Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer.

Abstract	An oral formulation of temsirolimus (Torisel), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to temsirolimus-related adverse events. Two patients who received 75-mg temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.
Authors	Jan C Buckner, Bahram Forouzesh, Charles Erlichman, Manuel Hidalgo, Joseph P Boni, Gary Dukart, Anna Berkenblit, Eric K Rowinsky
Journal	Investigational new drugs (Invest New Drugs) Vol. 28 Issue 3 Pg. 334-42 (Jun 2010) ISSN: 1573-0646 [Electronic] United States
PMID	19415181 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Intracellular Signaling Peptides and Proteins temsirolimus MTOR protein, human Protein Serine-Threonine Kinases TOR Serine-Threonine Kinases Sirolimus
Topics	Administration, Oral Adult Aged Aged, 80 and over Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics) Dose-Response Relationship, Drug Drug Administration Schedule Female Humans Intracellular Signaling Peptides and Proteins (antagonists & inhibitors) Male Maximum Tolerated Dose Middle Aged Neoplasms (drug therapy) Protein Serine-Threonine Kinases (antagonists & inhibitors) Sirolimus (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics) TOR Serine-Threonine Kinases Treatment Outcome

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