Brand Name:  Torisel^TM 

Generic Name ¹:  temsirolimus

Manufacturer ¹:  Wyeth Pharmaceuticals Inc

Drug Class ^2,3:  Antineoplastic Agent

Uses:   Labeled ^1-3:  Renal cell carcinoma

            Unlabled ¹:  Astrocytoma and Mantle cell lymphoma (MCL)

Mechanism of Action^1-4:  Temsirolimus is a water-soluble ester of sirolimus that binds selectively and with affinity to FKBP-12, an intercellular binding protein.  This complex inhibits mTOR signaling, thus halting the cell cycle at G1 phase in tumor cells.  In renal cell carcinoma, mTOR inhibition also exhibits anti-angiogenesis by reducing levels of HIF-1 and HIF-2 alpha and vascular endothelial growth factor (VEGF).

Pharmacokinetics ^1-4: 

Metabolism ^1-4:  Temsirolimus is extensively metabolized in the liver via CYP3A4.

                   Primary Metabolite:  sirolimus

Elimination ^1-3:  Major Route:  Fecal (78%).  Amount unchanged in Urine: 4.6%

Efficacy ^5,6,7,8: 

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A., et al.  Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.  N Engl J Med 2007 May;  356(22):  2271-81.

Study Design:  This study was a phase III, randomized, multicenter, multinational, open label, active-controlled study that evaluated the safety and efficacy of temsirolimus.  This study compared temsirolimus alone, interferon alfa alone, and a combination of the 2 for the treatment of metastatic renal-cell carcinoma.  Patients were randomized into 3 treatment groups.  Patients received temsirolimus 25mg/week, interferon 3 million U 3 times/week, or temsirolimus 15mg/week and interferon 3 million U 3 times/week.  Interferon doses were titrated as tolerability would allow.  Intent-to-treat was used for data handling.

Description of Study:  A total of 626 patients participated in the study. Patients had advanced renal-cell carcinoma, a >60 Karnofsky performance score, fit at least 3 predictors of short survival, and no previous systemic therapy.  The primary endpoint was overall survival and the secondary endpoint was median progression-free survival.  Temsirolimus group had significantly better hazard ratio for death compared to interferon (p=.008), but combo therapy was not significant (p=.70).  Median survival times of temsirolimus, interferon, and combo were 10.3, 7.4, and 8.4 months respectively.  Mean progression-free survival for the groups was 5.5, 3.1, and 4.7 months respectively.  Temsirolimus patients experienced fewer serious adverse events then did interferon patients (p=.02) and combination therapy patients (p=.02).  The authors concluded that compared with interferon, temsirolimus improved overall survival and progression-free survival among patients with metastatic renal-cell carcinoma.  The addition of temsirolimus to interferon did not improve survival compared to interferon alone.   

Limitations:  Wyeth Pharmaceuticals, manufacturer of temsirolimus, supported the study and many of the authors received consulting fees from Wyeth, and Wyeth also performed the studies statistical analysis.  Also no blinding was reported in this study, so there is a potential for bias.  Because of tolerability dose reductions were much more common in interferon and combo treatment groups.  As a result temsirolimus patients received 92% of planned dose, where the other groups only received 56% and 72.5% respectively. 

Conclusion:    Results suggest the possibility of temsirolimus as a first-line treatment, but additional trials with other new agents, like sunitinib and sorafenib, are needed to make conclusion on relative efficacy.     

Atkins MD, Hidalgo M, Stadler WM, Logan TF, Park Y, Marshall B, et al.  Randomized phase 2 study of multiple dose levels of CCI-779 (temsirolimus), a novel mammalian target of rapamycin kinase inhibitor, in patents with advanced refractory renal cell carcinoma.  J Clin Oncol 2004; 22(5):  909-18.

Study Design:  This was a long-term, phase II, open label, single arm, multi-dose, randomized study that evaluated the safety and efficacy of temsirolimus in patients with refractory renal-cell carcinoma (RCC).  Eligible patients had confirmed advanced RCC, had received previous therapy or were appropriate candidates for IL-2 therapy, and had a tumor diameter >1cm.  Patients were randomly assigned to receive 25, 75, or 250mg of temsirolimus as a weekly 30 min IV infusion.  Tumor size assessments were made at 8-week intervals.  Response was defined using WHO guidelines for complete response (CR), partial response (PR), and stable disease (SD).  In addition minor response (MR) was a >25% decrease in the sum of the 2 diameters. 

