This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shinkai, T. Articles by Saijo, N. Search for Related Content PubMed PubMed Citation Articles by Shinkai, T. Articles by Saijo, N.

Phase I Clinical Trial of Irinotecan (CPT-11), 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, and Cisplatin in Combination with Fixed Dose of Vindesine in Advanced Non-Small Cell Lung Cancer¹

Department of Internal Medicine, National Cancer Center Hospital [T. S., H. A., H. K., K. K., Y. S., T. T., Y. O., F. O., M. N., A. K., H. O., H. N., H. O., J. S., N. N., N. S.], Pharmacology Division, National Cancer Center Research Institute [N. S.] 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32–73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0–1) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied; in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m², i.v., on day 1) and vindesine (3 mg/m², i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m², and the dose was increased in increments of 25 mg/m². In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m², respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m². At least 3 patients were entered at each dose level in both trials. Use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 granulocytopenia and grade 3 diarrhea were dose limiting at 50 mg/m² CPT-11, which represented the maximum tolerated dose. At the subsequent dose of CPT-11, 7 new patients were requited at the 50% reduced dose level of 37.5 mg/m² on days 1 and 8. Nine patients were evaluable for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25–37.5 mg/m²), the maximum concentration in plasma of CPT-11 (>0.4 µg/ml) reached >10-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were grade 4 granulocytopenia lasting for 7 days and grade 3 diarrhea. The maximum tolerated dose was 100 mg/m² of CPT-11 and 60 mg/m² of cisplatin in this regimen. The other severe toxicity was to the liver. Ten of 30 patients entered (10 of 22 patients assessable for response) achieved a partial response. Intractable diarrhea induced by CPT-11 was associated with the dose of cisplatin used in our trials and occurred coincidentally with granulocytopenia of grade 4. For future phase II trials, we recommend doses of CPT-11 of 37.5 and 80 mg/m² on days 1 and 8 combined with vindesine and either high-dose cisplatin (100 mg/m²) or low-dose cisplatin (60 mg/m²), respectively.

¹ This work was supported in part by Grants-in-Aid for Cancer Research and by the Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare.

² To whom requests for reprints should be addressed.

Received 11/18/93. Accepted 3/21/94.

This article has been cited by other articles:

				J. Mora, O. Cruz, S. Gala, and R. Navarro Successful treatment of childhood intramedullary spinal cord astrocytomas with irinotecan and cisplatin Neuro-oncol, January 1, 2007; 9(1): 39 - 46. [Abstract] [Full Text] [PDF]

				A.-K. Souid, R. L. Dubowy, S. M. Blaney, L. Hershon, J. Sullivan, W. D. McLeod, and M. L. Bernstein Phase I Clinical and Pharmacologic Study of Weekly Cisplatin and Irinotecan Combined with Amifostine for Refractory Solid Tumors Clin. Cancer Res., February 1, 2003; 9(2): 703 - 710. [Abstract] [Full Text] [PDF]

				R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]

				R. F. DeVore, D. H. Johnson, J. Crawford, J. Garst, I. W. Dimery, J. Eckardt, S. G. Eckhardt, G. L. Elfring, L. J. Schaaf, C. K. Hanover, et al. Phase II Study of Irinotecan Plus Cisplatin in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., September 1, 1999; 17(9): 2710 - 2710. [Abstract] [Full Text] [PDF]

				J. A. Skirvin and V. Relias Review : Topoisomerase I inhibitors: 2. Irinotecan Journal of Oncology Pharmacy Practice, June 1, 1998; 4(2): 103 - 116. [Abstract] [PDF]