Lomeguatrib, a potent inhibitor of o-6-alkylguanine-DNA-alkyltrasnferase: phase i safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumours

Malcolm Ranson, Mark, R. Middleton, John Bridgewater, Siow Ming Lee, M. Dawson, Debra Jowle, G.W. Halbert, Sue Waller, Helen McGrath, Lindsey Gumbrell, R. Stanley McElhinney, Dorothy Donnelly, T. Brian H. McMurry, Geoffrey, P. Margison

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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 ≥10 mg/m2/d i.v. or ≥20 mg/m2/d orally, and tumor biopsies showed ≥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.

LanguageEnglish
Pages1577-1584
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number5
DOIs
Publication statusPublished - 2006

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temozolomide
Pharmacokinetics
Safety
DNA
Alkyl and Aryl Transferases
Neoplasms
Maximum Tolerated Dose
lomeguatrib

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Ranson, Malcolm ; Middleton, Mark, R. ; Bridgewater, John ; Lee, Siow Ming ; Dawson, M. ; Jowle, Debra ; Halbert, G.W. ; Waller, Sue ; McGrath, Helen ; Gumbrell, Lindsey ; McElhinney, R. Stanley ; Donnelly, Dorothy ; McMurry, T. Brian H. ; Margison, Geoffrey, P. / Lomeguatrib, a potent inhibitor of o-6-alkylguanine-DNA-alkyltrasnferase: phase i safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumours. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 5. pp. 1577-1584.
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title = "Lomeguatrib, a potent inhibitor of o-6-alkylguanine-DNA-alkyltrasnferase: phase i safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumours",
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 ≥10 mg/m2/d i.v. or ≥20 mg/m2/d orally, and tumor biopsies showed ≥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.",
author = "Malcolm Ranson and Middleton, {Mark, R.} and John Bridgewater and Lee, {Siow Ming} and M. Dawson and Debra Jowle and G.W. Halbert and Sue Waller and Helen McGrath and Lindsey Gumbrell and McElhinney, {R. Stanley} and Dorothy Donnelly and McMurry, {T. Brian H.} and Margison, {Geoffrey, P.}",
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Lomeguatrib, a potent inhibitor of o-6-alkylguanine-DNA-alkyltrasnferase: phase i safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumours. / Ranson, Malcolm; Middleton, Mark, R.; Bridgewater, John; Lee, Siow Ming; Dawson, M.; Jowle, Debra; Halbert, G.W.; Waller, Sue; McGrath, Helen; Gumbrell, Lindsey; McElhinney, R. Stanley; Donnelly, Dorothy; McMurry, T. Brian H.; Margison, Geoffrey, P.

In: Clinical Cancer Research, Vol. 12, No. 5, 2006, p. 1577-1584.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lomeguatrib, a potent inhibitor of o-6-alkylguanine-DNA-alkyltrasnferase: phase i safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumours

AU - Ranson, Malcolm

AU - Middleton, Mark, R.

AU - Bridgewater, John

AU - Lee, Siow Ming

AU - Dawson, M.

AU - Jowle, Debra

AU - Halbert, G.W.

AU - Waller, Sue

AU - McGrath, Helen

AU - Gumbrell, Lindsey

AU - McElhinney, R. Stanley

AU - Donnelly, Dorothy

AU - McMurry, T. Brian H.

AU - Margison, Geoffrey, P.

PY - 2006

Y1 - 2006

N2 - 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 ≥10 mg/m2/d i.v. or ≥20 mg/m2/d orally, and tumor biopsies showed ≥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.

AB - 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 ≥10 mg/m2/d i.v. or ≥20 mg/m2/d orally, and tumor biopsies showed ≥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.

UR - http://dx.doi.org/10.1158/1078-0432.CCR-05-2198

U2 - 10.1158/1078-0432.CCR-05-2198

DO - 10.1158/1078-0432.CCR-05-2198

M3 - Article

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SP - 1577

EP - 1584

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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