Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors.

Abstract

PURPOSE:

9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors.

PATIENTS AND METHODS:

Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay.

RESULTS:

Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer.

CONCLUSION:

DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

• Authors: M J de Jonge, C J Punt, A H Gelderblom, W J Loos, V van Beurden, A S Planting, M E van der Burg, L W van Maanen, B K Dallaire, J Verweij, D J Wagener, A Sparreboom
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 17 Issue 7 Pg. 2219-26 (Jul 1999) ISSN: 0732-183X [Print] United States
• PMID: 10561279 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• 9-aminocamptothecin
• Camptothecin

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Least-Squares Analysis
• Likelihood Functions
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Neutropenia (chemically induced)
• Pharmacokinetics
• Thrombocytopenia (chemically induced)