Summary Basis of Decision for Caprelsa ®
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:
Caprelsa®
Vandetanib, 100 mg, 300 mg, Tablet, Oral
AstraZeneca Canada Inc.
Submission control no: 126822
Date issued: 2012-06-19
Foreword
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:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02378582 - 100 mg
- 02378590 - 300 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
CAPRELSA® is a registered trademark of the AstraZeneca group of companies
2 Notice of decision
On January 12, 2012, Health Canada issued a Notice of Compliance to AstraZeneca Canada Inc. for the drug product, Caprelsa.
Caprelsa contains the medicinal ingredient vandetanib which is a receptor tyrosine kinase inhibitor.
Caprelsa is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable locally advanced or metastatic disease. Caprelsa use should be carefully considered based on a risk/benefit assessment in patients with indolent, asymptomatic or slowly progressive disease because of the significant treatment-related risks.
Medullary thyroid cancer is a distinct subtype of thyroid cancer which arises from the parafollicular cells (C-cells) of the thyroid gland. Caprelsa works by inhibiting the activity of tyrosine kinases, a subgroup of protein kinases which, when mutated, can continuously remain active and can contribute to uncontrolled growth, leading to certain types of cancer. Nonclinical studies showed that, by inhibiting these abnormal proteins, Caprelsa slows down or stops the growth of cancer cells.
Caprelsa is only available through a controlled program referred to as the Caprelsa Restricted Distribution Program. Under this program, only physicians and pharmacies that have completed the certification and are registered with the program are able to prescribe and dispense, respectively, Caprelsa. Only patients who are enrolled and meet all of the requirements of this program can receive Caprelsa. Caprelsa should only be prescribed by a qualified physician who is experienced in the use of antineoplastic therapy and in the treatment of medullary thyroid cancer.
The market authorization was based on quality, nonclinical, and clinical information submitted. The efficacy and safety of Caprelsa was based primarily on a multicentre, international, randomized, placebo-controlled, double-blind, parallel group, Phase III study in 331 patients with locally advanced or metastatic medullary thyroid cancer. Patients were randomized to receive either Caprelsa 300 mg daily or a matched placebo. The primary endpoint was progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumours (RECIST) as assessed by centralized independent blinded review. Key secondary endpoints, evaluation of overall objective response rate (ORR) and overall survival (OS) were also assessed. The median duration of treatment with Caprelsa was 90 weeks compared to 40 weeks on placebo. Results from the study showed a statistically significant improvement in PFS for patients randomized to Caprelsa compared to placebo. A statistically significant improvement in ORR was reported for Caprelsa and these were partial responses. There was no OS benefit established for Caprelsa.
Caprelsa (100 mg and 300 mg, vandetanib) is provided in tablet form. The recommended dose of Caprelsa is 300 mg taken once daily. Caprelsa monotherapy may be administered until adult symptomatic or progressive medullary thyroid cancer patients with unresectable locally advanced or metastatic disease are no longer benefiting from treatment. Further dosing guidelines are available in the Product Monograph.
Caprelsa is contraindicated in patients with:
- congenital long QT syndrome or with a persistent Fridericia-corrected electrocardiogram QT interval (QTcF) of ≥500 ms;
- uncorrected hypokalaemia, hypomagnaesemia or hypocalcaemia;
- uncontrolled hypertension;
- known hypersensitivity to the active substance, vandetanib, or to any of its excipients.
Caprelsa 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 Caprelsa are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Caprelsa is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Vandetanib, the medicinal ingredient of Caprelsa, is a receptor tyrosine kinase inhibitor. It is indicated for the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in adult patients with unresectable locally advanced or metastatic disease. Through potent and selective inhibition of vascular endothelial growth factor receptor-2 (VEGFR-2), endothelial growth factor receptor (EGFR), and Rearranged during Transfection (RET) receptor kinases, as well as VEGFR-3 and VEGFR-1 at sub-micromolar concentrations, vandetanib prevents VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation. This leads to a decrease in tumour-cell-induced angiogenesis, tumour vessel permeability, tumour microvessel density, and inhibited tumour growth and metastasis.
