Summary Basis of Decision for Jevtana ™
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:
JevtanaTM
Cabazitaxel, 40 mg/mL, Solution, Intravenous
sanofi-aventis Canada Inc.
Submission control no: 137421
Date issued: 2011-09-07
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):
- 02369524
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 16, 2011, Health Canada issued a Notice of Compliance to sanofi-aventis Canada Inc. for the drug product, Jevtana.
Jevtana contains the medicinal ingredient cabazitaxel which is an antineoplastic agent.
Jevtana in combination with prednisone or prednisolone is indicated for the treatment of patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel containing regimen. Jevtana acts by disrupting the microtubular network in cells, resulting in the inhibition of mitotic and interphase cellular functions. Jevtana should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Jevtana in combination with prednisone or prednisolone were evaluated in a randomized, open-label, international, multicentre, Phase III study, in patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel-containing regimen. A total of 755 patients were randomized to receive either Jevtana 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily [number (n) = 378], or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n = 377). Overall survival was significantly longer in the Jevtana arm with Jevtana-treated patients having a 30% relative reduction in the risk of death compared to patients that were treated with mitoxantrone. The hazard ratio (HR) was 0.70 [95% confidence interval (CI) 0.59-0.83]. An HR of <1 favours Jevtana. A sub-group of 59 patients received a prior cumulative dose of docetaxel <225 mg/m2 (29 patients in the Jevtana arm, 30 patients in the mitoxantrone arm). There was no significant difference in overall survival in this group of patients (HR = 0.96, 95% CI 0.49-1.86).
Jevtana (40 mg/mL, cabazitaxel) is presented as a concentrated solution for intravenous infusion. The recommended dose of Jevtana is 25 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily throughout Jevtana treatment. Dosing guidelines are available in the Product Monograph.
Jevtana is contraindicated for patients with:
- a history of severe hypersensitivity reactions to cabazitaxel or other drugs formulated with polysorbate 80, or to any ingredient in the formulation or component of the container;
- neutrophil counts ≤1,500/mm3;
- hepatic impairment [bilirubin ≥1 times (x) the Upper Limit of Normal (ULN), or aspartate aminotransferase (AST) or serum-glutamate-oxaloacetate transaminase (SGOT) and/or alanine transaminase (ALT) or serum glutamic pyruvic transaminase (SGPT) ≥1.5 x ULN]; or
- concomitant vaccination with yellow fever vaccine.
Jevtana 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 Jevtana 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 Jevtana in combination with prednisone or prednisolone is indicated for the treatment of patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel containing regimen.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Cabazitaxel is the active ingredient of Jevtana. Cabazitaxel is an antineoplastic agent that provides antitumour activity by disrupting the microtubular network in cells, resulting in the inhibition of mitotic and interphase cellular functions.
Manufacturing Process and Process Controls
The drug substance is a semi-synthetic derivative.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of cabazitaxel has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are satisfactory.
Impurities and residual solvents arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference of 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 cabazitaxel are considered acceptable.
Validation reports are considered satisfactory for all analytical procedures used for in-process testing of the drug substance.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
The drug product, Jevtana, has a two-vial formulation: one single-use concentrate vial of Jevtana 60 mg/1.5 mL (40 mg/mL) and one single-use diluent vial.
- The concentrated solution contains 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 mg polysorbate 80 (including citric acid for pH adjustment) in a total volume of 1.5 mL. Each mL of the concentrated solution contains 40 mg cabazitaxel (anhydrous) and 1.04 mg polysorbate 80. The concentrated solution is a clear yellow to brownish-yellow oily solution. It is contained in a 15 mL clear glass vial closed with a grey chlorobutyl rubber closure sealed by an aluminium cap and covered with a light green plastic flip-off cap.
- The diluent for Jevtana contains 13% (w/w) ethanol in water for injection, 4.5 mL (deliverable volume). The diluent is a clear and colourless solution. It is contained in a 15 mL clear glass vial closed with a grey chlorobutyl rubber closure sealed by a gold color aluminium cap and covered with a colourless plastic flip-off cap.
To compensate for losses during the preparation, the concentrate vial is filled with a 22% excess (total fill volume 1.83 mL) and the diluent vial has a 26% excess (total fill volume 5.67 mL).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
The test specifications and analytical methods are considered acceptable. Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Jevtana.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified, that is (i.e.) within ICH limits and/or qualified from toxicological studies.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life at 15-30°C for Jevtana 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 Jevtana are considered suitable for the activities and products manufactured.
The proposed manufacturing site complies with the requirements of Division 2 of the Food and Drug Regulations.
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
The Chemistry and Manufacturing information submitted for Jevtana 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
Cabazitaxel is a third-generation taxane. Taxanes bind the protein component of microtubules, and that was first demonstrated with paclitaxel. Taxanes such as paclitaxel and docetaxel promote tubulin assembly and stabilize the microtubules, such that they block mitosis at the metaphase/anaphase transition and induce cell death in highly proliferating tumour cells. Pharmacology studies demonstrated that the activity of cabazitaxel on pure tubulin polymerization and on microtubule depolymerization was comparable to that of docetaxel indicating that the compound retains the unique mechanism of action of taxanes. Cabazitaxel differs from paclitaxel and docetaxel in its ability to cross the blood brain barrier and its activity on multidrug resistant tumours.
Studies on tumour cell lines and in mice models with tumour xenografts demonstrated that cabazitaxel is effective on chemotherapy-resistant cells and tumour models in mice. The chemotherapy-resistant cells lines were expressing the multidrug resistance gene (mdr-1) expressions, and the cell lines were based on high to moderate expression of mdr-1. The inhibitory effect of cabazitaxel on cell proliferation was demonstrated in taxane sensitive and taxane-resistant cell lines. Cell motility, adhesion or other cellular processes were not evaluated. Other methods of resistance, other than overexpression of mdr-1, were not evaluated. Mice with xenografted tumour models responsive or resistant to taxanes also demonstrated the inhibitory effect of cabazitaxel. Taxane-resistant tumour models responded to cabazitaxel, however again the models used were mostly resistant due to mdr-1 overexpression.
Cabazitaxel is active on human prostate DU145, a tumour sensitive to docetaxel. Proof-of-concept information is lacking on the effects of cabazitaxel on taxane-resistant human prostate cancer cell lines and human prostate tumour models resistant to taxanes mimicking the clinical situation. However, based on the data provided, cabazitaxel appears to display efficacy against taxane-resistant tumour cells and tumour models. Thus, the provided data on the proof-of-principle in regard to the activity of cabazitaxel is sufficient.
The safety pharmacology studies demonstrated that cabazitaxel did not produce significant effects on the behavioural or physiological state of the animals with all of the doses tested.
The effects of cabazitaxel on the cardiovascular system were evaluated in a dog study, however the dose in the dog study (9 mg/m2) was much lower than the dose intended to be used in humans (25 mg/m2). This study and a hERG assay did not provide concrete evidence and a further in-depth electrocardiogram evaluation in patients is necessary. The sponsor does have an ongoing QT prolongation study, and has agreed to provide Health Canada with the results when available. To mitigate risk, text has been added to the Warnings and Precautions section of the Product Monograph to describe the data and thus inform healthcare professionals.
3.2.2 Pharmacokinetics
Absorption
In mice, the plasma exposure to cabazitaxel increased approximately proportional with the dose. The increase in exposure was more than dose proportional in rats and dogs. No plasma accumulation and no gender effect were observed in the tested regimen.
Distribution
In tumour-free and tumour-bearing mice and rats, cabazitaxel was rapidly and widely distributed into most organs, including brain and tumour, with no specific affinity for any organ nor for melanin. Low placental transfer was observed in rat foetuses.
Plasma protein binding of cabazitaxel was very high in mice (99.3%) and high in rats (95.5%), rabbits (91.4%), dogs (97.1%) and humans (91.9%) with no trend of saturation in the concentration range of 50 to 1,000 ng/mL.
Metabolism
Cabazitaxel is extensively metabolized in the liver. The rate of disappearance of the parent drug in liver microsomes was highest in human, followed by rabbits, dogs, mice, monkeys and rats.
Metabolism of cabazitaxel is nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) dependent with 3 major metabolites detected in rat, dog, monkey and human liver microsomes. The active metabolites were tested in vitro in a cell proliferation test and all displayed similar activity as cabazitaxel. The metabolites accounted for less than 10% on average of the systemic exposure of parent drug, therefore should not be of clinical concern.
