Summary Basis of Decision for Torisel ™

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:


Temsirolimus, 25 mg/mL, Liquid, Intravenous

Wyeth Canada

Submission control no: 109201

Date issued: 2009-01-06


Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

1 Product and submission information

Brand name:



Wyeth Canada

Medicinal ingredient:


International non-proprietary Name:



25 mg/mL

Dosage form:


Route of administration:


Drug identification number(DIN):

  • 02304104

Therapeutic Classification:

mTOR kinase inhibitor - antineoplastic agent

Non-medicinal ingredients:

Torisel concentrate: dehydrated alcohol (anhydrous ethanol); d,l-alpha-tocopherol; propylene glycol; anhydrous citric acid

Diluent: polysorbate 80; polyethylene glycol 400 (macrogol 400); dehydrated alcohol (anhydrous ethanol)

Submission type and control no:

New Drug Submission, Control No. 109201

Date of Submission:


Date of authorization:

2 Notice of decision

On December 21, 2007, Health Canada issued a Notice of Compliance to Wyeth Canada for the drug product Torisel.

Torisel contains the medicinal ingredient temsirolimus which is an mTOR (mammalian target of rapamycin) kinase inhibitor and antineoplastic agent.

Torisel is indicated for the treatment of metastatic renal cell carcinoma. Temsirolimus binds to an intracellular protein (FKBP12), and the protein-drug complex binds and inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity results in a G1 phase growth arrest in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins. The anti-tumour effect of temsirolimus may also stem from its ability to depress levels of HIF (hypoxia-inducible factors) and VEGF (vascular endothelial growth factor) in the tumour or tumour microenvironment, thereby impairing vessel development.

The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Clinical data supporting the safety and efficacy of Torisel were obtained primarily from a Phase II dose-finding study and a pivotal Phase III study. The pivotal study involved over 600 patients. An increase in overall survival of 3.6 months was seen with Torisel treatment when compared with interferon treatment. There were also significant improvements in secondary outcomes of progression-free survival, objective response rate, and time to treatment failure. In general, Torisel was well tolerated, and can be administered safely when used under the conditions stated in the Product Monograph. Please consult the Warnings and Precautions and Adverse Reactions sections of the Product Monograph regarding adverse events for Torisel.

Torisel (25 mg/mL, temsirolimus) is presented as a liquid concentrate for injection. The recommended dose of Torisel for metastatic renal cell carcinoma is 25 mg, infused over a 30-60 minute period once a week. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Dosing guidelines are available in the Product Monograph.

Torisel is contraindicated for patients who have a history of anaphylaxis after exposure to temsirolimus, sirolimus, or any other component of Torisel. Torisel should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Torisel are described in the Product Monograph.

Priority Review status was granted for the evaluation of Torisel as it appeared to demonstrate a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for metastatic renal cell carcinoma, a condition that is not adequately managed by a drug (interferon-α) marketed in Canada.

Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Torisel is favourable for the treatment of metastatic renal cell carcinoma.

3 Scientific and Regulatory Basis for Decision

A New Drug Submission (NDS) for Torisel was submitted by the sponsor on November 20, 2006. Deficiencies identified in the Quality portion of the review were communicated to the sponsor in a Notice of Non-Compliance (NON) on July 13, 2007. The sponsor submitted additional data in support of these concerns and all outstanding issues were adequately addressed. A Notice of Compliance (NOC) was subsequently issued for Torisel on December 21, 2007.

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Temsirolimus, the medicinal ingredient of Torisel, is an mTOR kinase inhibitor and antineoplastic agent indicated for the treatment of metastatic renal cell carcinoma. Temsirolimus binds to an intracellular protein (FKBP12), and the protein-drug complex binds and inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity results in a G1 phase growth arrest in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins. The anti-tumour effect of temsirolimus may also stem from its ability to depress levels of HIF (hypoxia-inducible factors) and VEGF (vascular endothelial growth factor) in the tumour or tumour microenvironment, thereby impairing vessel development.

Manufacturing Process and Process Controls

Temsirolimus is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:

  • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
  • The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
  • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.

Detailed characterization studies were performed to provide assurance that temsirolimus consistently exhibits the desired characteristic structure.

The structure of temsirolimus is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.

The proposed limits are considered adequately qualified (i.e. within ICH limits and/or qualified from toxicological studies). Control of the impurities and degradation products is therefore considered acceptable.

Control of Drug Substance

The drug substance specifications and analytical methods used for quality control of temsirolimus are considered acceptable.

Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of temsirolimus.

The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicate that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.

Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.

The drug substance packaging is considered acceptable.


Based on the long-term and accelerated stability data submitted, the proposed retest period, shelf-life, storage conditions, and shipping conditions for the drug substance are supported and considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Temsirolimus concentrate for injection (Torisel) is supplied as a non-aqueous, ethanolic, sterile solution. When combined with the separately manufactured diluent, the concentrate/diluent combination is suitable for dilution in 0.9% sodium chloride solution for intravenous administration. Torisel is packaged in Type I flint glass vials containing 1.2 mL concentrate (at 25 mg/mL), sealed with butyl rubber stoppers and colour-coded flip-top seals. The diluent is packaged in Type I flint glass vials containing 1.8 mL diluent sealed with butyl rubber stoppers and colour-coded flip-top seals. The two vials are co-packaged in a single carton.

Each vial of Torisel also contains the following excipients: dehydrated alcohol (anhydrous ethanol); d,l-alpha-tocopherol; propylene glycol; and anhydrous citric acid. The diluent also contains: polysorbate 80; polyethylene glycol 400 (macrogol 400); and dehydrated alcohol (anhydrous ethanol).

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of temsirolimus with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Torisel and the diluent, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Torisel and the diluent. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.

Manufacturing Process and Process Controls

The drug product is formulated, sterile-filtered, filled, and sealed using conventional pharmaceutical equipment and facilities.

The validated process is capable of consistently generating product that meets release specifications. The specifications for all of the ingredients are approved in accordance with USP/NF or Ph. Eur. standards.

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Torisel is tested to verify that the identity, appearance, strength, content uniformity, levels of degradation products, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.

Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Torisel.


Based on the long-term and accelerated stability data submitted, the proposed shelf-life for Torisel is considered acceptable. The proposed shelf-life for the diluent is also considered acceptable. Torisel and the diluent should be kept refrigerated (2-8ºC) and protected from light.

The drug concentrate-diluent mixture is stable for up to 24 hours at room temperature (20-25ºC) and protected from light. Any unused diluted mixture should be discarded after 24 hours.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

All sites are compliant with Good Manufacturing Practices (GMP) for the manufacturing activities.

3.1.4 Adventitious Agents Safety Evaluation

The rubber stoppers used in the packaging of Torisel contain porcine and bovine derived zinc stearate, which is used as a processing aid. The animals originate from the USA, Australia, and Canada. The zinc stearate is rigorously treated by one or more processes generally recognized as effective in reducing or eliminating the risk of BSE/TSE contamination in the final material. A certificate of suitability from the vendor has been provided.

The starting material of the synthesis is produced by a fermentation process that involves enzymes derived from porcine pancreas. The Animal Origin Position Statement and Certificate of Origin were provided by the vendor. The sponsor confirmed that the material is BSE/TSE free.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Torisel has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-Clinical Basis for Decision

3.2.1 Pharmacodynamics

Temsirolimus is an ester analog of sirolimus. It is proposed that temsirolimus prevents mTOR from signalling to downstream pathways that control cell growth and therefore is expected to have a cytostatic effect on tumor growth. The tumour growth inhibition effect of temsirolimus was observed over a wide range of doses. In the A498 human renal cancer xenograft model in nude mice, intravenous administration of temsirolimus at doses from 10-75 mg/kg were similarly effective in reducing tumour growth.

