A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer.
OBJECTIVE
Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy.


METHODS
Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite.


RESULTS
Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks.


CONCLUSIONS
Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.
Hidalgo
Manuel
M
Institute for Drug Development, Cancer Therapy and Research Center, Brook Army Medical Center, San Antonio, TX, USA. mhidalg1@jhmi.edu
Buckner
Jan C
JC
Erlichman
Charles
C
Pollack
Marilyn S
MS
Boni
Joseph P
JP
Dukart
Gary
G
Marshall
Bonnie
B
Speicher
Lisa
L
Moore
Laurence
L
Rowinsky
Eric K
EK
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus