title: A Phase 1 clinical study of temsirolimus (CCI-779) in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.
  
  
  METHODS
  Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.
  
  
  RESULTS
  Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.
  
  
  CONCLUSIONS
  The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.
authors.affiliation: Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D018926:Anti-Allergic Agents / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced; D004155:Diphenhydramine / Q000008:administration & dosage; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D005334:Fever / Q000139:chemically induced; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D015228:Hypertriglyceridemia / Q000139:chemically induced; D017674:Hypophosphatemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D007416:Intestinal Perforation / Q000139:chemically induced; D007680:Kidney Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011292:Premedication; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D018926:Anti-Allergic Agents; D000970:Antineoplastic Agents; C401859:temsirolimus; D004155:Diphenhydramine; D020123:Sirolimus