Sirolimus is the major metabolite of temsirolimus in humans and mice. The comparison of bioactivities of temsirolimus and sirolimus was not performed on renal cancer cells but on human ovarian cancer and prostate cancer cell lines. Nevertheless, the dose response curves of cell growth inhibition for both compounds were superimposable suggesting that temsirolimus and sirolimus are equipotent.

Temsirolimus was a strong immunosuppressant in mice but its effects on the immune system were short lived. In humans, the half-life of temsirolimus may be extended due to higher levels of temsirolimus binding proteins in formed blood elements. The immunosuppression period between weekly doses of temsirolimus may therefore be prolonged in humans, leading to more frequent opportunistic infections or secondary malignancies.

No adverse effects on the central nervous system and respiratory system were detected in rats administered temsirolimus intravenously. These studies did not assess the safety of sirolimus since it is not significantly produced in rats.

Intravenous (IV) administration of temsirolimus in male rats did not induce significant changes in mean arterial blood pressure or heart rate. Female rats were not tested. The cardiovascular studies in rats and dogs did not provide sufficient information to confirm the safety of IV administration of temsirolimus on the cardiovascular system.

3.2.2 Pharmacokinetics


In mice, temsirolimus rapidly converted into sirolimus, after IV administration. Sirolimus was detected very early after dosing and the time to reach maximum concentration (tmax) was approximately 3 minutes after dosing. The blood clearance increased with temsirolimus concentrations so exposure was less than dose-proportional in mice.

Gender-related effects were observed for temsirolimus in monkeys and rats, with the males showing significantly higher exposure than the females.


After IV administration of radiolabelled temsirolimus, tissue distribution in rats was extensive. The tmax was 5 minutes for a majority of the tissues, plasma, and blood. The presence of radioactivity in the gastrointestinal tract after IV administration indicates that biliary excretion and enterohepatic recycling of temsirolimus-related products occurred. Tissue: blood radioactivity ratios were highest in the adrenal, large intestine, liver, pituitary, stomach, thymus, and thyroid; and moderately lower in the kidney.

Placental transfer studies showed a high association of temsirolimus-derived radioactivity with the rat embryos.

Temsirolimus is subject to P-glycoprotein transport and may have the potential to alter the transport of agents that are p-glycoprotein substrates.


The biotransformation of temsirolimus was via hydroxylation, demethylation-hydroxylation, and macrocyclic ring-opening pathways. Temsirolimus was converted to sirolimus by a non-CYP450 dependent pathway, presumably via an esterase-mediated hydrolysis of the C42 ester bond. The formation of sirolimus and sirolimus-related products represented minor pathways in rats and monkeys. The predominant compound-related products were unchanged temsirolimus, seco-temsirolimus (M4) and a hydroxyl metabolite (M10). There was no evidence of glucuronide conjugates of temsirolimus or its metabolites.

In human liver microsomes, the metabolism of temsirolimus was primarily by CYP3A4 which formed demethylated and hydroxylated metabolites. Non-clinical studies showed that temsirolimus administered intravenously at the clinical dose in humans may result in potential interactions with substrates of CYP3A4 and CYP2D6 enzymes.

In rats and monkeys, sirolimus and sirolimus-derived products were present at very low levels in blood and plasma extracts. This is in contrast with humans, in which temsirolimus, sirolimus, and isomers of temsirolimus and sirolimus constituted the majority of the drug-related components in blood. Sirolimus is considered a human-specific metabolite.


Excretion of temsirolimus-related products in rats and monkeys was primarily via the feces. Urine was a minor route of elimination. The rate of excretion was different between species. Rats had the most rapid rate of excretion, while monkeys had an intermediate rate of excretion.

3.2.3 Toxicology

Most toxicology studies were performed with the rat and monkey species. Temsirolimus is readily converted into sirolimus in humans but not in rats and monkeys. The toxicity studies in rats and monkeys provided information on the toxicity of temsirolimus. However, they did not provide sufficient information on the toxicity of sirolimus at the exposure level observed in humans administered a clinical dose of temsirolimus.

