Torisel is a derivative of rapamycin, an agent that exhibits antifungal, immunosuppressant and antitumor activities. Torisel appears to block the effects of mTOR, an enzyme that has an important role in regulating the synthesis of proteins that control cell division. Therefore, Torisel may stop the production of proteins essential for cancer cell proliferation.

Torisel is specifically indicated for the treatment of advanced renal cell carcinoma.

Torisel is supplied as a 25 mg/mL injection with a 1.8 mL diluent designed for injection. The recommended initial dose of the drug is 25 mg infused over a 30-60 minute period once a week. Treat until disease progression or unacceptable toxicity.Torisel injection vial contents must first be diluted with the enclosed diluent before diluting the resultant solution with 250 mL of 0.9% sodium chloride injection. Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose. The concomitant use of strong CYP3A4 inhibitors should be avoided. If these are co-administered, a Torisel dose reduction to 12.5 mg/week should be considered.If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Torisel dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor. In addition, the use of concomitant strong CYP3A4 inducers should be avoided. If these are co-administered, a Torisel dose increase from 25 mg/week up to 50 mg/week should be considered. If the strong inducer is discontinued the Torisel dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

FDA Approval
FDA approval of Torisel was based on the results of one clinical trial. This multi-center, three-arm, randomized, open-label study enrolled previously untreated subjects with advanced renal cell carcinoma. Subjects were randomly assigned (1:1:1) to receive IFN-a alone, Torisel alone (25 mg weekly) or the combination arm. The median duration of treatment in the Torisel arm was 17 weeks. The median duration of treatment in the IFN arm was 8 weeks. The objectives were to compare Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients receiving IFN-a to those receiving Torisel or Torisel plus IFN-a. The intent to treat (ITT) population included 626 subjects. There was a statistically significant improvement in OS in the Torisel (25 mg) arm compared to IFN-a. The combination of TORISEL 15 mg and IFN-a did not result in a significant increase in overall survival when compared with IFN-a alone. The median progression free survival in the Torisel arm was 5.5 months compared to 3.1 months in the IFN-a arm and the overall response rate was 8.6% for the Torisel arm compared to 4.8% in the IFN-a arm.

Ongoing Study Commitments

• Wyeth has agreed to submit the completed report and data sets for the thorough QT prolongation evaluation for study entitled "A single-dose, single-blind, placebo and moxifloxacin controlled 2- period, randomized, crossover, 3rd-period sequential study of the effects of temsirolimus on cardiac repolarization in healthy subjects".
  Protocol Submission: March 2006
  Study Start: March 2006
  Final Report Submission: September 2007
• Wyeth has agreed to Submit the completed report and datasets for the hepatic impairment study (NCI study 6813 (3066K1-152-US))
  Protocol Submission: November 2005
  Study Start: January 2006
  Final Report Submission: September 2008

Adverse reactions associated with the use of Torisel may include, but are not limited to, the following:

• Rash
• Asthenia
• Mucositis
• Nausea
• Edema
• Anorexia

Torisel is a derivative of rapamycin, an agent that exhibits antifungal, immunosuppressant and antitumor activities. Torisel appears to block the effects of mTOR, an enzyme that has an important role in regulating the synthesis of proteins that control cell division. Torisel binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. Therefore, Torisel may stop the production of proteins essential for cancer cell proliferation.

Cai P, Tsao R, Ruppen ME IN VITRO METABOLIC STUDY OF TEMSIROLIMUS: PREPARATION, ISOLATION, AND IDENTIFICATION OF THE METABOLITES. Drug metabolism and disposition: the biological fate of chemicals 2007 May 31

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine 2007 May 31;356(22):2271-81

Lin F, Zhang PL, Yang XJ, Prichard JW, Lun M, Brown RE Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Annals of clinical and laboratory science 2006 Summer;36(3):283-93

Boni JP, Leister C, Bender G, Fitzpatrick V, Twine N, Stover J, Dorner A, Immermann F, Burczynski ME Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clinical pharmacology and therapeutics 2005 Jan;77(1):76-89

Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004 Mar 1;22(5):909-18

For additional information regarding Torisel or renal cell carcinoma, please visit the Torisel web page.