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Originally published as JCO Early Release 10.1200/JCO.2004.08.116 on May 10 2004

Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2336-2347
© 2004 American Society of Clinical Oncology.
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Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer

Eric Raymond, Jérôme Alexandre, Sandrine Faivre, Karina Vera, Eric Materman, Joseph Boni, Cathie Leister, Joan Korth-Bradley, Axel Hanauske, Jean-Pierre Armand

From the Department of Medicine, Gustave Roussy Institute, Villejuif, France; Onkologische Tagesklinik, Munich, Germany; and Wyeth, Collegeville, PA

Address reprint requests to Eric Raymond, MD, PhD, Department of Medical Oncology, Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France; e-mail: eric.raymond{at}sls.ap-hop-paris.fr

PURPOSE: To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer.

PATIENTS AND METHODS: Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (IV) infusion.

RESULTS: Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m2. No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m2. At 220 mg/m2, dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m2). Variability predicted with flat doses appears comparable with data based on body-surface area–normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma.

CONCLUSION: CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m2, the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

Supported by Wyeth Research, Collegeville, PA.

Eric Raymond and Jérôme Alexandre contributed equally to this work and shall be considered as joint first authors.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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