Single-Dose Toxicity

In a single-dose study in mice, IV administration of 50 mg/kg resulted in no reports of mortality. However, in the mouse micronucleus study, deaths were reported after a single IV dose of 4, 10, 25, and 100 mg/kg. The reason for this discrepancy between the two studies has not been explained. There was no evidence of a dose-response relationship.

Repeat-Dose Toxicity

In the repeat-dose toxicity studies, temsirolimus-related deaths were reported in mice at 10 and 100 mg/kg. Three female monkeys receiving 0.1, 0.5 and 2.5 mg/kg, respectively, were euthanized due to temsirolimus-related morbidity (thin appearance and fecal alterations, colitis was confirmed in two of the females). Necropsy on the euthanized animals showed microscopic erosions, cysts, or mixed cell inflammation in the cecal or colonic mucosa, and lymphoid atrophy in the thymus, mandibular lymph node, mesenteric lymph node, and gut associated lymphoid tissue (GALT). In the rat repeat-dose studies, two animals died of lower urinary tract disease. They had dilatation of the renal pelvis and discoloration or distension of the urinary bladder. The cause of death was not determined and may not be temsirolimus-related.

Many of the toxic effects observed during the repeat-dose toxicity studies were attributable to the antiproliferative effects of temsirolimus or secondary to that effect. The temsirolimus-related findings after administration of temsirolimus were consistent with those seen with the immunosuppressant sirolimus.

In monkeys, inflammation of the cecum/colon and fecal alterations was probably secondary to the antiproliferative effect of temsirolimus on the GALT and to the alteration of the normal flora in the intestine. Abrasions, inflammation, and ulceration of the skin were observed in rodents while rashes were observed on the limbs and trunks of monkeys. This was consistent with the antiproliferative effect of temsirolimus on regenerating tissue or on the immune system.

Lymphoid atrophy of the thymus and lymphoid tissues was seen in mice, rats, and monkeys. This was associated with decreased peripheral blood lymphocytes. Bone marrow hypocellularity was observed in rats. Hyperglycemia and pancreatic islet cell vacuolation were observed in rats, but not in monkeys.

An increased incidence and severity of myocardial degeneration was observed in rats. The lesions consisted of foci of any combination of infiltration with mononuclear or mixed inflammatory cells, myofiber degeneration or necrosis, and fibrosis. One case of both spontaneous cardiomyopathy and heart amyloidosis were reported in female mice.

Increased numbers of pulmonary alveolar macrophages which were probably caused by the accumulation of phospholipids were seen in rats. There is no clear relationship with the interstitial pneumonitis observed in humans.

Increased cholesterol values were seen in mice, rats, and monkeys. This is consistent with the hypercholesterolemia and hyperlipidemia observed in humans administered temsirolimus.

Reduction of body weight-gain was observed in mice, rats, and monkeys. The effect was more pronounced in males than in females across the species. In rats, it was attributed in part to the diabetic-like state induced by temsirolimus. In monkeys, it was considered a non-specific effect of temsirolimus administration and was associated with alterations in bowel flora and fauna, resulting in soft or fluid feces.

Lameness was observed in rats and monkeys. The specific cause of lameness is not known but sirolimus is known to induce lameness associated with osteopenia and bone fracture in male rats.


Temsirolimus and sirolimus (the main metabolite in humans) were not genotoxic when evaluated in the in vitro bacterial reverse mutation, forward mutation, and chromosome aberration studies or in the in vivo mouse micronucleus study. Therefore, temsirolimus is unlikely to cause a genotoxic risk to humans.


Carcinogenicity studies were not performed with temsirolimus.

Reproductive and Developmental Toxicity

Decreased testes weights, testicular tubular degeneration, testicular tubular giant cells and/or hypospermia were observed in mice, rats, and monkeys. Testicular tubular degeneration may not be reversible. In rats, there were decreased prostate weights and the presence of immature spermatocytes in the epididymides. Decreased ovary weights and atrophy of the uterus, cervix, and luteal and follicular cysts were observed in rats.

