title: Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medicine, Gustave Roussy Institute, Vellefaux, France. eric.raymond@sls.ap-hop-paris.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Karina
authors.initials: K
authors.lastname: Vera
authors.forename: Eric
authors.initials: E
authors.lastname: Materman
authors.forename: Joseph
authors.initials: J
authors.lastname: Boni
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
authors.forename: Axel
authors.initials: A
authors.lastname: Hanauske
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus