Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma Journal Article
| Authors: | Johnson, F. M.; Krug, L. M.; Tran, H. T.; Shoaf, S.; Prieto, V. G.; Tamboli, P.; Peeples, B.; Patel, J.; Glisson, B. S. |
| Article Title: | Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma |
| Abstract: | BACKGROUND. Small cell lung carcinoma (SCLC) cell lines commonly express KIT and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth, imatinib inhibits KIT kinase activity. SCLC cells treated with imatinib in vitro undergo cell cycle arrest. Imatinib reduces resistance to irinotecan in vitro. Common metabolic pathways suggest there may be drug interactions between imatinib and irinotecan or cisplatin. In the current study, the authors investigated the feasibility of combining these drugs in the treatment of patients with SCLC. METHODS. Two Phase I studies were conducted independently at two institutions. Patients with extensive-disease SCLC underwent therapy with cisplatin, irinotecan, and imatinib using two similar regimens. In one study, immunohistochemical analysis of the expression of potential imatinib targets was performed on pretreatment biopsy specimens, and blood specimens were collected and analyzed for imatinib, irinotecan, and cisplatin pharmacokinetic parameters. RESULTS. Nine patients were enrolled and were evaluable for toxicity. A high incidence of neutropenia, diarrhea, and thrombosis was observed that precluded dose escalation. Six patients were evaluable for response after four cycles; five patients experienced a partial response and the other patient had developed progressive disease. Four of six tumor specimens tested expressed platelet-derived growth factor receptor-α and two expressed KIT. Irinotecan clearance was found to be significantly decreased by imatinib (P < 0.04). No significant alteration in the disposition of cisplatin was observed. CONCLUSIONS. The maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was identified as imatinib at a dose of 300 mg/day with irinotecan (at a dose of 65 mg/m2) and cisplatin (at a dose of 30 mg/m2) given on Days 1 and 8, every 21 days. The decreased irinotecan clearance may explain the high incidence of diarrhea and neutropenia noted in the current study. © 2005 American Cancer Society. |
| Keywords: | immunohistochemistry; adult; cancer survival; clinical article; human tissue; treatment outcome; aged; middle aged; clinical trial; drug tolerability; neutropenia; cisplatin; area under the curve; diarrhea; drug safety; imatinib; platelet derived growth factor alpha receptor; stem cell factor; proto-oncogene proteins c-kit; computer assisted tomography; neutrophil count; anemia; bleeding; blood toxicity; nausea; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; lung neoplasms; incidence; fluorescence; protein; camptothecin; calcium; creatinine; deep vein thrombosis; tumor regression; enzyme activity; abelson kinase; pyrimidines; irinotecan; febrile neutropenia; lung embolism; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bilirubin; lung small cell cancer; albumin; thrombosis; platelet-derived growth factor; thrombocyte count; heparin; drug clearance; tandem mass spectrometry; thorax radiography; drug blood level; high performance liquid chromatography; maximum tolerated dose; phase 1 clinical trial; kit; piperazines; drug half life; lung biopsy; granulocyte colony stimulating factor; phosphotransferase; nitrogen; arginine; creatinine clearance; electrolyte disturbance; platelet derived growth factor beta receptor; small cell lung carcinoma; carcinoma, small cell; magnesium; imatinib mesylate; electrolyte; ultracentrifugation |
| Journal Title: | Cancer |
| Volume: | 106 |
| Issue: | 2 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2006-01-15 |
| Start Page: | 366 |
| End Page: | 374 |
| Language: | English |
| DOI: | 10.1002/cncr.21640 |
| PUBMED: | 16342249 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 31" - "Export Date: 4 June 2012" - "CODEN: CANCA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work