Description of Study:  A total of 111 patients enrolled in this study. The primary endpoint % objective tumor response (CR +PR) was 7% and an additional 26% had MR. For total population, 51% had CR, PR, MR, or SD > 24 weeks.  Median tumor progression time was 6.3, 6.7, and 5.2 months for the 25, 75, and 250mg dose groups respectively.  Median survival was 15.0 months in the total population and 13.8, 11.0, and 17.5 months for the 25, 75, and 250mg dose groups.  The probability of survival at 2 years was 29% for total population and 24%, 26%, and 36% for the 25, 75, and 250mg dose groups.  The most common adverse events were rash, mucositis, asthenia, nausea, and hyperglycemia.  There were no statistically significant differences in adverse events between dose groups.  The authors concluded in patients with advanced RCC, temsirolimus showed anti-tumor activity, encouraging survival, and was generally well tolerated over the 3 dose levels.  The authors also concluded that 25mg should be the recommended dose. 

Limitations:  Potential bias could exist since Wyeth, manufacturer of temsirolimus, funded the study and several of the authors work for or own stock in Wyeth.  There was no control group for comparison and the sample size was relatively small.  Also lack of blinding was another risk factor for bias.

Conclusion:  Twenty-five mg should be the optimum dose for additional investigations since tumor response and median survival were similar between doses and less dose reduction and discontinuation was seen at the 25mg dose.  Additional study of temsirolimus, either alone or in combination, in appropriately selected patients is warranted.

Motzer RJ, McDermott DF, Curti BD, Escudier BJ, Negier S, Duclos B, et al.  Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma.  J Clin Oncol 2007 Sept; 25(25):  3958-64.

Study Design:  This was a phase I/II, open label, multinational, multi-dose study that determined a recommended dose and evaluated the safety and efficacy of using temsirolimus in combination with interferon alfa in patients with advanced RCC.   Eligible patients had stage 4 RCC, a measurable tumor per RECIST, and may have received up to 2 regimens of chemotherapy or immunotherapy.  While determining a recommended dose, patients receive 6 or 9 million units (MU) interferon (INF) and were started on 5mg weekly IV infusions of temsirolimus.  Temsirolimus doses were escalated in 5mg increments from 5-25mg.  Then patients were enrolled to receive the determined recommended dose (temsirolimus 15mg / IFN 6MU).  Anti-tumor activity was measured using objective response rate (CR+PR), progression-free survival, stable disease (SD) > 24 weeks, and overall survival.  All adverse events were also recorded at all dose levels.

Description of Study:  A total of 71 patients were enrolled to determine the recommended dose and 37 patients were reenrolled to receive the recommended dose.  No dose-limiting toxicities were seen in dose levels up to temsirolimus 15mg / IFN 6MU, where as grade 3-4 toxicities were seen in all doses above temsirolimus 15mg / IFN 6MU.  In the total population objective response was 11%,  35% had SD>24 weeks, resulting in a clinical benefit rate of 46%.  Patients in the recommended dose cohort objective response was 8%, 36% had SD>24 weeks, resulting in a clinical benefit rate of 44%.  Median progression-free survival was 9.1 and 7.6 months for the total and recommended dose populations.  Median overall survival was 18.8 and 22.1 months for the total and recommended dose populations.  Most frequent adverse events were chills, nausea, diarrhea, rash, and dyspnea.  Most frequently reported grade 3-4 adverse events for all patients were leucopenia (32%), hypophosphatemia (27%), asthenia (21%), and anemia (21%).  The authors concluded that this study established temsirolimus 15mg / IFN 6MU as the recommended dose when used in combination to treat patients with RCC.  The authors also concluded that the study established the feasibility of combining targeted and biological therapies for the treatment of advanced RCC.

Limitations:  Potential bias could exist since Wyeth, manufacturer of temsirolimus, funded the study and several of the authors work for or own stock in Wyeth.  Lack of blinding and small sample size were also weaknesses of this study.  Also for the efficacy section of the study there was no placebo or active-control group.  The authors also state that the analysis of overall survival data is limited by the possibility that some patients may have subsequently entered trials with other agents. 

Conclusion:   This study had severe limitations and additional clinical trials with temsirolimus in combination with IFN and other target agents are needed to further define its role in the treatment of advanced RCC.

Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, et al.  Phase II trial of single agent temsirolimus for relapsed mantle cell lymphoma.  J Clin Oncol 2005 Aug; 23: 5347-55.