Manufacturing Process and Process Controls
Vandetanib 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 International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
The structure of vandetanib has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
The sponsor has provided a summary of all drug-related impurities. Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH)-established limits and/or were qualified from toxicological studies and, therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of vandetanib are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated 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.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
Stability
Based on the long-term, accelerated and stress test stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Caprelsa is available in tablet form in two strengths. Each tablet contains vandetanib (100 mg or 300 mg) and the following excipients: calcium hydrogen phosphate dehydrate; crospovidone; hypromellose 2910; macrogol 300; magnesium stearate; microcrystalline cellulose; povidone; and titanium dioxide E171. Tablets are presented in a polyvinyl chloride/polyvinylidene chloride (PVC/PVDC) blister pack of 30 tablets (2 x 15) per pack.
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 vandetanib with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the 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 Caprelsa, rationale for choice of formulation, manufacturing process including packaging, information on batches used for in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Caprelsa. Studies that justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
The Phase III clinical studies were conducted using the same formulation as proposed for marketing in Canada.
Manufacturing Process and Process Controls
The drug product is formulated, dry mixed, wet granulated, milled, blended, compressed, film-coated, and packaged using conventional pharmaceutical equipment and facilities.
The validated process is capable of consistently generating product that meets release specifications.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Caprelsa is tested to verify that its identity, assay, content uniformity, dissolution, and levels of degradation products 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.
Validation results of the analytical method used for the determination of vandetanib and the drug-related impurities are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed 48-month shelf-life at 15-30°C for Caprelsa is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through 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 of Caprelsa are considered suitable for the activities and products manufactured.
All facilities involved in the production of Caprelsa are compliant with good manufacturing practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
Caprelsa is manufactured based on a Quality Risk Management and Quality by Design approach. Suppliers of the starting materials are subject to change in accordance with the change control procedures documented; however, AstraZeneca has confirmed that all changes outside of the approved Design Space will follow Post-Notice of Compliance (NOC) Changes - Quality Guidance Appendix 1 for Human Pharmaceuticals effective October 17, 2011.
A re-assessment of genotoxic impurities will be carried out if new suppliers of starting materials are used, and where the synthetic route to the starting material has been changed. In the case of a new supplier of a starting material, where the synthetic route to the starting material is the same as a current supplier, then it will be confirmed that the levels of genotoxic impurities meet the starting material specification.
The Chemistry and Manufacturing information submitted for Caprelsa 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
3.2.1.1 Primary Pharmocodynamics
This New Drug Submission (NDS) is supported by primary pharmacodynamic (PD) studies demonstrating that vandetanib is an inhibitor of VEGF-dependent angiogenesis and EGFR and RET-dependent tumour growth. In in vitro models of angiogenesis, vandetanib inhibited endothelial cell migration, proliferation, survival and new blood vessel formation. It should be noted that although the selectivity of vandetanib was demonstrated against various additional tyrosine kinases, vandetanib was shown to inhibit protein tyrosine 6 (BRK), which is a cytoplasmic non-receptor tyrosine kinase. To date there is no evidence that BRK plays a role in MTC or that inhibition of BRK would contribute to the anti-tumour effects of vandetanib in thyroid cancer.
In several in vivo assays, the ability of vandetanib to reduce angiogenesis (both VEGF-induced and tumour-cell-induced) was demonstrated. In in vivo primary PD studies, it was clearly demonstrated that daily oral administration of vandetanib (25-100 mg/kg inhibits the growth and tumour volume of established human tumour xenografts.
3.2.1.2 Secondary Pharmacodynamics
Secondary PD studies demonstrated that vandetanib slows wound healing but does not inhibit it, consistent with the recognized role of VEGF in wound healing. This information is clearly indicated in the Product Monograph as it may be an issue if the need for surgery arises. Additional secondary PD studies confirmed that vandetanib is not selective for VEGF, EGFR and RET alone by demonstrating that vandetanib is also an antagonist for histamine H1, histamine H2 and adrenergic α2C. The relevance of this remains unknown.
Safety pharmacology studies identified some areas of concern, specifically the effects on cardiac repolarisation and blood pressure. Vandetanib has the potential to cause QT prolongation in humans [via inhibition of the human ether-a-go-go (hERG) channel] by using the highest free maximum plasma concentration (Cmax) exposures seen in clinical studies with 100 and 300 mg/day doses. Studies in dogs demonstrated increased blood pressure (20%) after vandetanib administration.
