Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors
| Autor: | R F Struck, Eric K. Rowinsky, K Bowling, Louise B. Grochow, N R Hartman, Seamus O'Reilly, T L Chen, Ross C. Donehower |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Adult
Male Cancer Research Ataxia medicine.medical_treatment Nystagmus Pharmacokinetics Central Nervous System Diseases Neoplasms Vertigo Humans Medicine Dosing Antineoplastic Agents Alkylating Aged Chemotherapy biology Platelet Count business.industry Middle Aged biology.organism_classification Penclomedine Oncology Anesthesia Picolines Female medicine.symptom business Somnolence |
| Zdroj: | Journal of Clinical Oncology. 15:1974-1984 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.1997.15.5.1974 |
| Popis: | PURPOSE To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|