Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer
| Autor: | Russell L. Basser, Richard M. Fox, Jonathan Cebon, John S. Hill, Andrew H. Kaye, Kerrie Clarke, Howard Geldard, Michael D. Green, Carole Alt, Jane Bartlett, Denis J. Morgan, Darryl W. Maher |
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| Rok vydání: | 1998 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Neutropenia Filgrastim Anthracycline medicine.medical_treatment Pharmacology Gastroenterology Neoplasms Internal medicine Granulocyte Colony-Stimulating Factor Mucositis Humans Medicine Aged Chemotherapy Antibiotics Antineoplastic Dose-Response Relationship Drug business.industry Carubicin Middle Aged medicine.disease Recombinant Proteins Granulocyte colony-stimulating factor Treatment Outcome Oncology Vomiting Female medicine.symptom business medicine.drug Epirubicin |
| Zdroj: | Journal of Clinical Oncology. 16:2181-2187 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | PURPOSE To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies. |
| Databáze: | OpenAIRE |
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