3.2.2 Pharmacokinetics
Absorption
In single-dose studies, vandetanib was highly absorbed in both rats and dogs, and had a long half-life (~20 hours in dogs and ~30 hours in rats). In repeat-dose studies, vandetanib plasma concentrations increased with increasing dose; however, there was strong evidence that vandetanib accumulates over time, which is consistent with the long half-life.
Distribution
Vandetanib was widely distributed in various tissues, including tumour tissue, but was not selective for tumour tissues. The studies demonstrated that vandetanib penetrates the central nervous system (CNS) in rats, which is also expected to occur in humans, and that vandetanib (and/or its metabolites) binds to melanin, although the toxicological significance of this is unknown. A particular concern was that a higher drug plasma concentration was observed in female rats compared with males, although this was not consistently seen in repeat-dose studies. Chronic dosing with 5 mg/kg/day vandetanib led to a 3-fold accumulation of vandetanib in rats and a 1.5-fold accumulation in dogs.
Metabolism
The metabolism of vandetanib led to two major metabolites in non-clinical species, N-desmethyl-vandetanib and vandetanib-N-oxide, but together these metabolites accounted for <5% of the parent drug. The pharmacological activity of the N-desmethyl metabolite was shown to be about the same as that for vandetanib, whereas that of the N-oxide was ~50 times lower. The N-desmethyl metabolite was formed via cytochrome P450 (CYP) enzyme metabolism, specifically CYP3A4, whereas N-oxide-vandetanib formation was via flavin-containing monooxygenase (FMO) polymorphisms FMO1 and FMO3. Therefore, inter-individual differences in the expression of these enzymes in humans may lead to exposure variability. Metabolite levels were not measured in repeat-dose toxicity studies.
Excretion
Excretion of vandetanib was mainly via the faeces in mouse, rat and dogs. Vandetanib was excreted in the mammary milk and was detected in the plasma of nursing pups following dosing of lactating rats.
3.2.3 Toxicology
Single and Repeat-Dose Toxicity
Single high oral doses of vandetanib (1,000 and 2,000 mg/kg) were not tolerated in mice or rats. Even a single intravenous dose of 50 mg/kg vandetanib, lead to the death of 1/10 rats. In the 1-month repeat-dose study in rats, a dose of 75 mg/kg/day led to the death of 9/10 rats, indicating that doses that were pharmacological protective in the tumour studies (100 mg/kg/day) were too high to conduct long-term toxicology studies with. Dose-limiting signs of toxicity included hepatotoxicity (elevated liver enzyme activities) and death in rats. These effects were attributed to the high level of EGFR found in the liver. A 25 mg/kg dose, while better tolerated than 75 mg/kg, still led to several clinical signs including loose faeces and epidermal microabscess formation. The 1-month rat study showed a clear increase in peak plasma concentrations of vandetanib in female rats compared with male rats and suggested that vandetanib would accumulate upon repeat dosing.
The 6-month repeat-dose study in rats did not show a difference in plasma concentrations of vandetanib in females compared with males. Absorption after the first 5 mg/kg/day dose was very slow and there was again evidence of accumulation of vandetanib as plasma levels were much higher at the end of the study than at the beginning. In this study, effects on the lungs (foamy macrophages) were observed at doses as low as 5 mg/kg/day. Although small dose-related increases in hemoglobin, hematocrit, red and white blood cell counts and decreased reticulocytes were seen in rats, this was reversible and, given the indication, the overall toxicological concern would be outweighed by the therapeutic benefit. Dysplasia of incisor teeth was observed with long-term treatment of vandetanib, which is thought to be due to the pharmacological activity of the drug. Vandetanib did not affect epididymal sperm count, sperm motility or cause changes in testis histopathology.
In the 9-month repeat-dose toxicity study in the dog, the major concern was the prolonged QT interval (associated with decreased heart rate) observed in dogs treated daily with vandetanib. Although this was only observed in animals treated with 40 or 15 mg/kg/day and was similar to pre-dose values, this potential adverse effect (AE) needs to be monitored. Other clinical signs included loose faeces and decreased body weight.
In terms of comparison between plasma levels achieved in the chronic non-clinical studies compared with those observed in humans, a clinical dose of 300 mg/kg/day in humans leads to steady-state levels that are greater than those observed in the 6- and 9-month studies (~2 times higher than levels observed in the rat and 9 times higher than in dogs).
Genotoxicity
Genotoxicity studies using a high dose of vandetanib (1,000 mg/kg/day) demonstrated that the drug did not induce micronuclei following oral administration and that in vitro vandetanib did not cause revertant colonies in the Ames test or chromosomal aberrations in cultured human peripheral lymphocytes. Thus, vandetanib is unlikely to be genotoxic. Identified potential impurities of vandetanib raise no genotoxic concern.
Carcinogenicity
Carcinogenicity studies were not conducted as no unusual hyperplasia was observed in the chronic studies and most patients receiving this drug will have most likely received other agents that are known to be genotoxic.
Reproductive and Developmental Toxicity
Reproductive studies were conducted only in the rat. Vandetanib is clearly teratogenic in this species at doses as low as 1 mg/kg/day. Signs of developmental toxicity included increased post-implantation loss; smaller litter sizes; decreased foetal weights; dose-dependent increased incidence of reduced ossification and other ossification abnormalities; and increased incidence of foetuses with defects, including heart vessel and eye abnormalities. Maternal toxicity included reduced weight gain and food consumption. Pups were exposed to vandetanib via milk. Several pups died during the lactation period. Given that these effects were seen at doses lower than those to be used clinically, the potential exists that vandetanib could cause developmental toxicity in humans. There was no evidence of adverse events (AEs) of vandetanib on behaviour, mating performance, fertility and gestation of the filial 1 (F1) generation. Vandetanib does not adversely affect male fertility.
Other Studies
Studies evaluating the potential for vandetanib to be phototoxic were positive and hence patients should be counselled to avoid sun exposure.
3.2.4 Summary and Conclusion
Several toxicities were observed in the non-clinical studies with doses that achieved lower plasma concentrations than those seen in humans. Many of the observations are thought to be due to extension of the pharmacological properties of vandetanib in inhibiting both VEGFR and EGFR. Based on the non-clinical data, the main issues concerning the therapeutic use of vandetanib are:
- Possible QT prolongation, increased blood pressure and decreased heart rate in humans;
- Increased diarrhoea, weight loss, and skin rashes;
- Increased liver enzyme activities;
- Teratogenicity and transfer to young via breast milk;
- Accumulation over time, requiring plasma levels to be monitored.
All of these concerns are highlighted in the product labelling. It should be noted that all cancer therapies have some degree of toxicity associated with them. Given that fatality occurs in 90% of patients with MTC and there is currently no effective or approved treatment for these patients, the toxicity associated with vandetanib is outweighed by the therapeutic benefit of the drug.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical PD parameters of Caprelsa were not specifically examined in the clinical studies as they were adequately assessed through the non-clinical programme as described in section 3.2.1 Pharmacodynamics or in combination with the clinical pharmacokinetic (PK) evaluation as presented below.
3.3.2 Pharmacokinetics
A series of Phase I studies in healthy volunteers and patients with malignant tumours were conducted to assess the PK parameters as well as the safety profile of vandetanib.
Absorption
Following oral dosing of vandetanib in healthy volunteers, absorption was slow, with peak plasma concentration achieved at approximately 6 hours after dosing (range 4-10 hours). A high-fat meal did not change the level of exposure. Absorption appears to be linear, with slow clearance (~12 L/hour). The mean half-life was 19 days, and steady state was achieved at Day 56 with daily dosing.
Distribution
The protein binding of vandetanib was determined ex vivo in healthy volunteers and patients with hepatic impairment and renal impairment. The ex vivo plasma protein binding of vandetanib was found to be 94.0% (range 91.6-96.0%).
Metabolism
In vitro studies showed that vandetanib is metabolized to an N-desmethyl metabolite by CYP3A4 and to an N-oxide metabolite by FMO1 and FMO3. In a Phase I study, the presence of circulating metabolites was reported. Metabolites were shown to prolong the QTc interval using the hERG assay. However, the 50% drug transport inhibition concentration (IC50) values were 3- and 10-fold greater in healthy volunteers and non-small-cell lung cancer patients, respectively, indicating that the metabolites are less likely to cause QT prolongation compared with unchanged vandetanib.
Excretion
Urine and faeces were the main routes of elimination of vandetanib after a single 800 mg dose of radiolabelled vandetanib was administered to healthy male volunteers. Over 21 days, 44.1%, 25.2%, and 69.3% of the administered radioactive dose was recovered in faeces, urine, and in total, respectively. The elimination of radioactivity was very slow, with ~1-3% of the dose excreted daily from Day 8 to Day 21. Vandetanib was eliminated unchanged, as an N-desmethyl metabolite, as an N-oxide metabolite, and as a glucuronide.
