Antitumor Activity and Clinical Pharmacology of Sulofenur in Ovarian Cancer
| Autor: | Yei Mei Peng, Gerald B. Grindey, Marta Hamilton, Thomas M. McCloskey, Charles W. Taylor, Denise J. Roe, David S. Alberts, David E. Seitz, Patricia M. Plezia, Monika Matzner |
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| Rok vydání: | 1992 |
| Předmět: |
Adult
Cancer Research medicine.medical_specialty Anemia medicine.medical_treatment Antineoplastic Agents Methemoglobinemia Gastroenterology Drug Administration Schedule Methemoglobin law.invention Pharmacokinetics law Internal medicine medicine Humans Aged Aged 80 and over Ovarian Neoplasms Chemotherapy Clinical pharmacology business.industry Carcinoma Middle Aged medicine.disease Sulfonylurea Compounds Endocrinology Oncology Toxicity Female Ovarian cancer business |
| Zdroj: | JNCI Journal of the National Cancer Institute. 84:1798-1802 |
| ISSN: | 1460-2105 0027-8874 |
| Popis: | BACKGROUND Sulofenur is a diarylsulfonylurea with demonstrated antitumor activity in patients with advanced epithelial ovarian cancer refractory to standard chemotherapy. The dose-limiting toxic effects observed in phase I clinical trials have been anemia and methemoglobinemia, resulting in cyanosis. PURPOSE The purposes of this study were to further define the response rate, toxic effects, and pharmacokinetics and pharmacodynamics of sulofenur in patients with advanced ovarian cancer. METHODS We conducted a phase II trial of sulofenur at a dose of 800 mg/m2 per day in 35 patients with stage III or IV ovarian cancer refractory to standard chemotherapy. Pharmacokinetics and pharmacodynamics were analyzed by comparing sulofenur parent and metabolite plasma levels with methemoglobin levels. RESULTS Partial responses lasting 6.5-18 weeks occurred in four (15%; 95% confidence interval = 4%-35%) of the 26 patients assessable for response. In addition, 42% (11) of the assessable patients had prolonged stable disease (median, 20 weeks). The first nine patients received sulofenur as a daily oral dose for 14 days, with a 21-day treatment cycle. However, they developed substantial anemia and methemoglobinemia. As a result, the next 26 patients received sulofenur daily for 5 days followed by 2 days of rest for 3 consecutive weeks, with a 28-day treatment cycle (5/2-day schedule). Preclinical models predicted that 2 days of rest would decrease toxicity while maintaining antitumor activity. Patients treated with the 5/2-day schedule had relatively less severe anemia and methemoglobinemia and needed fewer red blood cell transfusions (31% versus 78% of patients), but 31% still required dose reductions because of these toxic effects. The hydroxy and keto metabolites of sulofenur had prolonged plasma half-lives relative to the parent compound, and the difference was statistically significant. In addition, the correlations of metabolite concentrations with methemoglobin levels were higher than the correlation of sulofenur concentrations with methemoglobin levels, and those differences were statistically significant. CONCLUSION We conclude that sulofenur has modest clinical activity in heavily pretreated patients with ovarian cancer. IMPLICATIONS The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified. |
| Databáze: | OpenAIRE |
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