Study Design:    This was a phase II, open label, single arm study which tested whether temsirolimus could produce tumor responses in patients with MCL.  Patients were eligible if they had previously received therapy and had relapsed or were refractory to their last treatment, and have a measurable lymph node or tumor mass >2cm.  Patients were treated with a flat dose of 250mg temsirolimus IV infusion weekly and 4 weeks was considered a cycle.  Patients who did not meet retreatment criteria followed a stepwise dose modification to 175, 125, 75, or 50mg.  Patients were restaged after 1 cycle and every 3 cycles thereafter. 

Description of Study:  A total of 35 patients enrolled in this trial.  The overall response rate (ORR) was 38%, with 1 CR and 12 PR.  Median time to response was 1 month.  Median time to progression was 6.5 months and median overall survival was 12 months.  For the 13 responders the median duration of response was 6.9 months.  Dose reductions were necessary in all but 4 patients.  Nine patients were able to receive 250mg for at least 1 cycle with a median of 2.5 cycles.  The most common adverse events were thrombocytopenia, hyperglycemia, anemia, neutropenia, increased triglycerides, and mucositis.  The authors concluded that temsirolimus has substantial anti-tumor activity in relapsed MCL and that further studies of this agent in MCL and other lymphoid malignancies are warranted. 

Limitations:  Potential conflicts of interest exist because of the lack of blinding and some of the authors are associated with temsirolimus’ manufacturer.  Also 35 patients is a relatively small sample size.  The authors also state that several features of the study design could’ve predisposed patients to thrombocytopenia, which was the most common side effect.  These features included the fact patients could enroll with grade 1 thrombocytopenia and the majority of patients were heavily pretreated.

Conclusion:  This study does have several limitations.  However, temsirolimus does show promising anti-tumor activity in relapsed MCL.  Additional clinical trials investigating temsirolimus efficacy in treating relapsed MCL are warranted.   

Contraindications ^1,3: 

• Hypersensitivity to temsirolimus, sirolimus, or any component of the formulation
• Breast Feeding -  risk category D
• Pregnancy – excretion in milk unknown, but metabolite sirolimus has potential for tumorigenicity

Precautions ^3,4: 

• Anaphylactic/hypersensitivity reactions:  Hypersensitivity reactions (eg, anaphylaxis, dyspnea, flushing and/or chest pain), have been reported; premedicate with an antihistamine prior to infusion.
• Angioedema:  Has been reported; concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors) may increase risk. 
• Bowel perforation:  Cases of bowel perforation (fatal) have occurred; promptly evaluate any new or worsening abdominal pain or bloody stools.
• Infection:  Treatment may result in immunosuppression, may increase risk of opportunistic infections and/or sepsis
• Interstitial lung disease(ILD):  sometimes fatal, has been reported; symptoms include dyspnea, cough, hypoxia and/or fever, although asymptomatic cases may present; promptly evaluate worsening respiratory symptoms.
• Renal failure:  Acute renal failure with rapid progression has been reported, including cases unresponsive to dialysis.
• Wound healing:  May be associated with impaired wound healing; use caution in the perioperative period.

Adverse Reactions ^2,3: 

Those that occur at an incidence > 10%

• Cardiovascular: Edema (35%), peripheral edema (27%), chest pain (16%)
• Central nervous system: Pain (28%), fever (24%), headache (15%)
• Dermatologic: Rash (47%), pruritus (19%), nail thining(14%), dry skin (11%)
• Endocrine & metabolic: Hyperglycemia (35%), hypercholesterolemia (38%), hyperlipidemia (26%), hypokalemia (21%)
• Gastrointestinal: Mucositis (41%), nausea (37%), anorexia (32%), diarrhea (27%), abdominal pain (21%), constipation (20%), stomatitis (20%), taste disturbance (20%), vomiting (19%), weight loss (19%)
• Neuromuscular & skeletal: Weakness (51%), back pain (20%)
• Renal: Creatinine increased (14-57%)
• Respiratory: Dyspnea(28%), cough(26%), epistaxis(12%), pharyngitis(12%)

Those that occur at an incidence 1-10%

• Cardiovascular:  Hypertension(7%), thromboembolism(2%), thrombophlebitis (1%)
• Central nervous system: Chills (8%), depression (4%)
• Dermatologic: Acne (10%), wound healing impaired (1%)
• Hepatic:  Hyperbilirubinemia (8%)
• Ocular:  Conjunctivitis
• Respiratory:  Rhinitis (10%), pneumonia (8%), upper respiratory tract infection (7%), interstitial lung disease (2%)

Drug Interactions ^2,3,4: 