Drug Interaction and CYP2D6/CYP3A4 Metabolic Pathways
Vandetanib is a CYP3A4 substrate. In healthy male vounteers, exposure to vandetanib was reduced by 40% when given together with rifampicin. Concomitant administration of itraconazole, a potent CYP3A4 inhibitor, caused a 9% increase in the area under the curve (AUC). Concomitant use of known strong CYP3A4 inducers should be avoided in patients treated with vandetanib.
Special Populations
A dedicated renal impairment study showed that a single dose administration of vandetanib 800 mg resulted in increases in AUC of 46%, 62%, and 79% in patients with mild, moderate and severe renal impairment, respectively, compared to a control group of individuals with normal renal function. A dose reduction to 200 mg for patients with moderate and severe renal impairment is recommended.
Single-dose PK data from healthy volunteers with hepatic impairment showed that there were no differences in PK parameters compared with patients with normal hepatic function. However, the use of vandetanib is not recommended in patients who have moderate and severe hepatic impairment, as safety and efficacy have not been established.
3.3.3 Clinical Efficacy
Clinical efficacy and safety evaluations were based primarily on the efficacy and safety data from a pivotal Phase III randomized, double-blind, placebo-controlled study in 331 patients with locally advanced or metastatic MTC. Vandetanib was administered as an oral daily dose of 300 mg. The median duration of treatment with vandetanib was 90 weeks and 40 weeks on placebo. Several supporting studies including Phase II clinical studies and clinical pharmacology studies were also reviewed in this submission.
The primary efficacy endpoint was progression-free survival (PFS). Vandetanib showed a statistically significant improvement in PFS in favour of the 300 mg daily oral dose (PFS events: 31.6% for vandetanib versus (vs) 51.0% for placebo; 95% CI, 0.31 to 0.69, p = 0.0001). The median PFS for patients receiving placebo was 19.3 months, whereas the median PFS for patients receiving vandetanib had not been reached by data cut-off (July 2009). The predicted median PFS for vandetanib-treated patients is 30.5 months.
Statistically significant advantages were also seen for vandetanib for the secondary endpoint, objective response rate (ORR); showing evidence of anti-tumour activity with a response rate of 45% for patients randomized to vandetanib compared to 13% for patients randomized to placebo (95% CI, 2.99 to 10.79, p<0.0001). Secondary endpoints of disease control rate, biochemical response (both calcitonin and carcinoembryonic antigen), and time to worsening of pain are not considered to be validated endpoints for the treatment of MTC. There was no statistically significant difference in overall survival (OS) between the two treatment groups; however, the OS data are immature given that, at the time of data analysis, 15% of patients had died. Quality of life (QoL) as measured by the patient-reported Functional Assessment of Cancer Therapy General (FACT-G) Scale was an exploratory endpoint and no formal statistical analyses were performed regarding this endpoint. Owing to the low compliance rate (77%), no conclusions can be made regarding an association between PFS and QoL.
The mutation status of RET was originally a co-primary endpoint. However, the co-primary analysis population of patients with a known RET mutation was later removed from the study in a protocol amendment because assays used to identify RET mutation were unable to establish mutation status in 41% of the patients. Patient selection was not based on RET mutation status, and RET subgroup analysis was an exploratory endpoint.
It is not established whether a lower dose of vandetanib is as effective as the recommended 300 mg daily dose. The results of a Phase III randomized dose-finding study comparing 150 mg with 300 mg vandetanib are expected in 2015.
3.3.4 Clinical Safety
In keeping with the mechanisms of action of the drug and its metabolic pathways, the following AEs observed in healthy volunteers enrolled in the Phase I studies of the clinical development programme for vandetanib are concerning:
- Increased alanine aminotransferase (ALT);
- Changes in heart rate and systolic/diastolic blood pressure;
- QTc interval prolongation;
- Increased serum creatinine.
In the pooled Phase II and Phase III monotherapy studies, deaths related to toxicity were observed in the vandetanib arm due to respiratory failure, respiratory arrest, cardiac arrhythmia, sepsis, pneumonia, and cardiopulmonary insufficiency. One sudden death and one case of Torsade de pointes were also observed. Overall, the five most frequently reported AEs in the vandetanib group were diarrhoea; rash; nausea; hypertension; and headache.