Because cabazitaxel is extensively metabolized in the liver, hepatotoxicity is noted as a clinical adverse event. In vitro studies in rat hepatocytes demonstrated that cabazitaxel is an inducer of cytochrome P450 (CYP) 3A, although this finding has not been confirmed in human hepatocytes. Of concern is that studies evaluating the effect of potent CYP3A4 inhibitors and inducers on cabazitaxel exposure were not performed. Furthermore, detailed drug-drug interaction studies are lacking in both the non-clinical and clinical settings. To address this lack of information, the sponsor has agreed to provide results from ongoing studies that will address the issues of CYP3A induction and inhibition, with a planned report available in the fourth quarter of 2012. This approach is acceptable to Health Canada and the Product Monograph has been revised to highlight that no formal drug-drug interaction studies have been performed.
Excretion
Metabolism was the main elimination pathway of cabazitaxel in all species tested and almost no parent drug was excreted in urine or faeces (<2.5% dose).
Following intravenous dosing of radiolabelled cabazitaxel in mice, rats, and dogs, radioactivity was mainly excreted in the faeces via the bile (≥87% of the dose) and urinary excretion was minimal (≤4% of the dose).
Following intravenous dosing of radiolabelled cabazitaxel to lactating rats, a small amount of radioactivity was excreted into milk (between 0.23% and 1.5% of the dose).
3.2.3 Toxicology
All toxicology studies utilized the IV route of administration since this is the intended clinical route of administration. In addition, both male and female animals were tested since Gaucher disease is an autosomal recessive disease which can affect both male and female humans.
Single-Dose Toxicity
Single-dose toxicity studies were conducted in mice, rats, and dogs.
In mice, the dose that was lethal for 10% of the population tested (LD10) was between 120-150 mg/m2. Signs of peripheral neurotoxicity, including absence of hindlimb extension, incoordination, decrease in motor activity and prostration were observed at the cabazitaxel doses of 90 mg/m2. Microscopically, degeneration and vacuolation of the sciatic nerve and degeneration, vacuolation, dilatation and swelling of the lumbosacral nerve root, and axon fragmentation were observed at this same dose. Lumbosacral nerve root dilatation and swelling was observed at 45 mg/m2 in mice. The observed changes were not reversible after 10 or 20 weeks following single administration of cabazitaxel. Male mice appeared to be more sensitive than female mice to the effects of cabazitaxel.
In rat studies, lethality was observed following a single cabazitaxel dose of 30 mg/m2 (LD10). Further microscopic observations included enhanced peripheral neurotoxicity (presence of ellipsoids and spheroids) at this dose. Lymphoid atrophy, decreased myelopoiesis of the bone marrow and depressed haematological parameters were observed at doses of 15 mg/m2.
Cabazitaxel was lethal (4/4) in dogs following a single dose of 20 mg/m2. Microscopic findings included signs of peripheral neurotoxicity, hepatic and lymphoid atrophy and degeneration of the gastrointestinal tract (GI) tract. Female dogs appeared to be more sensitive to cabazitaxel. Polysorbate-treated dogs exhibited oedema and erythema of the head and legs, agitation and decrease in motor activity. These findings were enhanced by the effects of cabazitaxel.
Repeat-Dose Toxicity
Five-day studies were conducted in rats, dogs, and mice. In rats and dogs, lymphoid and bone marrow depletion were observed. In mice, infusion of 5 daily 15 mg/m2 doses was lethal and resulted in vacuolation and axonal fragmentation of the sciatic nerve. In mice, the highest non-lethal dose (HNLD) was 9 mg/m2. The HNLD in rats following 5 daily doses of cabazitaxels was 3 mg/m2. Some of the observed effects included decreases in white blood cells, reticulocytes, and platelets; and lymphoid atrophy and hepatocellular necrosis was observed at doses of 1.5 mg/m2. In addition, decreases in red blood cells, bone marrow depletion, thymic haemorrhage and necrosis of seminal vesicles were exhibited at 3 mg/m2.
Subcapsular lens fibre swelling/degeneration was observed in rats during a 10-cycle toxicity study at 10-20 mg/kg [60-120 mg/m2, approximately twice the system exposure in cancer patients at the recommended human dose]. These effects were partially reversible after 8 weeks. Although lens fiber swelling and degeneration are not noted in the human studies, this finding is concerning given that the intended patient group who will receive Jevtana is at risk of developing cataracts. This finding has been added to the Product Monograph and further evaluation of this issue will be monitored by Health Canada through Periodic Safety Update Reports (PSURs).
Daily doses of 4 mg/m2 administered over 5 days to dogs were lethal, neurotoxic, and resulted in hepatocellular necrosis and atrophy. In a separate study, hyperplasia and congestion of the organs of the GI tract and decreases in platelet counts were exhibited at doses of 0.5 and 2 mg/m2 administered daily over 5 days to dogs. The hepatotoxic changes observed were not reversible. Further, testicular degeneration was observed at 2 mg/m2.
A 13-day study was conducted in rabbits. Lethality, body weight loss, and dilatation and irritation of the GI tract were observed at 1.2 mg/m2.
Overall, the toxicity studies demonstrated that the mode of action of cabazitaxel and the expected adverse events are consistent and are in parallel with the expected class-effect adverse events.
Genotoxicity
Cabazitaxel was found negative in the in vitro chromosome aberration test in cultured human peripheral blood lymphocytes in the presence and in the absence of metabolic activation. The elevated mitotic indices and the increased numbers of polyploid cells are consistent with the pharmacological activity of cabazitaxel (inhibition of microtubule depolymerisation).
Carcinogenicity
Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.
Reproductive and Developmental Toxicity
Overall, in the male female fertility studies and the embryo-foetal development studies, the highest exposure levels without any adverse effects (NOEL) were well below the dose intended for human use.
In the rat studies, there were no compound-related effects on mating performance and fertility. A significant decrease in corporea lutea and implant sites, and an increase in preimplantation loss were noted at 0.2 mg/kg/day. The highest exposure level at which there were no significant increases in adverse events (NOAEL) for mating performance and male fertility in rats was considered to be 0.2 mg/kg/day (1.2 mg/m2/day). The dose of 0.1 mg/kg/day (0.6 mg/m2/day) was considered to be the NOAEL for paternal toxicity.
A significant and dose-related increase in postimplantation loss (early resorptions) was observed at 0.1 and 0.2 mg/kg/day and a significant decrease in the number of total live foetuses was noted at 0.2 mg/kg/day. The maternal NOAEL was 0.1 mg/kg/day (0.6 mg/m2/day), the NOAEL on female fertility was 0.2 mg/kg/day (1.2 mg/m2/day), and the developmental NOAEL was 0.05 mg/kg/day (0.3 mg/m2/day).
At 0.25 and 0.16 mg/kg/day, the maternal toxicity was associated with embryo-foetal toxicity including deaths (increased postimplantation loss), a lower number of live foetuses, and decreased foetal weight. External examination of foetuses did not reveal any compound-related effects. The maternal NOAEL was 0.08 mg/kg/day (0.48 mg/m2/day).
The potential of cabazitaxel to induce embryo-foetal toxicity was evaluated in pregnant rats. At 0.16 mg/kg/day, the maternal toxicity was associated with embryofoetal toxicity including deaths (increased postimplantation loss), and decreased mean foetal weight associated with delay in skeletal ossification and slight increase in incidence of skeletal variations (misaligned sternebra and supernumerary rib). The maternal NOAEL was 0.08 mg/kg/day (0.48 mg/m2/day) and the developmental NOAEL was 0.04 mg/kg/day (0.24 mg/m2/day).
The effect of cabazitaxel on pregnant rabbits, demonstrated that there were no compound-related effects on litter data, on embryo-foetal survival, on foetal weight or on the type or incidence of external, visceral, or skeletal foetal observations. The maternal and the developmental NOAELs were above 0.03 mg/kg/day (0.36 mg/m2/day).
Due to the NOAEL values in both the rat and rabbit studies, cabazitaxel was found to be embryotoxic, foetotoxic, and abortifacient at doses significantly below the dose recommended for humans. In light of the indication of cabazitaxel, the current labelling addresses the issues noted in regard to male fertility. Re-evaluation of the Product Monograph labelling for pregnant women and use of cabazitaxel should be performed if the indication is changed.