In female fertility studies in rats, there were a decreased number of corpora lutea and increased incidences of pre- and post-implantation loss resulting in a decreased number of live fetuses, and decreased fetal weights. In the developmental toxicity studies in rats and rabbits, there was increased embryo/fetal mortality and decreased fetal growth (decreased fetal weight and delayed skeletal ossification). In rabbits, there was also an increased incidence of omphalocele (intestinal protrusion through the umbilicus). The fertility and reproductive findings are consistent with effects of antiproliferative agents.

3.2.4 Conclusion

The non-clinical studies were generally performed according to the ICH guidelines. However, the safety of sirolimus, the main metabolite of temsirolimus in humans, was not properly assessed due to inadequate exposure in animals. Nevertheless, clinical studies have demonstrated that temsirolimus was well-tolerated in humans at the proposed clinical dose. Adequate statements are in place in the Product Monograph to address the identified safety concerns. In view of the intended use of Torisel, there are no pharmacological/toxicological issues within the submission which preclude approval of the requested product indication.

3.3 Clinical basis for decision

3.3.1 Pharmacodynamics

A pharmacodynamic (PD) study was conducted in healthy subjects to evaluate the exposure/response relationship of temsirolimus after a single intravenous administration. Fluorescence response associated to phosphorylated S6-ribosomal protein (p-S6RP) in CD3+ and CD19+ peripheral blood mononuclear cells was chosen to indirectly measure the effect of temsirolimus on mTOR. Data showed that the inhibition of S6RP phosphorylation was dose-dependent at the dose levels between 1-25 mg of temsirolimus. Following the clinical recommended 25 mg dose, the maximum inhibition of p-S6RP in CD3+ cells was 50% for at least 3 days. Temsirolimus was well-tolerated when given as a single intravenous dose up to 25 mg to healthy subjects. Overall, the most common (>10%) treatment-emergent adverse events were stomatitis (dose-related), acne, pain, and leucopenia.

3.3.2 Pharmacokinetics


Following a 30-minute infusion of temsirolimus 25 mg, the maximum plasma concentration (Cmax) of temsirolimus was reached by the end of the infusion period. The Cmax and the drug exposure (AUC) of temsirolimus and its major metabolite (sirolimus) in whole blood increased in a dose-related but non-proportional manner. Sirolimus Cmax accounted for approx. 1/10th of the temsirolimus Cmax but contributed to approximately 72% of the total exposure due to the longer half-life of sirolimus (73 h vs. 18 h for temsirolimus).


Temsirolimus and sirolimus exhibited preferential portioning into red blood cells. Distribution was extensive, increased with dose, and exceeded total body water. In vitro, temsirolimus binding to plasma proteins was approximately 87% at the concentration of 100 ng/mL.


Temsirolimus is primarily metabolized in the liver by the cytochrome P450 isozyme, CYP3A4. Temsirolimus is also a substrate of β-glycoprotein and potential inhibitor for CYP3A4, CYP2D6 and β-glycoprotein.

After intravenous administration of temsirolimus, sirolimus was observed to be the major metabolite. Sirolimus is considered to be equally potent to the parent drug.


Elimination of temsirolimus was primarily via the feces and only a small percentage of the drug was excreted via the kidney (<5%). The clearance of temsirolimus from whole blood increased as the dose increased. Following repeated doses, exposure was slightly reduced from cycle to cycle for both temsirolimus and sirolimus with little or no accumulation observed between weekly treatment cycles.

Drug Interactions

Concomitant use of a CYP3A4/5 inducer, rifampicin, reduced sirolimus exposure by 56% and total exposure for temsirolimus and sirolimus (AUCsum) by 41% with little effect on temsirolimus exposure.

A CYP3A4 inhibitor, ketoconazole, increased sirolimus exposure by 3.1-fold and total exposure by 2.3-fold with no apparent effects on the pharmacokinetics (PK) of temsirolimus.

Temsirolimus showed no effects on the PK of CYP2D6 substrate, desipramine, however, there was an 8-hour gap between the two peak concentrations of the drugs which may have reduced the magnitude of the interaction.

An increased risk of serious adverse events was demonstrated when temsirolimus was co-administered with other anti-neoplastic drugs, e.g., sunitinib, gemcitabine or 5-fluorouracil. Fatal cases of bowel perforation were observed when temsirolimus was combined with 5-fluorouracil. Synergistic interactions between temsirolimus and gemcitabine resulted in significant higher incidence rates of hematologic dose-limiting toxicities.

Special Populations and Conditions

No dosage adjustments are required based on patient age, gender, or weight. No PK data are available for pediatric patients. The PK effects caused by renal impairment were not studied. PK studies were not conducted in patients with moderate to severe liver impairment.

A small study with 7 Japanese patients showed that exposure levels were nearly doubled that of the non-Japanese patients at the same dose. A larger study with Asian patients is needed to demonstrate whether dose adjustment is required for patients of oriental origin.

Patients with higher hematocrit values treated with temsirolimus resulted in higher trough drug concentrations in the blood, leaving the peak concentrations unaffected.

The Phase I studies did not provide sufficient information to evaluate the cardiovascular safety of temsirolimus. Therefore, the effect of temsirolimus on QTc interval is unknown at this time. A thorough QT study will be submitted at a later date.

3.3.3 Clinical Efficacy

Clinical data supporting the efficacy and safety of Torisel (temsirolimus) for treatment of metastatic renal cell carcinoma (RCC) were obtained primarily from one Phase II dose-finding study and one pivotal Phase III study. The Phase III study involved 626 patients, randomized to one of three treatment arms: Torisel 25 mg IV weekly (n=209), Interferon alfa (IFN-a) up to 18 MU IV three times weekly (n=207), and a combination of Torisel 15 mg IV weekly and IFN-a up to 6 MU IV three times weekly (n=210).

The supportive Phase II study led to the choice of dose for Torisel by demonstrating efficacy at a dose of 25 mg IV per week with no additional efficacy at a dose of 75 mg weekly and 250 mg weekly. Furthermore, the incidence of adverse events increased with the higher doses.

In the Phase III study, the primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints included progression free survival (PFS), objective response rate (ORR), clinical benefit rate, time to treatment failure (TTF), and the quality adjusted survival measurement (a measurement of time without symptoms of progression of disease or treatment toxicity using the Q-TWiST approach). The OS results showed an increase of 3.6 months for the patients treated with Torisel compared to the patients treated with IFN-a. The median OS was 10.9 months and 7.3 months for the Torisel group and IFN-a group, respectively (p=0.0078). There were also significant improvements in the secondary outcomes and an increase in quality adjusted survival time, without symptoms of progression of disease or toxicity, in the Torisel group compared with the IFN-a group. The Q-TWiST measurement was increased by an estimated 1.3 months in patients that were treated with Torisel compared to patients treated with IFN-a. The importance of Q-TWiST is to demonstrate that the increase in OS does not come at the cost of poor quality of life. The actual duration of improvement seen in this study of first-line treatment of poor prognosis RCC is small, but taken in the context of a statistically and clinically significant increase in OS, the improvement is worthwhile.

3.3.4 Clinical Safety

The clinical safety data was taken primarily from the Phase III, three-arm, randomized, open-label study described in section 3.3.3 Clinical Efficacy. Generally, Torisel (temsirolimus) was well tolerated. Adverse events (AEs) in the Torisel arm were less severe than in the IFN-a arm, consequently fewer treatment emergent adverse events (TEAEs) led to discontinuation, (18.3% vs 30.5%) or dose reduction (20.2% vs 39.5%). The incidence of TEAEs leading to dose-delay was similar for Torisel and IFN-a, at 51.4% and 47.0% respectively. Grade 3 or 4 asthenia and anemia were the most common events leading to modification of Torisel treatment.

