Abstract | PURPOSE: PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
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Authors | Michael A Carducci, Joel B Nelson, M Kathy Bowling, Theresa Rogers, Mario A Eisenberger, Victoria Sinibaldi, Ross Donehower, Terri L Leahy, Robert A Carr, Jeffrey D Isaacson, Todd J Janus, Amy Andre, Balakrishna S Hosmane, Robert J Padley |
Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology
(J Clin Oncol)
Vol. 20
Issue 8
Pg. 2171-80
(Apr 15 2002)
ISSN: 0732-183X [Print] United States |
PMID | 11956279
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Endothelin Receptor Antagonists
- Pyrrolidines
- Atrasentan
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Topics |
- Adenocarcinoma
(drug therapy)
- Adult
- Aged
- Antineoplastic Agents
(pharmacokinetics, therapeutic use)
- Atrasentan
- Endothelin Receptor Antagonists
- Female
- Humans
- Male
- Middle Aged
- Prostatic Neoplasms
(drug therapy)
- Pyrrolidines
- Salvage Therapy
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