3.2.4 Summary and Conclusion
The submitted non-clinical studies provide sufficient pre-clinical information in regard to the pharmacodynamics, pharmacokinetics and toxicology of cabazitaxel. Overall, the data indicates that cabazitaxel has similar activity to paclitaxel and docetaxel in respect to mode of action. Cabazitaxel was found to be active on taxane-resistant tumour cells and tumour models. The pharmacokinetics of the drug was primarily linear and the dose-response was observed with regard to exposure. In the toxicology section, the observed effects are in line with the expected class-effect induced adverse events. There are no major concerns with the non-clinical data.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Jevtana demonstrated a broad spectrum of antitumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. In addition, Jevtana demonstrated activity in tumour models resistant to chemotherapy, including docetaxel.
3.3.2 Pharmacokinetics
All of the pharmacokinetic studies with cabazitaxel were conducted in cancer patients. Studies specifically in prostate cancer patients were not performed. A population pharmacokinetic analysis was carried out in 170 patients including patients with advanced solid tumors (n=69), metastatic breast cancer (n=34) and metastatic prostate cancer (n=67). Patients received doses of Jevtana ranging from 10 to 30 mg/m2 weekly or every 3 weeks.
Absorption
Drug absorption studies are not applicable as cabazitaxel is administered by intravenous (IV) infusion.
Distribution
Cabazitaxel demonstrated a three-compartment pharmacokinetic model such that rapid initial and intermediate phases were followed by a long terminal phase. The terminal half-life was approximately 95 hours.
Cabazitaxel exhibited a large volume of distribution at steady-state (4,870 L for a patient with a median body surface area of 1.84 m2).
Cabazitaxel was highly bound to total plasma proteins with a mean value of 91.57%. This value was in the range of the in vitro human plasma protein binding values obtained with the same method (89.23%-93.11%).
Metabolism
Jevtana is extensively metabolized in the liver mainly by the CYP3A4 isoenzyme (80 to 90%). Jevtana is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including three active metabolites issued from O-demethylation), with the main one accounting for 5% of parent exposure. Approximately 20 metabolites of Jevtana were excreted into human urine and faeces.
Excretion
After a single 1-hour IV infusion of radiolabelled cabazitaxel at 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Jevtana was mainly excreted as numerous metabolites in the faeces (76% of the dose) while renal excretion of Jevtana and metabolites accounted for <4% of the dose.
Jevtana had a high plasma clearance of 48.5 L/h (26.4 L/h/m2 for a patient with a median body surface area of 1.84 m2) and a long terminal half-life of 95 hours.
Drug Interactions
No formal clinical drug-drug interaction studies were performed. In vitro studies demonstrated that CYP3A contributes 80-90% to cabazitaxel metabolic clearance, therefore strong CYP3A inhibitors or inducers should not be concomitantly used with cabazitaxel. The sponsor has agreed to provide results from ongoing studies that will address the issues of CYP3A induction and inhibition, with a planned report available in the fourth quarter of 2012. The Product Monograph has been revised accordingly.
Special Populations
Studies in patients with hepatic impairment or renal impairment were not performed. Even though cabazitaxel is primarily metabolized in the liver, the population pharmacokinetic study did not demonstrate a relationship between clearance and increase in liver function test. Cabazitaxel is minimally excreted through the kidneys; therefore renal impairment should not have an influence on the pharmacokinetics of cabazitaxel. Interestingly, renal impairment was found to be a severe adverse event for this drug, thus further studies should evaluate the causality effect.
The assessment of age did not demonstrate to be a covariate influencing the pharmacokinetics of cabazitaxel.
3.3.3 Clinical Efficacy
The efficacy and safety of Jevtana in combination with prednisone or prednisolone were evaluated in a randomized, open-label, international, multicentre, Phase III study, in patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel-containing regimen. A total of 755 patients were randomized; 378 patients received Jevtana 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily, and 377 patients received mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily. Of the randomized patients, 18% in both treatment groups were of 75 years of age and above. In addition, 45.9% of patients in the mitoxantrone group and 46.8% of patients in the Jevtana group did not have a measurable disease. This is in keeping with the typical metastatic prostate cancer population in Canada.