The following adverse events are of special interest. Unless otherwise stated, the following AE percentages for Torisel were taken from the Torisel 25 mg IV arm in the Phase III study.

Hypersensitivity Reactions

Prior to the start of a Torisel infusion, an IV antihistamine was administered as hypersensitivity reactions were anticipated. Despite this, a number of patients developed symptoms of hypersensitivity and required an interruption of the infusion. All but one patient was able to continue treatment after management of the event. A protocol for managing drug-related events during the infusion is provided in the Product Monograph, and this seems a reasonable approach. No cases of anaphylaxis and hemodynamic or respiratory compromise were encountered in the Phase III study, or in other studies to the best of our knowledge. The development of an anaphylactic event related to temsirolimus or sirolimus is identified in the Product Monograph as an absolute contraindication for continuing with the agent.

Respiratory-related Events

Dyspnea and cough were the most common events, noted in 27.9% and 25.5% of patients respectively. Grade 3 or 4 dyspnea was reported in 8.7% of patients, and while a small number required dose modifications, no patients discontinued the study due to dyspnea. Of more concern was the apparent association of interstitial lung disease (ILD) in patients receiving Torisel. Reports of ILD have been made from patients receiving Torisel for a broad range of malignancies. At least one death is referred to in the submission. The actual incidence of ILD is unknown at this time. Some patients have been able to continue treatment with the addition of steroids and/or antibiotics, but the long-term results of this are unknown. This particular issue has been identified as important in the risk management program.

Gastrointestinal Events

Mucositis and stomatitis were common in patients treated with Torisel, occurring in 24.6% and 20.1% of the patients, respectively. Grade 3 or 4, or serious AEs were uncommon at 1-3%, and while dose modifications were required for these patients, none of the patients discontinued treatment due to these adverse events. Other significant GI adverse events leading to discontinuation or dose modification included nausea, vomiting, anorexia, and diarrhea. Outside of the Phase III study, there were two reports of bowel perforation in patients who received 5-fluorouracil in combination with temsirolimus. This adverse event has been addressed in the Product Monograph.

Skin-related Events

Rash of all types was very common, occurring in over 47% of the patients taking Torisel. The majority of these were classified as "generalized rash" and most were considered to be treatment related. Acne was the most common specific rash, occurring in 10.1% of the patients. The incidence of Grade 3 or 4 rash-related events was very low (5% or less).

Hematological Events

Anemia was the most frequent hematologic TEAE in patients receiving Torisel, with over 94% of patients reporting at least one low haemoglobin value on treatment. Almost 20% of these values were Grade 3 or 4. Transfusion of at least one unit of blood was given to 30.3% of the patients receiving Torisel.

Thrombocytopenia was also common, and it occurred in >40% of the patients receiving Torisel. Of these only 3 patients (1.4%) reported Grade 3 or 4 thrombocytopenia. In the Phase I dose-escalation study of temsirolimus given weekly, thrombocytopenia was found to be dose-limiting.

Bleeding events were frequent (24.5%), but generally Grade 1 or 2. The most common bleeding event was epistaxis which was reported in 25 (12.0%) of the patients.

Thrombosis was uncommon in all arms of the study, approximately 4-6% overall. In particular, deep vein thrombosis and pulmonary embolus occurred in 3 patients (1.4%) and 2 patients (1.0%), respectively, in the Torisel arm.

Leukopenia and neutropenia were less common and rarely led to dose modification.

Infection-related Events

Infection-related TEAEs were reported in 32% of patients taking Torisel compared with 4.5% of patients taking IFN-a. The most common types of infection recorded were respiratory, including pneumonia in 7.8% and bronchitis in 3.7% of the patients. These two categories included infections classified as Grade 3 or 4, in approximately half of the cases.

Clinical Laboratory Related Events

The incidence of hyperglycemia and hyperlipidemia was very high. With 15.9% of the cases of hyperglycemia Grade 3 or 4 (>13.9 mmol/L), it is likely that a proportion of patients will need specific treatment for diabetes while receiving Torisel. The long-term outcome of patients who develop hyperglycemia on treatment is not known.

