP9IN9BiZo_WbGmBg-FIrAw2I00b_bS1NjAmhU1UPaarTuPjlupHF786ll0-bAsF4_xzvJ7j85vNLkalZIGuXebVCRCzEU6-3fxG4eKdnM</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Ranson, Malcolm</creator><creator>Middleton, Mark R</creator><creator>Bridgewater, John</creator><creator>Lee, Siow Ming</creator><creator>Dawson, Martin</creator><creator>Jowle, Debra</creator><creator>Halbert, Gavin</creator><creator>Waller, Sue</creator><creator>McGrath, Helen</creator><creator>Gumbrell, Lindsey</creator><creator>McElhinney, RStanley</creator><creator>Donnelly, Dorothy</creator><creator>McMurry, TBrian H</creator><creator>Margison, Geoffrey P</creator><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20060301</creationdate><title>Lomeguatrib, a Potent Inhibitor of O super(6)-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors</title><author>Ranson, Malcolm ; Middleton, Mark R ; Bridgewater, John ; Lee, Siow Ming ; Dawson, Martin ; Jowle, Debra ; Halbert, Gavin ; Waller, Sue ; McGrath, Helen ; Gumbrell, Lindsey ; McElhinney, RStanley ; Donnelly, Dorothy ; McMurry, TBrian H ; Margison, Geoffrey P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_miscellaneous_201008023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ranson, Malcolm</creatorcontrib><creatorcontrib>Middleton, Mark R</creatorcontrib><creatorcontrib>Bridgewater, John</creatorcontrib><creatorcontrib>Lee, Siow Ming</creatorcontrib><creatorcontrib>Dawson, Martin</creatorcontrib><creatorcontrib>Jowle, Debra</creatorcontrib><creatorcontrib>Halbert, Gavin</creatorcontrib><creatorcontrib>Waller, Sue</creatorcontrib><creatorcontrib>McGrath, Helen</creatorcontrib><creatorcontrib>Gumbrell, Lindsey</creatorcontrib><creatorcontrib>McElhinney, RStanley</creatorcontrib><creatorcontrib>Donnelly, Dorothy</creatorcontrib><creatorcontrib>McMurry, TBrian H</creatorcontrib><creatorcontrib>Margison, Geoffrey P</creatorcontrib><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ranson, Malcolm</au><au>Middleton, Mark R</au><au>Bridgewater, John</au><au>Lee, Siow Ming</au><au>Dawson, Martin</au><au>Jowle, Debra</au><au>Halbert, Gavin</au><au>Waller, Sue</au><au>McGrath, Helen</au><au>Gumbrell, Lindsey</au><au>McElhinney, RStanley</au><au>Donnelly, Dorothy</au><au>McMurry, TBrian H</au><au>Margison, Geoffrey P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lomeguatrib, a Potent Inhibitor of O super(6)-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors</atitle><jtitle>Clinical cancer research</jtitle><date>2006-03-01</date><risdate>2006</risdate><volume>12</volume><issue>5</issue><spage>1577</spage><epage>1584</epage><pages>1577-1584</pages><issn>1078-0432</issn><abstract>PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O super(6)-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/m super(2) 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/m super(2) 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 greater than or equal to 10 mg/m super(2)/d i.v. or greater than or equal to 20 mg/m super(2)/d orally, and tumor biopsies showed greater than or equal to 92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m super(2) 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.</abstract></addata></record> |
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| title | Lomeguatrib, a Potent Inhibitor of O super(6)-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors |
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