The primary efficacy endpoint was overall survival (OS), which is considered the gold standard for this patient population and it provides assessment of direct clinical benefit. Patients that received Jevtana demonstrated statistically significantly longer OS compared to those that received mitoxantrone (p<0.0001), which is less than the target statistical significance level of 0.0452. The hazard ratio (HR) was 0.70 (95% confidence interval [CI], 0.59 - 0.83) in favour of Jevtana corresponding to a 30% relative reduction in the risk of death compared to mitoxantrone. The median survival for patients in the Jevtana group was 15.1 months in comparison to 12.7 months in the mitoxantrone group. The median difference in overall survival was 2.4 months. The results of the unadjusted OS analysis (HR = 0.71) were similar. These results constitute both a statistically significant and clinically relevant improvement in this patient population.
A sub-group of 59 patients (29 patients in the Jevtana group, 30 patients in the mitoxantrone group) received a prior cumulative dose of docetaxel <225 mg/m2. There was no significant difference in OS in this group of patients (HR = 0.96, 95% CI 0.49 - 1.86).
The secondary efficacy endpoints included the difference in overall progression-free survival (PFS) which was statistically significant in favour of the Jevtana group (p<0.0001). The median PFS was 2.8 months in the Jevtana group and 1.4 months in the mitoxantrone group. The HR was 0.74 (95% CI, 0.64 - 0.86) in favour of Jevtana corresponding to a 26% reduction in risk of progression.
Overall tumour response rate was evaluated only in patients with measurable disease (201 Jevtana patients and 204 mitoxantrone patients). The overall tumour response rate was 14.4% in the Jevtana group compared to 4.4% in the mitoxantrone group (p<0.0005). The median time to tumor progression was 8.8 months in the Jevtana group and 5.4 months in the mitoxantrone group. Time to tumor progression was statistically significantly longer in favour of Jevtana (p<0.0001).
Median time to prostate-specific antigen (PSA) progression was 6.4 months in the Jevtana group and 3.1 months for the mitoxantrone group. PSA progression was statistically significantly longer in favour of Jevtana (p=0.0010). The PSA response rate was 39.2% in the Jevtana group compared with 17.8% in the mitoxantrone group and was statistically significant in favour of Jevtana (p=0.0002). The PFS, tumour response, and PSA evaluations are all secondary endpoints and offer supportive information for the primary efficacy endpoint.
Regarding present pain intensity (PPI) scores, there was no statistically significant difference between treatment groups in the time to pain progression, and no statistically significant difference in pain response between the treatment groups. Therefore, PPI scores were comparable in both treatment groups.
3.3.4 Clinical Safety
The safety of Jevtana was evaluated primarily in the Phase III study described in section 3.3.3 Clinical Efficacy. In the Jevtana group, 29.4% of patients received 10 cycles of treatment compared with 13.5% of patients in the mitoxantrone group. Among patients in the Jevtana group, 9.8% of the cycles were administered at a reduced level compared with 5.1% in the mitoxantrone group. Overall, the treatment discontinuations occurred in 18% of patients in the Jevtana group compared to 8% in the mitoxantrone group. The dose delays in the Jevtana group were 28% versus (vs.) 15% in the mitoxantrone group. Similarly, the dose reductions were higher in the Jevtana group (12%) when compared to the mitoxantrone group (4%). These results point to the more toxic profile of Jevtana relative to mitoxantrone.
General disorders and administration site conditions that were Grade ≥3 occurred in 13.5% of patients in the Jevtana group and 9.7% of patients in the mitoxantrone group. Of note, peripheral neuropathies were more frequent in the Jevtana group (14.0% cabazitaxel, 3.2% mitoxantrone). One case of serious peripheral neuropathy (Grade 2) was reported in the Jevtana group.
The most common all grade serious adverse events (≥2%) in the Jevtana group were febrile neutropenia (6.7%), neutropenia (4.9%), haematuria (2.7%), and diarrhea (2.4%). Cardiac disorders (all grades) were more common in the Jevtana group (6.7% all grades; 1.9% Grade ≥3) compared with the mitoxantrone group (4.6% all grades; 0.8% Grade ≥3). Adverse events (AEs) in the renal and urinary disorders System Organ Class (Grade ≥3) were also more common in the Jevtana group (8.6% Jevtana, 2.4% mitoxantrone). These events consisted of renal failure and impairment (3.2% Jevtana, 0.3% mitoxantrone), as well as renal obstructive disorders (0.8% Jevtana, 0.5% mitoxantrone). In the Jevtana group, 15 patients were reported to have acute renal AEs Grade ≥3, the etiology of which was multifactorial consisting of pre-renal, renal, or obstructive causes.
Deaths due to AEs other than disease progression were reported in 18 patients (4.9%) in the Jevtana group, all of which were within 30 days of the last dose, and 7 patients (1.9%) were in the mitoxantrone group. Of the 18 deaths in the Jevtana group, 7 were the result of neutropenia and its clinical consequences, 4 were due to cardiac events, 1 was due to dehydration and electrolyte imbalance, 4 were pre- or post-renal events leading to renal failure, and 2 were due to other causes, including a death of unknown etiology and a death from a cerebral hemorrhage following a fall in a patient taking concomitant clopidogrel. Again, these results point to the toxic nature of Jevtana and the need to label the Product Monograph appropriately. Neutropenia (including febrile neutropenia) is included in the "Serious Warnings and Precautions" box of the Product Monograph. Under the "Warnings and Precautions" section of the Product Monograph are included the following subtitles: Cardiovascular, Gastrointestinal, Haematologic (including anemia and neutropenia), Hepatic, Immune, Neurologic, and Renal.
Because more than one-third of the patient population was >65 yrs of age, and 18% in each treatment group were men >75 years, it was important to provide relevant data pertaining to this patient population in the Product Monograph. The treatment-emergent adverse events (Grade ≥3) with a higher incidence in patients ≥65 years old in the Jevtana group were blood and lymphatic disorders (including neutropenia and febrile neutropenia), cardiac disorders, and infections and infestations. All grade asthenia, fatigue, and dehydration were also more common in patients ≥65 years old. Jevtana-treated patients ≥75 years had a higher incidence of Grade ≥3 neutropenia, infections and infestations, fatigue, and asthenia. In summary, the toxicity of Jevtana is particularly noted in the elderly population. During the submission review, the Product Monograph was revised to mitigate the risks.
3.3.5 Additional Issues
Dose 20 mg/m2 versus 25 mg/m2
A major issue identified during the review is the Jevtana dose of 25 mg/m2. The Jevtana 25 mg/m2 dose every 3 weeks caused considerable toxicity and may be unnecessarily high. Two Phase I studies demonstrated that the dose levels of 20 mg/m² and 25 mg/m² every 3 weeks can be both defined as the recommended doses for further clinical development with the intermittent schedule. However, information from other studies evaluating the efficacy and safety of the dose of 20 mg/m2 currently is not available. Because it is important to understand if a lower dose is as efficacious as the higher dose, the sponsor is conducting a comparative trial with the 20 and 25 mg/m2 doses. The results will be submitted to Health Canada when available (expected date is 2018). Currently the recommended dose remains 25 mg/m2, however risk mitigation is achieved through labelling. Myelosupression is listed in the "Serious Warnings and Precautions" box, and in "Warnings and Precautions" under "Hematologic-Neutropenia". Prescribers are advised to use prophylactic granulocyte colony-stimulating factor (G-CSF) as per American Society of Clinical Oncology (ASCO) guidelines and/or current institutional guidelines. In conclusion, the drug-related adverse events for the currently prescribed dose have been clearly addressed in the Product Monograph.
Patient group treated with <225 mg/m2 docetaxel
Hormone refractory prostate cancer patients with previous treatment with <225 mg/m2 cumulative dose of Taxotere or docetaxel were initially included in the Phase III study. However amendment 4 in the protocol added an exclusion criterion to exclude patients who had not received at least 3 cycles or <225 mg/m2 cumulative dose of prior docetaxel therapy, in light that docetaxel resistance might have not been reached. The results in the subgroup with prior docetaxel of <225 mg/m2 demonstrated that these patients might not benefit from the Jevtana therapy. The subgroup included 59 patients and this group size is considered too small to provide confirmative conclusion. This information is available within the Product Monograph.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Jevtana has demonstrated clinically and statistically significant improvements in overall survival in patients with castrate resistant (hormone refractory) prostate cancer. In the pivotal Phase III study (described in section 3.3.3 Clinical Efficacy), patients that were treated with Jevtana had a median overall survival of 15.1 months compared to 12.7 months in the mitoxantrone group. It can be safely assumed that the survival benefit of 2.4 months is a meaningful clinical benefit. Additionally, subgroup analyses showed consistent results in favour of Jevtana.
