Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer.

Abstract

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 (I.V.) infusion.

RESULTS:

Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 mg/m(2), 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/m(2)). 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/m(2), 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.

• Authors: Eric Raymond, Jérôme Alexandre, Sandrine Faivre, Karina Vera, Eric Materman, Joseph Boni, Cathie Leister, Joan Korth-Bradley, Axel Hanauske, Jean-Pierre Armand
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 22 Issue 12 Pg. 2336-47 (Jun 15 2004) ISSN: 0732-183X [Print] United States
• PMID: 15136596 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Protein Kinase Inhibitors
• temsirolimus
• Protein Kinases
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Antineoplastic Agents (administration & dosage)
• Drug Administration Schedule
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Humans
• Immunity (drug effects)
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors
• Protein Kinases
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Skin (drug effects)
• TOR Serine-Threonine Kinases