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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.

AbstractPURPOSE:
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.
AuthorsEric Raymond, Jérôme Alexandre, Sandrine Faivre, Karina Vera, Eric Materman, Joseph Boni, Cathie Leister, Joan Korth-Bradley, Axel Hanauske, Jean-Pierre Armand
JournalJournal 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
PMID15136596 (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

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