However, the toxicity profile is significant and includes life threatening sepsis/myelosupression, hepatotoxicity, hypersensitivity, cardiovascular toxicity, neurotoxicity, gastrointestinal toxicity and renal toxicity. Within the pivotal study, serious treatment-emergent adverse events were reported in 39.1% of patients in the Jevtana group and 20.8% of patients in the mitoxantrone group. Deaths not directly attributed to disease progression and occurring within 30 days of the last dose of study drug were reported in 18 (5%) of the Jevtana-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in cabazitaxel-treated patients were infections and renal failure. The majority (80%) of fatal infection-related adverse reactions occurred after a single dose of cabazitaxel. Other fatal adverse reactions in cabazitaxel-treated patients included electrolyte imbalance in a patient with diarrhea, ventricular fibrillation, cerebral haemorrhage, and dyspnea.
Despite the toxic effects of the drug, an overall survival benefit was still demonstrated in the pivotal study. As such, Jevtana is considered a useful drug in the armamentarium against prostate cancer and Canadian prostate cancer patients should have this treatment option.
To mitigate the risks associated with Jevtana, Health Canada has added important labelling changes to the Product Monograph. To further address the issues of dose and toxicity, the sponsor has been asked and has agreed to provide the results of the following studies to Health Canada, when they become available:
- TES 10884 - An open-label study to investigate the effect of cabazitaxel on the QTc interval in cancer patients;
- POP6792 - Phase I safety and pharmacokinetic study of cabazitaxel in advanced solid tumour patients with varying degrees of hepatic impairment;
- TCD10870 - A dose-escalation study of the safety, tolerability, and pharmacokinetics of cabazitaxel with cisplatin administered every 3 weeks in subjects with advanced solid malignancies, including an evaluation of the effects of a strong CYP3A inducer and the effects of a strong CYP3A inhibitor;
- A randomized, open-label multicentre study comparing cabazitaxel at 25 mg/m2 and at 20 mg/m2 in combination with prednisone in patients with metastatic castration resistant prostate cancer not pretreated with chemotherapy;
- A randomized open-label multicentre study comparing cabazitaxel at 25 mg/m2 and at 20 mg/m2 in combination with prednisone for the treatment of metastatic castration resistant prostate cancer previously treated with a docetaxel-containing regimen.
Due to the observed drug-related renal failure cases, the sponsor has committed to continue to monitor renal safety in future studies. The recommendations of the renal expert board, which has reviewed and analyzed the renal safety data from all currently available cabazitaxel clinical trials, have already been implemented in the two Phase III cabazitaxel clinical trials, in order to further monitor the renal safety of cabazitaxel. In addition, the sponsor will conduct integrated analyses of renal safety data from two randomized Phase III studies in patients with metastatic hormone refractory prostate cancer every 6 months for 3 years from the initiation of the clinical study.
Therefore, with clear labelling and agreement by the sponsor to provide the above information, Health Canada is satisfied that Jevtana can be used in a safe and efficacious manner in the proposed indication.
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 Jevtana in combination with prednisone or prednisolone is favourable in the treatment of patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel containing regimen. 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: JevtanaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-05-13 |
| Request for priority status | |
| Filed: | 2010-05-25 |
| Rejection issued by Director; Bureau of Metabolism, Oncology, and Reproductive Sciences: | 2010-06-30 |
| Submission filed: | 2010-07-02 |
| Screening | |
| Screening Acceptance Letter issued: | 2010-08-20 |
| Review | |
| Quality Evaluation complete: | 2011-06-15 |
| Clinical Evaluation complete: | 2011-06-16 |
| Biostatistics Evaluation complete: | 2011-01-17 |
| Labelling Review complete: | 2011-06-14 |
| Notice of Compliance issued by Director General: | 2011-06-16 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| JEVTANA | 02369524 | SANOFI-AVENTIS CANADA INC | CABAZITAXEL 40 MG / ML |