• ACE inhibitors:  Concurrent use with temsirolimus may increase the risk of angioedema.
• Antifungal agents (itraconazole, ketoconazole, voriconazole):  May increase the levels/effects of the active metabolite of temsirolimus.
• Calcineurin inhibitors (cyclosporine, tacrolimus):  may increase the risk of HUS/TTP/TMA
• CYP3A4 inducers:  May decrease the levels/effects of  temsirolimus.
• CYP3A4 inhibitors:  May increase the levels/effects of temsirolimus.
• Macrolide antibiotics: May increase the levels/effects of temsirolimus.
• Rifampin:   May decrease the levels/effects of temsirolimus.
• Sunitinib:  Concomitant use with temsirolimus may lead to dose-limiting toxicity.
• Vaccines (dead organisms):  May be less effective during temsirolimus therapy.
• Vaccines (live organisms):  Concurrent therapy with temsirolimus may increase the adverse/toxic effect of the live vaccine; vaccinial infections are possible; avoid concurrent use.

 Dosing ^1-4:  Pre-medicate with 25-50mg of diphenhydramine IV 30 mins prior to each dose.

Adult dosing:  25 mg IV infused over 30-60 mins once weekly.  Max of 25mg/week.      

Geriatric dosing:  same as adult.

Pediatric dosing:  safety and efficacy has not been established.

Hepatic dosing:  No specific guidelines available

Renal dosing:  No dosing adjustment needed.

   CYP3A4 dosing:  50mg/week with inducer and 12.5mg/week with inhibitor.

Use in special populations (i.e. pregnancy, lactation) ^3,4:  Pregnancy category D.  Further studies are needed to determine the effects of temsirolimus in pregnancy.  Until then this product should only be used if absolutely necessary and the benefits outweigh the risks.

Storage ³:  Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Diluted solution in the vial (10 mg/mL) is stable for 24 hours at room temperature. Solutions diluted for infusion (in normal saline) must be infused within 6 hours of preparation. Protect from light during storage, preparation, and handling.

Reconstitution ³:  Vials should be diluted with 1.8 mL of provided diluent to a concentration of 10 mg/mL (vial contains overfill). Mix by inverting vial. After allowing air bubbles to subside, further dilute in 250 mL of NS in a non-DEHP/non-PVC container (glass, polyolefin or polypropylene). Avoid excessive shaking (may result in foaming).

Compatibility ³:  Compatible with normal saline; do not mix with other solutions or medications. Acids and bases degrade Temsirolimus.

Monitoring Parameters ³:  CBC with differential and platelets (weekly), serum chemistries including glucose (baseline and every other week), serum cholesterol and triglycerides (baseline and periodic), liver and renal function tests

Conclusion:  Temsirolimus is a new antineoplastic agent that is FDA approved for the treatment of renal cell carcinoma.  In clinical studies it has shown promising efficacy and should be considered as an alternative (monotherapy or in combination with IFN) for those patients not responsive to current first line agents. Additional clinical trials directly comparing temsirolimus to other new agents, like sunitinib and sorafenib, are needed before considering it a first line treatment.  Treatment of MCL is an off-label indication of temsirolimus.  In limited clinical trials temsirolimus has shown promising anti-tumor activity.  Further studies of temsirolimus in the treatment of MCL are warranted.                                                                                   

Recommended References:

1. Torisel.  Clinical Pharmacology [Internet Database].  Gold Standard Inc.  2007.  Available at: http://www.clinicalpharmacology.com. Accessed:  September 25, 2007.
2. Torisel.  In: DRUGDEX® System [Internet Database].  Grenwood Village, Colorado:  Thomson Micromedex.  Updated periodically.
3. Torisel.  Lexi-Drugs [database online].  Lexi-Comp Inc:  September 25, 2007.
4. Torisel^TM [package insert].  Madison, NJ:  Wyeth Pharmaceuticals Inc:  2007. 
5. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A., et al.  Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.  N Engl J Med 2007 May;  356(22):  2271-81. 
6. Atkins MD, Hidalgo M, Stadler WM, Logan TF, Park Y, Marshall B, et al.  Randomized phase 2 study of multiple dose levels of CCI-779 (temsirolimus), a novel mammalian target of rapamycin kinase inhibitor, in patents with advanced refractory renal cell carcinoma.  J Clin Oncol 2004; 22(5):  909-18.
7. Motzer RJ, McDermott DF, Curti BD, Escudier BJ, Neiger S, Duclos B, et al.  Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma.  J Clin Oncol 2007 Sept; 25(25): 3958-64.
8. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, et al.  Phase II trial of single agent temsirolimus for relapsed mantle cell lymphoma.  J Clin Oncol 2005 Aug; 23: 5347-55.

Prepared by:  Hamilton Rake, Doctor of Pharmacy Candidate