Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer Journal Article
| Authors: | Milton, D. T.; Riely, G. J.; Azzoli, C. G.; Gomez, J. E.; Heelan, R. T.; Kris, M. G.; Krug, L. M.; Pao, W.; Pizzo, B.; Rizvi, N. A.; Miller, V. A. |
| Article Title: | Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer |
| Abstract: | BACKGROUND. Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS. Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS. Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t max, Cmax, and AUC0-8h of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients. CONCLUSIONS. For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way. © 2007 American Cancer Society. |
| Keywords: | adult; clinical article; aged; middle aged; survival rate; clinical trial; fatigue; carcinoma, squamous cell; advanced cancer; area under the curve; diarrhea; drug dose reduction; recommended drug dose; side effect; united states; adenocarcinoma; anemia; blood toxicity; lung non small cell cancer; nausea; stomatitis; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; carcinoma, non-small-cell lung; lung neoplasms; weight reduction; creatinine blood level; dose-response relationship, drug; phosphatidylinositol 3 kinase; drug dose escalation; lymphocytopenia; pneumonia; rash; hypotension; mammalian target of rapamycin; gefitinib; maximum tolerated dose; phase 1 clinical trial; egfr; mammalian target of rapamycin inhibitor; quinazolines; everolimus; sirolimus; hypertriglyceridemia; mtor; rad001; nsclc; acidosis |
| Journal Title: | Cancer |
| Volume: | 110 |
| Issue: | 3 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2007-08-01 |
| Start Page: | 599 |
| End Page: | 605 |
| Language: | English |
| DOI: | 10.1002/cncr.22816 |
| PUBMED: | 17577220 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 45" - "Export Date: 17 November 2011" - "CODEN: CANCA" - "Source: Scopus" |
