PT  - JOURNAL ARTICLE
AU  - Hidalgo, Manuel
AU  - Buckner, Jan C.
AU  - Erlichman, Charles
AU  - Pollack, Marilyn S.
AU  - Boni, Joseph P.
AU  - Dukart, Gary
AU  - Marshall, Bonnie
AU  - Speicher, Lisa
AU  - Moore, Laurence
AU  - Rowinsky, Eric K.
TI  - A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer
AID  - 10.1158/1078-0432.CCR-06-0118
DP  - 2006 Oct 01
TA  - Clinical Cancer Research
PG  - 5755--5763
VI  - 12
IP  - 19
4099  - http://clincancerres.aacrjournals.org/content/12/19/5755.short
4100  - http://clincancerres.aacrjournals.org/content/12/19/5755.full
SO  - Clin Cancer Res2006 Oct 01; 12
AB  - Purpose: 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. Experimental Design: 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/m2/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m2/d for patients with extensive prior treatment because, in the 19 mg/m2/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/m2/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m2/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. Conclusion: Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.