Similarly, hypercholesterolemia and hypertriglyceridemia were very common, occurring in 87% and 83% of patients, respectively, receiving temsirolimus. Treating physicians may have to institute specific therapy for these conditions while treating with Torisel. There is the potential for increased exposure to statins while concurrently receiving Torisel. Consequently, the risk of developing rhabdomyolysis may be increased.

Other specific clinical chemistry abnormalities noted in this study included hypophosphatemia (49% overall, 18.3% Grade 3 or 4). Hypophosphatemia can contribute to muscle weakness, an overall decline in clinical status, and may contribute to rhabdomyolysis.

Renal Events

Renal insufficiency was a common TEAE with Torisel. Elevated creatinine levels were reported in 57.2% of the patients treated with Torisel and 3.4% of these patients had elevations greater than 3x the upper limit of normal.

Acute kidney failure and kidney failure occurred in 4 patients receiving Torisel. However, in the Torisel arm, 39 AEs were reported that infer the development of renal insufficiency. In addition, hyperkalemia (which was likely associated with renal insufficiency) was reported in 10 of the patients treated with Torisel.

Renal failure is referred to as an AE requiring special monitoring in the Product Monograph.

Cardiovascular Events

Little in the way of cardiotoxicity was noted in this study, however, patients with significant cardiac history were excluded from randomization. Chest pain was reported in 16% of the patients treated with Torisel as compared to 9% in the IFN-a arm. Two myocardial infarctions were reported in both the Torisel arm and in the IFN-a arm. There was no clear increase in the incidence of congestive heart failure, but it is possible that at least some of the 42% of patients with edema were in fact demonstrating cardiac failure.

The issue of QT interval prolongation is not finished. There were no clear signals of QT prolongation in this study and it was not possible to make a statement based on those findings. A thorough QT study has been started by the sponsor, and the results will be made available. Presently, the Product Monograph contains a general warning about the concurrent use of QT prolonging drugs, and a precaution for patients with congenital long QT syndromes.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Torisel was granted Priority Review status as it appeared to demonstrate a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for metastatic renal cell carcinoma. The pivotal Phase III study showed a clear increase in OS with patients treated with Torisel compared to patients treated with IFN-a which is the currently accepted first-line systemic treatment. The primary efficacy endpoint was supported by the demonstration of benefit in the secondary outcome measurements. The Torisel measurement of Q-TWiST demonstrated a gain of approximately one to two months of survival without symptoms of progression or toxicity from treatment, when compared to IFN-a.

Torisel is generally well tolerated at the dose recommended for treatment of metastatic renal cell carcinoma. A number of toxicities have become apparent, and will need to be anticipated in the management of patients treated with Torisel. These conditions include diabetes, hyperlipidemia, anemia, together with an increased risk of renal insufficiency and interstitial lung disease. The important toxicities have been addressed in the Product Monograph, and a risk management plan is in place to attempt to monitor these and other safety issues. Despite the presence of a number of serious possible toxicities, the benefits of Torisel in metastatic renal cell carcinoma outweigh the risks at this time.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Torisel is favourable in the treatment of metastatic renal cell carcinomas. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: ToriselTM

Submission MilestoneDate
Pre-submission meeting 12005-11-08
Pre-submission meeting 22006-07-27
Request for priority status
Approval issued by Director, BMORS2006-09-26
Submission filed2006-11-20
Screening 1
Screening Deficiency Notice issued2006-12-14
Response filed2006-12-22
Screening Acceptance Letter issued2007-01-15
Review 1
Quality Evaluation complete2007-06-15
Clinical Evaluation complete2007-07-12
Labelling Review complete2007-07-13
NOC issued by Director General (quality issues)2007-07-13
Response filed2007-08-29
Screening 2
Screening Acceptance Letter issued2007-09-27
Review 2
Quality Evaluation complete2007-12-18
Labelling Review complete2007-12-18
NOC issued by Director General2007-12-21