Adverse events of particular concern given the low numbers of patients that have been treated thus far included interstitial lung disease; Stevens-Johnson Syndrome (SJS); Torsades de pointe; and cerebrovascular events. Stevens-Johnson Syndrome (6 patients); erythema multiforme (3 patients); toxic epidermal necrolysis (4 patients); and toxic skin eruption (5 patients) were observed, including one death in a patient with a toxic skin eruption receiving 100 mg vandetanib and docetaxel. Nine of these events occurred on 100 mg vandetanib + docetaxel, while nine occurred on monotherapy. Time of onset for severe skin disorders varied from Day 17 to Day 255 and, in some patients, these events persisted for several months. Skin disorders such as rash, acne, and photosensitivity were common. In addition, SJS or toxic epidermal necrolysis were uncommon, and these events can result in death. Risk factors for evolution of rash into SJS are unclear given that several patients received radiation prior to development of SJS. The two cases of drug hypersensitivity that led to discontinuation of vandetanib appear to have been related to Grade 4 SJS. Interestingly, they both occurred in the same centre in two different Chinese patients; however, due to the low number of patients involved, it is not possible to conclude whether there is an ethnic pre-disposition to developing SJS.
QTcF prolongation was also associated with vandetanib treatment, and the frequency of this AE was higher for the vandetanib arm than for the placebo arm. Vandetanib at a dose of 300 mg was associated with a substantial (mean maximum increase from baseline effect, 35 ms) and concentration-dependent prolongation in QTcF. This increase in mean QTcF did not lessen over time and the mean half-life of vandetanib (19 days) makes this prolongation in QTcF interval particularly problematic. QTcF prolongation occurred in 14% of patients receiving vandetanib in the pivotal study. Two patients in the vandetanib arm discontinued treatment owing to QTcF prolongation or electrocardiogram QTcF prolongation, with both patients meeting protocol-defined QTcF prolongation criteria. There have been approximately 5,000 patients treated with vandetanib in clinical studies, and at least 2,000 at the 300 mg dose. Of those, there have been two reports of documented Torsade de pointes, both of which occurred in patients taking vandetanib 300 mg, and these patients recovered.
During the randomized portion of the pivotal study, a Grade 3 cerebrovascular event (cerebral ischemia, transient ischemic attack) occurred in 1.3% of patients in the vandetanib arm and in no patients in the control arm, while coronary occlusion was reported in 1 (0.4%) patient in the vandetanib arm and in no patients in the control arm. There were 13 cases (0.8%) of cardiac failure noted in the pooled data for the 300 mg vandetanib monotherapy group, some of which led to death. Echocardiograms were not monitored regularly throughout most studies so it was unclear whether this number under-represents the true incidence of cardiac failure. A higher percentage of patients in the vandetanib arm than in the placebo arm had elevations in blood pressure.
Haemorrhages and epistaxis were reported more frequently in the vandetanib arm than the placebo arm however these events were mostly Grades 1 and 2, based on Common Toxicity Criteria for Adverse Events (CTCAE). A slightly higher percentage of patients in the vandetanib arm relative to the placebo arm reported haemoptysis. Proteinuria was also reported more frequently in the vandetanib arm than the placebo arm. All AEs of proteinuria were Grade 1 or 2. One patient treated with vandetanib had renal failure during randomised treatment. During open-label treatment, 3 patients in the placebo arm had renal failure or acute renal failure while receiving vandetanib. Urinalysis data also showed that vandetanib was associated with an increased incidence of new-onset proteinuria or deterioration of existing proteinuria and haematuria.
Grade 3 or 4 increases in alanine aminotransferase (ALT) were seen in 1.7% of patients in the vandetanib arm while on randomised treatment compared with no patients in the placebo arm. A small number of patients reported AEs of Grade 3 or higher liver function test (LFT) elevations. Hypocalcemia was seen more frequently in vandetanib-treated patients.
Visual abnormalities were more common in the vandetanib arm vs. the placebo arm. Abnormalities of the epithelium were evident in ~50% of patients in the vandetanib arm. Review of the findings by a consultant ophthalmologist revealed that ~33% of patients assessed had opacities in the epithelial layer of the cornea. The consultant's overall opinion was that there is an association between vandetanib and the development of corneal vortex keratopathy.
Additional safety concerns with vandetanib treatment included pneumonitis; interstitial lung disease; and intestinal perforation. However, the association of these events in relation to treatment with vandetanib for MTC is unclear.
It is concluded that additional risk minimization activities are required to help manage the risk of QT prolongation associated with the use of Caprelsa.
3.3.5 Additional Issues
Risk Management Plan
Given the risk of severe QT prolongation associated with the use of Caprelsa, Health Canada considered risk mitigation through labelling alone to be insufficient. A Risk Management Plan including a program referred to as the Caprelsa Restricted Distribution Program was therefore agreed. Under this program, only prescribers and pharmacies that have completed certification and are registered within the program are able to prescribe and dispense, respectively, Caprelsa. Only patients who are enrolled and meet all of the requirements of the Caprelsa Restricted Distribution Program can receive Caprelsa. This program includes a centralized pharmacy distribution model, along with a comprehensive, mandatory physician- and pharmacist-training program (web-based and paper training materials) with educational and certification components. Communication materials include a patient wallet card with details about Caprelsa (including adverse effects and drug-drug interaction information). All relevant communication issues to provide safe distribution of Caprelsa have been addressed.
Caprelsa received United States Food and Drug Administration (FDA) authorization in 2011 and a similar risk mitigation program has been implemented in the United States. Throughout submission review, Health Canada has extensively consulted the FDA risk mitigation program materials and is satisfied that the Canadian risk management program for Caprelsa is at least as comprehensive.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
It is estimated that each year in Canada, there will be up to 22 patients diagnosed with MTC. The prevalence of the disease in Canada is approximately up to 200 patients. Those with symptomatic or progressive disease are the patients who may benefit from Caprelsa therapy. Recognizing that there is both a statistically significant and clinically meaningful benefit of Caprelsa in this patient population, Health Canada considers that this drug should be made available to those patients within the market authorized indication. And that physicians and patients should be appropriately educated on the toxicity profile associated with Caprelsa.
Medullary thyroid cancer, even in the metastatic setting, has a relatively long survival time when compared to other tumour types, and should be taken into consideration when assessing the benefit/risk of treating with Caprelsa. QoL as measured by the FACT-G and time to worsening of pain were exploratory endpoints with low compliance rates. Therefore, it is not clear if PFS is supported by QoL. In addition, there is a potential that lower doses of Caprelsa could help minimize the toxicities while maintaining efficacy. To continue to evaluate the benefit/risk of Caprelsa for treatment of MTC, going forward the Sponsor has commited to providing the following clinical data upon their availability:
- The final OS data from the pivotal Study 58. (Current OS data are immature, with only ~76% of patients on study at data cut-off, precluding any conclusions of an association between PFS and OS).
- Data from a randomized dose-finding study investigating the 300 mg and 150 mg daily doses of Caprelsa in patients with progressive or symptomatic MTC.
Patients with unresectable locally advanced or metastatic progressive or symptomatic MTC have an unmet need in that they have no current treatment options. Health Canada considers that the serious risks are very well communicated via the labeling and via the Restricted Distribution Program and Risk Mitigation Plan, ensuring that prescribers, pharmacies, patients and their attending physicians are well-informed of these risks. Considering this and the demonstrated efficacy of Caprelsa in terms of PFS, the drug is deemed to have a favourable benefit/risk profile.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Caprelsa is favourable in the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable locally advanced or metastatic disease. Caprelsa use should be carefully considered based on a risk/benefit assessment in patients with indolent, asymptomatic, or slowly progressive disease because of the significant treatment-related risks. The New Drug Submission (NDS) 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: Caprelsa®
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2011-01-27 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-03-18 |
| Review | |
| Quality Evaluation complete: | 2012-01-09 |
| Clinical Evaluation complete: | 2012-01-11 |
| Biostatistics Evaluation complete: | 2011-11-28 |
| Labelling Review complete: | 2012-01-11 |
| Notice of Compliance (NOC) issued by Director General: | 2012-01-12 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| CAPRELSA | 02378582 | SANOFI-AVENTIS CANADA INC | VANDETANIB 100 MG |
| CAPRELSA | 02378590 | SANOFI-AVENTIS CANADA INC | VANDETANIB 300 MG |