Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies

Maarten J. Deenen, Heinz-Josef Klümpen, Dick J. Richel, Rolf W. Sparidans, Mariette J. Weterman, Jos H. Beijnen, Jan H. M. Schellens, Johanna W. Wilmink

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Everolimus is an oral mTORinhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3×3 phase I design in four predefined dose levels (500-1,000 mg/m2 bid). Results: In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and handfoot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion: Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies. © Springer Science+Business Media, LLC 2011.
Original languageEnglish
Pages (from-to)1557-1565
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Deenen, Maarten J. ; Klümpen, Heinz-Josef ; Richel, Dick J. ; Sparidans, Rolf W. ; Weterman, Mariette J. ; Beijnen, Jos H. ; Schellens, Jan H. M. ; Wilmink, Johanna W. / Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies. In: Investigational New Drugs. 2012 ; Vol. 30, No. 4. pp. 1557-1565.
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title = "Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies",
abstract = "Background: Everolimus is an oral mTORinhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3×3 phase I design in four predefined dose levels (500-1,000 mg/m2 bid). Results: In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56{\%}), stomatitis (50{\%}), and handfoot syndrome (33{\%}). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion: Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39{\%} of patients with advanced solid malignancies. {\circledC} Springer Science+Business Media, LLC 2011.",
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Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies. / Deenen, Maarten J.; Klümpen, Heinz-Josef; Richel, Dick J.; Sparidans, Rolf W.; Weterman, Mariette J.; Beijnen, Jos H.; Schellens, Jan H. M.; Wilmink, Johanna W.

In: Investigational New Drugs, Vol. 30, No. 4, 2012, p. 1557-1565.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies

AU - Deenen, Maarten J.

AU - Klümpen, Heinz-Josef

AU - Richel, Dick J.

AU - Sparidans, Rolf W.

AU - Weterman, Mariette J.

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N2 - Background: Everolimus is an oral mTORinhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3×3 phase I design in four predefined dose levels (500-1,000 mg/m2 bid). Results: In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and handfoot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion: Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies. © Springer Science+Business Media, LLC 2011.

AB - Background: Everolimus is an oral mTORinhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3×3 phase I design in four predefined dose levels (500-1,000 mg/m2 bid). Results: In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m2 bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and handfoot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion: Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m2 bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies. © Springer Science+Business Media, LLC 2011.

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